Next Article in Journal
Targeting Age-Related Impaired Bone Healing: ZnO Nanoparticle-Infused Composite Fibers Modulate Excessive NETosis and Prolonged Inflammation in Aging
Next Article in Special Issue
Biofilm-Associated Amyloid Proteins Linked with the Progression of Neurodegenerative Diseases
Previous Article in Journal
Genome-Wide Identification and Expression Analysis of the AP2/ERF Transcription Factor Gene Family in Hybrid Tea Rose Under Drought Stress
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 25
Issue 23
10.3390/ijms252312850
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Medication Exposure and Risk of Dementia and Alzheimer’s Disease

by
Niti Sharma
1,
Seong Soo A. An
1,* and
Sang Yun Kim
2,*
1
Bionano Research Institute, Gachon University, 1342 Seongnam-daero, Sujeong-gu, Seongnam-si 13120, Republic of Korea
2
Department of Neurology, Seoul National University Bundang Hospital & Seoul National University College of Medicine, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si 13620, Republic of Korea
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(23), 12850; https://doi.org/10.3390/ijms252312850
Submission received: 4 November 2024 / Revised: 19 November 2024 / Accepted: 26 November 2024 / Published: 29 November 2024
(This article belongs to the Special Issue Molecular Pathology of Neurodegenerative Diseases and Neuroprotective Agents)
Browse Figures
Versions Notes

Abstract

:
Alzheimer’s disease (AD), a complex neurodegenerative disease (ND), is the most predominant cause of dementia among the elderly. Generally, elderly people have multiple chronic health conditions, like hypertension, arthritis, diabetes, insomnia, bowel problems, and depression. Although prescribed medications have beneficial therapeutic compositions, some may have side effects that could hinder cognitive function or worsen cognitive decline. Hence, we should evaluate those medications to guarantee their safety. In the present mechanistic review, we discussed frequently used categories of medication (analgesics, anticholinergics, benzodiazepines, proton pump inhibitors, and statins), concerning their possible involvement in increasing AD and dementia risks. This review summarized the results of various observational studies, meta-analyses, randomized case–control studies, and systematic reviews. As the results were contradictory, it was difficult to ascertain the clear associations between medication usage and increased risks of dementia or AD. The blood-based biomarkers (BBMs) offer a low-cost and accessible alternative for early diagnosis of AD. Systematic reviews combined with meta-analysis would be crucial tools for accurately assessing and summarizing the efficacy of health interventions, yet randomized clinical trials have always been the best way to help with clinical care decisions. Thus, an open discussion is necessary to help individuals determine whether the advantages of utilizing medications outweigh the possible drawbacks.

1. Introduction

Alzheimer’s disease (AD) is a complex neurodegenerative disease (ND), associated with progressive decline in memory and cognition. AD is defined by distinct alterations in the brain, such as the accumulation of amyloid-beta (Aβ) protein and neurofibrillary tangles (NFTs) of phosphorylated tau (p-tau) proteins, leading to progressive neuronal loss. Nearly 6.9 million elderly in the United States (US) have AD with 0.2 million under 65 years old believed to have early-onset AD (EOAD). This number could increase to 13.8 million by 2060 [1]. Statistically, the healthcare expenditure and long-term care for individuals with AD have increased, reaching a projected total of USD 360 billion in 2024, reflecting a USD 15 billion rise from the previous year [2]. AD is the most common cause of dementia and may contribute to over 60% of the cases [3], followed by vascular dementia (VD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and mixed-type dementia. Dementia is a syndrome marked by a gradual decline in cognitive and functional abilities significant enough to impact daily activities. With the rising life expectancies, the global population of individuals with dementia is predicted to increase. Globally, approximately 57 million individuals are impacted by dementia and this number is expected to increase to 153 million by 2050 [2].
As life expectancy increases due to better healthcare and lifestyle, the global population of individuals aged 65 years or older would increase with numbers set to surpass 1.6 billion by 2050, more than double the 761 million in 2021. The population of individuals 80 years and older will increase at an accelerated rate and is expected to triple by 2050 [4]. Generally, elderly people have multiple chronic health conditions, like hypertension, arthritis, diabetes, obstructive chronic pulmonary disease, insomnia, indigestion, bowel problems, and depression. As a result, they often consume a higher number of both prescription and non-prescription drugs and thus, they are prone to drug–drug interactions that may enhance adverse outcomes, like falls, injury, and delirium. Moreover, the organs responsible for detoxification also become less effective at this age, which may cause drug toxicity. The risk of potentially inappropriate medications (PIMs) administration would increase in polypharmacy. If these medications would affect cognition, their prolonged use could lead to dementia [5]. Recent research indicated that certain drugs, like anticonvulsants and anticholinergic medications, might be linked to a higher likelihood of developing dementia. This suggested that by avoiding these medications, the risk of developing dementia could potentially be reduced. Yet, it will be frequently challenging to determine the factors contributing to cognitive alterations in the elderly using polypharmacy that can independently impact cognitive abilities. It would be crucial to closely monitor the risks of AD and dementia by addressing modifiable risk factors and assessing through various blood-based biomarkers to prevent dementia on a worldwide scale effectively.
The presence of extensive healthcare data from large populations, along with advancements in computational power, allowed the systematic investigation into the link between medications and diseases. As a result, several meta-analyses, observational studies, cohort studies, and clinical studies were carried out on several suspicious drugs for increasing AD and dementia risks. Still, a comprehensive review of the studies’ outcomes would be required. Therefore, in this review, we searched and summarized the existing literature and discussed various classes of drugs that have been associated with the risk of dementia and AD. We anticipate that this review will be helpful to clinicians, researchers, and policymakers and assist in best prescribing guidelines for medicines for preventing and treating patients to reduce AD and dementia.

2. Categories of Drugs Linked to Increased Risks of Dementia and AD

According to the literature, the use of certain medications, such as analgesics, anticholinergics, and benzodiazepines, could be associated with varying risks for developing AD and other forms of dementia [6,7,8]. On the other hand, PPIs and statins have unclear or varied connections to dementia, with some indications of potential protective effects or minimal risks [9,10]. The elderly (60+ years) tended to have higher usage rates in comparison to young adults due to age-related health conditions and the prevalence of chronic diseases. Table 1 presents the general breakdown of their use, though exact percentages may vary based on country, healthcare system, and population demographics.
For a drug to affect brain function, it must reach the brain by crossing the blood–brain barrier (BBB), which depends on several criteria including lipophilicity. Analgesics like ibuprofen and naproxen have low permeability [23], whereas anticholinergics and benzodiazepines show powerful penetration through the BBB for their therapeutic effect [24,25]. Proton pump inhibitors and statins have different levels of permeability, indicating the possibility of both positive and negative effects in brain-related disorders [26,27]. This comprehension is crucial for improving drug development and therapeutic approaches in central nervous system disorders. Brief information on the targets, protein expression, and location of the targets has been provided (Table 2).

2.1. Analgesics

Analgesics are drugs employed for the control and therapy of pain. They function by either diminishing inflammations or altering the brain’s processing and perceptions of pain. Significant global use of pain relievers was driven by the common need for managing various types of pains, such as headaches, muscle pain, injuries, chronic pain, and post-operative recovery. The global analgesics market generated USD 91.62 billion in 2024 and is expected to fetch USD 143.65 billion by 2034 [28]. Over-the-counter (OTC) pain relievers, like paracetamol (acetaminophen), ibuprofen, and aspirin, were among the most widely consumed medications with a global market size of USD 28.6 billion in 2022, which is expected to grow USD 40.9 billion by 2032 [29]. Analgesics have been broadly categorized as non-opioid analgesics (acetaminophen and nonsteroidal anti-inflammatory drugs: NSAIDs, e.g., aspirin, diclofenac, ibuprofen), compound analgesics (combination of non-opioid and weak opioids, e.g., co-codamol a combination of paracetamol and codeine), and opioid analgesics (e.g., fentanyl, codeine, tramadol, morphine) (Figure 1). Regular to high doses of non-aspirin traditional NSAIDs could lead to serious adverse effects on the gastrointestinal and cardiovascular systems.
Opioids function by stimulating opioid receptors in both the central and peripheral nervous systems, which decreases the activity of neurons, resulting in a decrease in the transmission of pain signals. Opioid pain medications, such as morphine, oxycodone, and tramadol, were frequently prescribed in healthcare environments to manage intense or prolonged pain, particularly for ailments, like cancer or after surgical procedures. A study indicated that 84% of elderly (62–86 years) were on prescription analgesic medications, among which NSAIDs were the most common (77%), followed by paracetamol (41%), and opioids (32%). This status showed a significant usage of painkillers and their quantities in elderly people, underscoring the necessity of overseeing and controlling pain in this population with opioids [11].

Association of Analgesics with Dementia and AD Risk

Opioids may cause cognitive decline by affecting various cognitive functions in the mu (μ)- and kappa (κ)-opioid receptor systems. They could impact primarily hippocampal neurons by boosting glutamate release in presynaptic neurons and enhancing the activities of postsynaptic receptors. The presence of opioids in a synapse prevented the blockage of the N-methyl-D-aspartate receptor (NMDAR) by Mg2+ and increased the NMDAR conductance, eventually inducing long-term potentiation (LTP) [30]. Opioids might change the levels of neurotransmitters, which could impact cognitive function [31,32], and have also been reported to reduce neurogenesis [33].
Individuals on opioids or NSAIDs had slightly increased risks of dementia in comparison to those with less frequent usage or none. In a prospective study (n = 194,758) from the UK Biobank, individuals were grouped into different painkiller categories. In comparison to those without NSAIDs, the aspirin, paracetamol, and 2–3 NSAIDs groups had a greater risk of all-cause dementia (ACD) (Hazard ratio [HR]: 1.12, 1.15 and 1.2, respectively, 95% confidence interval [CI]: 1.01–1.24, 1.05–1.27 and 1.08–1.33, p < 0.05 for aspirin and 2–3 NSAIDs, p < 0.01 for paracetamol). The ibuprofen group did not exhibit a noteworthy correlation with the likelihood of ACD, AD, or VD [34]. Frequent use of paracetamol was also linked to an increased chance of developing dementia in older individuals, irrespective of genetic predisposition to the disease [35]. Extended use of aspirin has been associated with gastrointestinal bleeding, which may result in anemia and reduced blood supply to the brain, leading to cognitive decline [36,37]. Aspirin blocks cyclooxygenase-2 (COX-2), an enzyme involved in the synthesis of prostaglandin E2 (PGE2), a neurotransmitter managing synaptic plasticity and memory [38]. Paracetamol is converted to a toxic metabolite named N-acetyl-p-benzoquinoneimine (NAPQI) in the liver, leading to a decrease in glutathione levels and causing oxidative stress in the body [39].
Recently, a population cohort-based study was conducted on 1,261,682 Korean patients suffering from chronic non-cancer pain (CNCP), 21,800 of whom were opioid users [40], which demonstrated the increased risks of dementia (15%), AD (15%), and unspecified dementia (16%) in adults with CNCP on opioids in comparison to the control group. However, no significant association was observed for VD. A nationwide study in Israel discovered that the elderly population (75 to 80 years) on opioid drugs had a 1.39-fold increased likelihood of developing dementia (aHR: 1.39, 95% CI: 1.01–1.92, p < 0.05) in comparison to non-users [41]. In another population-based study of diagnosed participants aged 65 and older with dementia, 42% were on opioid therapy [42]. The nested case–control study on UK Biobank participants with chronic pain and regular analgesic usages indicated increased opioid use in correlation with an escalated risk of dementia (1 to 5 prescriptions: Odds ratio [OR]: 1.21, 95% CI: 1.07–1.37, Wald χ2: 3.02, degrees of freedom (df):1, p: 0.003; 6 to 20: OR: 1.27, 95% CI: 1.08–1.50, Wald χ2: 2.93, df:1, p: 0.003; more than 20: OR: 1.43, 95% CI: 1.23–1.67, Wald χ2: 4.57, df: 1, p < 0.001) [43] (Figure 2).
Among participants in the adult with changes in thought (ACT) study, elevated NSAID consumptions were linked to higher chances of being clinically diagnosed with AD dementia (HR: 1.55, 95% CI: 1.07–2.24) [44] and elevated neuritic plaque (NP) scores (Relative risk [RR]: 2.37; 95%, CI 1.24–4.67) [45]. Although opioid use had a slight association with dementia (HR:1.29, 95%; CI: 1.02–1.62), it was not associated with greater neuropathologic changes (higher NP or NFT scores) [46]. Studies concluded that participants with persistent exposures to NSAIDs had a higher likelihood of developing AD (HR:1.57; 95%; CI:1.10–2.23) and dementia (HR:1.66; 95%; CI:1.24–2.24) [44]. In addition, increased NSAID usages were correlated to higher levels of Aβ42 in the middle frontal gyrus (MFG) and superior and middle temporal gyri (SMTG) regions, but not to increased p-tau levels in any of the above areas. On the other hand, increased opioid usage correlated with higher p-tau levels in the MFG specifically, but did not correlate with Aβ42 levels in any brain region in comparison to those with minimal or no opioid usage. Additionally, frequent opioid usage was linked to the decreased grey matter and hippocampal volumes, as well as the increased white matter hyperintensity volumes. The variation in results could be explained by different mechanisms of action of the two drugs [47].
On the other hand, considerable data indicated that NSAID drugs may delay or even stop the development of AD in other studies [48,49,50,51,52]. A meta-analysis of 17 epidemiological studies found a negative association between the use of NSAIDs and AD risk in individuals from eight countries [49]. AD lesions are defined by persistent neuroinflammation that could lead to the destruction of neurons. The anti-inflammatory drugs delay the onset of inflammation, helping delay AD progression. The probable mechanisms involve the activation of the peroxisome proliferator-activated receptor gamma (PPARγ) and inhibition of COX and β-secretase gene promoter activities by NSAIDs [48,53,54], suppressing the formation of amyloid plaques and inflammatory substances. In a systematic review and meta-analysis of observational studies (n = 13,211), the risk for short-term users (<1 month) was 0.95 (0.70–1.29), while the risk for the intermediate-term users (<24 months) was 0.83 (0.65–1.06) and 0.27 (0.13–0.58) for long-term users (>24 months). The combined relative risk among the eight studies with aspirin users was 0.87 (0.70–1.07) [52]. The relative risk (RR) for AD decreased with the increased duration of NSAID usage [RR: 0.40 (>2 years); RR: 0.65 (<2 years)] [50]. In a prospective cohort study [55], no association was found between the use of prescription opioids (HR: 1.29, 95% CI: 1.02–1.62) or NSAIDs (HR: 1.31, 95% CI: 1.07–1.62) and increased risks of cognitive decline or dementia. Individuals who used high doses of opioids did not show a faster decrease in mental performance upon aging [55]. Likewise, in a Finnish nationwide nested case–control study on a Medication use and Alzheimer’s disease (MEDALZ) cohort (n = 70,718), no link was found between opioid use and a higher risk of AD (aOR: 1.00, 95% CI: 0.98–1.03). Extended use of opioids (>365 days: aOR: 1.02, 95% CI: 0.96–1.08) or high cumulative doses (>90 total standardized doses (TSDs): aOR: 1.02, 95% CI: 0.98–1.07) did not increase the risks of AD [56]. Furthermore, no dementia-like pathology was observed in the community-based autopsy cohort (n = 420) for opioids or NSAID users [46]. A recent systematic review and meta-analysis from 16 cohort studies (n = 236,022) revealed a significant link between using NSAIDs and a decreased risk of AD, in comparison to those without using NSAIDs (RR: 0.81, 95% CI: 0.70 –0.94) [57]. The results varied based on the geographical location; a significant association was observed with the European population (RR: 0.72, 95% CI: 0.56–0.92); a modest association with the North American population (RR: 0.87, 95% CI: 0.72–1.06), while no association in the Asian group (RR: 0.87, 95% CI: 0.36–2.10) was observed in the context of reduced risk of AD [57]. Moreover, prolonged use of NSAIDs could lower the risk of developing AD, but do not provide the same protection against VD [58]. A summary of related studies is presented in Table 3.
Hence, the above pieces of evidence highlighted the complex relationship between opioid and NSAID usage and cognitive decline, particularly in the context of dementia risks. While opioids may contribute to cognitive impairment through neurobiological mechanisms, NSAIDs appeared to have a protective effect against dementia from extended usage. As far as analgesics were concerned, the reported literature was contradictory and did not provide conclusive evidence for any association between analgesic usage and increased risks of AD/dementia. Further research is required to clarify these associations and comprehend the underlying mechanisms (Figure 3).

2.2. Anticholinergic Drugs

Anticholinergics can cross the BBB and block neurotransmitter acetylcholine (ACh) actions at synapses in the central and peripheral nervous systems (CNS and PNS). Based on the target, drugs have been divided into antimuscarinic and antinicotinic agents. Antimuscarinic agents inhibit ACh binding to muscarinic receptors (mAChR) without affecting nicotinic receptors at the neuromuscular junction, while antinicotinic agents target the nicotinic acetylcholine receptors (nAChR). The majority are non-depolarizing skeletal muscle relaxants used in surgery. Medications with anticholinergic activity impacted mAChR mainly. Anticholinergics have a spectrum of therapeutic applications, like antiemetics, anesthetics, antispasmodics, bronchodilators, and mydriatics [59]. Several commonly used anticholinergics are antiallergic (brompheniramine, clemastine), antidepressants (amitriptyline, paroxetine), antispasmodic (atropine, scopolamine); antipsychotics (clozapine, loxapine), antiemetics (prochlorperazine, promethazine), muscle relaxant (cyclobenzaprine, orphenadrine), antimuscarinics (flavoxate, oxybutynin); anti-Parkinson’s (benztropine, trihexyphenidyl), and antiarrhythmic (disopyramide); blood-pressure lowering medicine (beta (β)-blockers like atenolol, metoprolol) (Figure 4).
Elderly people with multiple health conditions have been commonly given medications with anticholinergic effects, which are often used to treat various conditions like insomnia, chronic obstructive pulmonary disease (COPD), depression, Parkinson’s disease (PD), allergies, and overactive bladder. Anticholinergic burden (ACB) is the term used to describe the increased risk of medication-related adverse effects caused by the accumulation of higher levels of exposure to one or more anticholinergic medications. The ACB scale has been frequently used to classify anticholinergics. Drugs with ACB scores of 3 (e.g., atropine and flavoxate) had strong anticholinergic properties in comparison to drugs with a score of 2 (moderate; e.g., cyclobenzaprine and loxapine), and 1 (mild; e.g., atenolol and codeine). Typically, 64.3% of older individuals used anticholinergics, while 9.9% used strong anticholinergics [60]. The common side effects of these drugs include confusion and memory loss, especially in the elderly [61].

Association of Anticholinergics with Dementia and AD Risk

Anticholinergic drugs may cause short-term cognitive side effects [61,62] and it was generally believed that cognitive impairment could be reversed by stopping the medication [63]. Nonetheless, multiple reports indicated that anticholinergic drugs could potentially lead to a higher likelihood of long-term cognitive issues [64,65,66]. To ascertain whether prolonged usages of these medications were associated with a higher risk of developing dementia, several studies were conducted as follows [64]. In a German cohort study, 2605 elderly (age > 75 years) without dementia were followed for 4.5 years after starting anticholinergic drugs, revealing a doubled risk of developing dementia (HR: 2.08; 95%). There was a substantially higher risk of developing dementia (HR:1.54) and AD (HR: 1.63) in patients with the greatest anticholinergic burden in comparison to those not taking such medication [7]. Several observational studies were conducted to prove a relationship between anticholinergics and dementia risks [67,68,69]. In a nested case–control study of 58,769 patients, Coupland et al. [70] discovered a higher risk of dementia linked to the cumulative use of anticholinergic medication in a large (284,343 case patients and matched controls) nested case–control study. The antidepressants (aOR: 1.29; 95% CI: 1.24–1.34), bladder antimuscarinics (aOR: 1.65; 95% CI: 1.56–1.75), antipsychotics (aOR: 1.70; 95% CI: 1.53–1.90), antiepileptic (aOR: 1.39; 95% CI: 1.22–1.57), and anti-Parkinson’s drugs (aOR: 1.52; 95% CI: 1.16–2.00) revealed the most significant associations (Figure 5).
Antihistamines, antiarrhythmics, antimuscarinic bronchodilators, skeletal muscle relaxants, and gastrointestinal antispasmodics did not show any noteworthy increases in risk factors in the study. Similarly, Richardson and colleagues [67] also discovered higher risks of developing dementia in individuals taking antidepressant, urological, and anti-Parkinson’s medications, while no link was found for gastrointestinal or antihistamine drugs. Stronger associations were also found in individuals diagnosed with VD before the age of 80 rather than AD, suggesting that the mechanism of anticholinergic action might affect vascular and inflammatory pathways along with inhibiting cholinergic actions [70]. Zheng and coworkers pooled fourteen longitudinal and case–control studies of 1,564,181 participants. They concluded that the use of anticholinergics was linked to a higher risk (1.2 folds) of developing ACD and AD [71]. In a population-based study (n = 750; age > 65), individuals taking anticholinergics had a higher probability of cognitive impairment in comparison to non-users (OR: 3.18; 95% CI: 1.93–5.23; p < 0.001) [72]. A cohort study in three French cities revealed a 1.4 to 2.0-fold dementia risk in anticholinergic users in comparison to the non-users [66]. The increased risks of dementia were linked to both low and high anticholinergic drug burdens (ACBs). The anticholinergics seemed to pose a greater risk of cognitive decline, which was accelerated with the changes in AD biomarkers [73]. Taylor-Rowan et al. assessed the risk factor of high anticholinergic burden in elders with no known cognitive issues, who may have experienced a significant rise in their risk of cognitive decline or dementia, potentially up to 227% [74]. Compared to other antidepressants, paroxetine was associated with the highest risk of dementia and AD [75]. Among the anticholinergic drugs, the dementia risk was pronounced with the usage of anti-Parkinson’s, urological, and antidepressant medications [63,71,76,77]; yet, cardiovascular and gastrointestinal medications may offer some level of protection [71]. Additionally, the risk of dementia and AD was directly proportional to the dosage of anticholinergics used (1.6, 2.1, 2.6, and 2.6 times increased risk with one, two, three, and four anticholinergic drugs) [78]. Among the antidepressants, clomipramine, trimipramine, imipramine, amitriptyline, doxepin maprotiline, and tranylcypromine were linked to a higher likelihood of developing dementia in a 12-year follow-up study [79]. Anticholinergic drugs do not just hinder cognitive function by reducing ACh neurotransmission, they also speed up neurodegeneration by inhibiting an ACh-dependent anti-inflammatory system [80].
On the contrary, no significant association between anticholinergics and dementia risk (HR: 1.043; 95% CI: 0.958–1.212, p: 0.139) was observed in a nationwide 15-year follow-up study in Taiwan. However, male patients, age group 65 to over 80 years, long anticholinergic treatment (≥4 years), and high ACB were associated with dementia risk [81]. Low et al. found no significant effect of anticholinergics on cognitive decline in persons in their early to mid-60s [82]. There was no significant difference in the likelihood of developing dementia between users and non-users during an 8-year monitoring period in a French cohort study [65]. The beta-blocker therapy also did not show a higher chance of developing ACD, AD, or mixed dementia (HR: 1.15; 95% CI: 0.80–1.66; p: 0.44; HR: 0.85; 95% CI: 0.48–1.54; p: 0.59 and HR: 1.35; 95% CI: 0.56–3.27; p: 0.50, respectively), but was responsible for increased VD risks, irrespective of cardiovascular risk factors or history of coronary events, stroke, or heart failure [83]. Further research is required to investigate the mechanisms linking beta(β)-blockers to a higher VD risk. In a recent study, various subgroups of antihypertensive medication (AHM), including β-blockers, were associated with lower dementia risk in primary care patients [84]. Moreover, the permeability of β-blockers towards the BBB exerted neuroprotective activity by removing toxic aggregates through the glymphatic system [85]. Table 4 summarizes the results of the studies discussed above.
In short, no results supported the connection between an anticholinergic mechanism and an increased risk of dementia. Insufficient data could not confirm a causal mechanism for these drug categories. Nonetheless, in some cases, the advantages of anticholinergics may outweigh the disadvantages of specific clinical syndromes, supporting their suitable use for the elderly.

2.3. Benzodiazepine Drugs

Benzodiazepines (BZDs) are CNS depressants that bind to gamma (γ)-aminobutyric acid-A (GABA-A) receptors. These drugs increase the effect of GABA, resulting in sedative, anticonvulsant, anxiolytic, and muscle relaxant effects. Hence, they reduce the brain’s sensitivity to stimulation, leading to a calming effect. They were primarily utilized to address anxiety, insomnia, and seizures. The side effects of these medications include drowsiness, unsteadiness, and confusion. The most commonly prescribed drugs in this category include alprazolam, diazepam, clonazepam, and lorazepam (Figure 6).

Association of BZDs with Dementia and AD Risk

There has been a notable rise in AD and dementia risk among older individuals using BZDs with extended half-lives and for a prolonged period [86,87,88,89,90,91,92]. Additionally, AD patients prescribed with BZDs had a 41% increased risk of mortality [93] and a 50% increased risk of AD [91] in comparison to those who did not take these medications. Likewise, patients on hypnotic drugs had a 21% higher chance of developing dementia than those who do not use them (OR: 1.21, 95% CI: 1.13–1.29; p < 0.001) [94]. The combined results from a meta-analysis indicated a notable link between taking BZDs and the likelihood of developing dementia (OR: 1.38, 95% CI: 1.07–1.77). Moreover, no variation in the risk of dementia between individuals using short-acting and long-acting BZDs (RR: 1.09 vs. 1.24) was observed [95]. On the other hand, another study reported a higher risk of dementia in individuals using long-acting BZDs (OR: 1.21, 95% CI: 0.99–1.49) in comparison to those using short-acting BZDs (OR: 1.13, 95% CI: 1.02–1.26) [96].
There is a possibility that BZDs impact cognition and may raise the chance of AD by affecting hippocampal α5GABAA receptors [97]. Zhong and colleagues examined how long-term use of BZDs was linked to dementia by conducting a meta-analysis with 45,391 participants and 1891 cases of dementia. A possible link between an increase in BZD dose and a 22% higher risk of developing dementia (Risk ratio [RR]:1:22, 95% CI: 1.18–1.25) was reported in the study [98]. Mura et al. [99] observed that long-term BZD usage was linked to worse cognitive function, but was not associated with faster cognitive deterioration in older age. Pietrzak et al. [100] observed that elders with anxiety could be at a heightened risk of developing AD, which may lead to elevated levels of Aβ in individuals with MCI and AD. There was a significant increase in the risk of MCI among APOEe4 carriers (HR 1.30; 95% CI 1.14—1.50) [101].
However, some other studies disapprove of any correlation between BZD use and AD or cognitive loss [6,102,103,104,105]. Wu et al. found weak evidence to conclude any correlation between BZD use and dementia in an umbrella review comprising five meta-analyses and 30 observational studies [105]. The strength of evidence was weak. BZD use in patients did not show a link to dementia, with Adjusted risk ratios of 1.06 (95% CI: 1.02–1.10), 1.05 (95% CI: 1.01–1.09), and 1.05 (95% CI: 1.02–1.09) for low, medium, and high users of benzodiazepines [106]. Extended use of BZDs over 2 years was linked to higher chances of being diagnosed with dementia, yet the findings lack statistical significance at the 5% or 10% thresholds (1.190; 95% CI: 0.925–1.531 and 1.167; 95% CI: 0.919–1.483) [8]. As individuals grow older, the likelihood of sleep disorders rises, which can impact the brain’s ability to remove toxic substances like Aβ [107]. Hence, it can be suggested that BZDs might indirectly have a protective impact on preventing AD by enhancing sleep quality [108]. Moreover, BZDs protect against glutamate excitotoxicity in AD [109]. Table 5 summarizes the results of the studies discussed above.
The data compiled in this review do not warranty increased dementia/AD risk with BZD use. The use of BZDs had both advantages and disadvantages. Healthcare providers need to be aware of the dangers of long-term benzodiazepine use, such as dependence, withdrawal, and cognitive impairment, to promote safe and effective medication use. The injudicious use of medication can be prevented by alternate medications such as cognitive behavioral therapy for insomnia (CBT-i); the use of melatonin could also be a safer choice as medication, but further evidence would be needed to evaluate its long-term effect on health. Treating anxiety in elderly patients may be better addressed using alternative medications such as serotonin uptake inhibitors like sertraline or other compounds.

2.4. Proton Pump Inhibitors (PPIs)

PPIs rank high among the drugs that are frequently prescribed on a global scale with an expected expenditure of USD 9 billion worldwide [111]. These medications inhibit the hydrogen-potassium adenosine triphosphatase enzyme (H+/K+ ATPase; Proton pump) present in the cells lining the stomach that produce acid. They are mainly used to treat stomach/duodenal ulcers and gastroesophageal reflux disease (GERD), as they assist in healing ulcers and reducing acid reflux by reducing gastric acid production. Some of the commonly prescribed PPIs include omeprazole, lansoprazole, rabeprazole, and pantoprazole (Figure 7). Although they work well for treating specific gastrointestinal problems, the potential risks require close supervision and evaluation of discontinuation methods to guarantee the best health results for the elderly. Therefore, it is advised to regularly assess PPI treatment to confirm that the lowest effective dose is being utilized for symptom management. Extended use of PPIs can alter the gut bacteria equilibrium, leading to a higher chance of infection, particularly pneumonia and Clostridium difficile (CDI). They have also been associated with a risk of cardiovascular, liver, and kidney disease [112]. PPIs hinder the absorption of vitamins and minerals like vitamin B12, magnesium, calcium, and iron, causing bone fractures, hypomagnesemia, and megaloblastic and iron-deficiency anemia [110]. PPTs can cross the BBB [113], and have also been reported to block acetylcholine synthesis by Choline acetyltransferase (ChAT), thereby potentially disrupting neurotransmission [114].

Association of PPIs with Dementia and AD Risk

In recent years, some studies proposed a possible link between PPI use and dementia risk [9,115,116,117]. A 51% increased risk of developing dementia was observed by Welu et al. [118] in war veterans. A significant increase in dementia risk was also observed in Asian [119] and German [120] populations. A two-fold increased risk of developing dementia by PPI users [117] raised safety concerns over the use of PPIs. The association between PPIs and dementia may be due to increased Aβ accumulation that is linked to dementia, or by PPI-induced malabsorption, leading to vitamin B12 deficiency. Considerably reduced levels of vitamin B12 were reported in dementia and AD patients in comparison to the healthy controls [121,122,123]. Acidification of lysosomes was important for activated microglia to degrade Aβ [124] and was seen as an important factor in AD pathogenesis. PPIs are lipophilic weak bases that can cross the BBB and block lysosomal vacuolar (V)-ATPase, inhibiting lysosomal acidification. Eventually, the de-acidification results in a decrease in Aβ breakdown, and an increase in Aβ accumulation. PPIs increase their uptake by disturbing tight junctions in the BBB, affecting spatial memory [125,126] (Figure 8).
Some other studies [127,128,129,130] found no association between the risk of dementia or AD and the use of PPIs, including in individuals with significant long-term exposure [131]. An increased dosage of PPIs did not show a higher risk for either AD or non-AD dementias (OR: 1.20; 95% CI: 0.91–1.61 and OR: 0.95; 95% CI: 0.74–1.22, respectively) [132]. Another meta-analysis study including 642,305 participants found no significant link between PPI use and dementia (HR: 1.04; 95% CI: 0.92–1.15) [10]. No connection between PPI and dementia risk was seen in the extensive meta-analysis (HR: 0.98; 95% CI: 0.85–1.13) either [133]. A clinical trial also supported the above results, where no statistically significant association (OR: 1.20; 95% CI: 0.81–1.78) between dementia and PPI (pantoprazole, 40 mg) use was seen [134]. A comprehensive review published last year, including meta-analyses and experimental and observational studies, also found no strong link between PPI use and the onset of cognitive decline or dementia [135]. Table 6 summarizes the results of the studies discussed above.
While looking for further conclusive proof, doctors need to prescribe PPIs by weighing the advantages against possible drawbacks. The legitimate use of PPI medications should not be denied due to worries about dementia risk. Increased awareness and following evidence-based recommendations are crucial for maximizing PPI treatment and minimizing associated risks. Regularly checking and carefully planning how to reduce PPI prescriptions are important for effective management. For those with suitable reasons for PPI treatment, it is important to always start with the smallest effective dose and avoid unnecessary long-term or continuous treatment in appropriate individuals. A gradual reduction in dosage may be suitable for individuals who no longer have symptoms, and/or need to discontinue the PPI. Regular monitoring of serum vitamin B12 is necessary, particularly in older patients on long-term PPI treatment. Using cyanocobalamin may enhance vitamin B12 levels in cases where discontinuing PPI therapy is not possible.

2.5. Statins

Statins are utilized in the treatment of high cholesterol levels and the management of atherosclerotic cardiovascular disease (CVD). Statins inhibit the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Statins reduce total cholesterol levels, low-density lipoprotein (LDL), and triglycerides (TGs). Examples of FDA-approved statins are atorvastatin, rosuvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, and pitavastatin (Figure 9). The side effects of statins include fatigue, myopathy, and hepatic injury [137].

Association of Statins with Dementia and AD Risk

In 2012, the US FDA expressed worries over the negative cognitive impact of statins [138], after some studies indicated their effect on memory [136]. The decreased statin use following the negative publicity resulted in increased myocardial infarction and CVD mortality [139]. Later, several other studies found that statin use does not increase dementia or AD risk [140,141,142,143,144], but helps reduce them instead. Studies suggested the role of statins in decreasing proinflammatory markers and controlling microglial activation in NDs [145] and by modulating G protein-gated inwardly rectifying potassium (GIRK) channel function [146] in neurons. Jeong and coworkers [147] found that less persistent use of statins (<540 days) was associated with increased AD risk, while consistent use of statins decreased the risk of AD [Adjusted hazard ratio (aHR); 95% CI  =  0.87 (0.80–0.95)]. A meta-analysis with 30 observational studies (n = 9,162,509) indicated that statin use was associated with reduced dementia risk (Risk ratio [RR]: 0.83; 95% CI: 0.79–0.87), AD (RR: 0.69; 95% CI: 0.60–0.80, p < 0.0001), and VD (RR: 0.93; 95% CI: 0.74–1.16, p = 0.54) [148]. No adverse effect of statins was observed in randomized clinical trials and observational studies constituting 1,404,459 participants [149]. During follow-up, individuals taking statins had a lower chance of developing dementia, or cognitive impairment without dementia [150], and AD [151]. Similar results were reported by a nationwide cohort study in Taiwan where statin use significantly lowered the dementia risk in the aging population [152]. The outcomes were alike for lipophilic and hydrophilic statins and were additionally more pronounced for potent statins than the less potent statins [153]. Statins may play a therapeutic role in preventing Aβ-induced toxicity and improving insulin signaling by activating AMP-activated protein kinase (AMPK) [154] and decreasing neuroinflammation [155]. Statin use was linked to a reduced risk of AD by 28%, VD by 18%, and unspecified dementia by 20% [156] (Figure 10).
With the rise in life expectancy, it will be crucial to define precise guidelines for prescribing statin therapy to elderly individuals to promote a healthier aging society. It was noted that several factors must be considered when utilizing statin therapy in elderly patients, including multiple health conditions and the use of polymedications, which can impact the effectiveness and safety of treatment. Drug interactions frequently occur in patients who are taking several medications. Lovastatin, simvastatin, and atorvastatin, metabolized by cytochrome p450, may interact with drugs like diltiazem, verapamil, amiodarone, and azole antifungals. These interactions were common in patients with atherosclerotic cardiovascular disease (ASCVD). In the elderly, pravastatin and rosuvastatin were preferable due to their lower risk of drug interactions and improved safety record [157]. On the other hand, discontinuing the treatment led to a higher likelihood of cardiovascular issues and increased risk of death [158]. Table 7 summarizes some of the important results discussed above.

3. Methods

A comprehensive search was done for the published scientific research available on various databases (PubMed, Google Scholar, and Web of Science) until September 2024. These included observational studies, randomized case–control studies, meta-analysis and systematic reviews, and clinical studies on medications associated with AD and dementia risk. The search terms used were “drugs” and “medication” with the filters “Alzheimer’s disease risk” and “dementia risk”. Exclusion criteria: articles not specifying AD, or dementia were excluded. Non-English literature was excluded.

4. Conclusions

Several searches using various factors and databases were carried out to find a piece of concrete evidence between the use of several medications and increased risks of dementia or AD, yet the results were inconclusive. The conflicting results in research could be due to the variability in the study design (sample size, ethnicity, methodology); biological differences (pharmacokinetic, pharmacodynamic, multiple health conditions); and other cofounding variables (sociodemographic factors, polypharmacy, comorbidities). Moreover, the studies considered only prescription medicine; therefore, it was impossible to determine if patients took additional over-the-counter drugs (allergy medicine, motion sickness patches, cough syrups, muscle relaxants). Like other geriatric syndromes, the risk factors for cognitive impairment are complex and could vary among individuals. Cognitive impairment is largely influenced by biological factors such as age, gender, and genetics. Furthermore, cognitive health can be significantly affected by psychological factors like depression and anxiety. The databases were expected to be trustworthy, but the accuracy of the recorded information could be ambiguous at times. With this information and the possibility of confusion, it is extremely difficult to determine the specific amount of risk linked to any category or specific medication.
In the elderly, polypharmacy might result in potential drug–drug interaction; therefore, the patients should be regularly evaluated for their medications and any negative effects, opting for single-drug therapy over fixed-dose combinations, selecting medications with confirmed effectiveness, and discontinuing drugs as early as feasible. Adjusting the dosage timing for elderly patients susceptible to nutrient deficiencies can also help lessen interactions and side effects caused by multiple medications used by this population. In 2019, the American Geriatrics Society (AGS) Beers Criteria advised against using drugs with potent anticholinergic properties in elderly individuals with dementia or cognitive decline [160]. Instead, medications with a lower ACB like SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin and norepinephrine reuptake inhibitors) were seen as safer options. Several other criteria limited the PPI usage for not more than 8 weeks in the elderly [159,161]. Other risk factors for cognitive decline need to be acknowledged and possibly addressed, along with a focus on non-pharmacological treatments. Hence, it is crucial to consider the pros and cons of every medication. The possibility exists that the danger of dementia could be significantly lower than the danger to one’s health of not using the medication as directed. Hence, individuals should refrain from discontinuing prescribed medications without consulting their doctor.

Author Contributions

Conceptualization, N.S. and S.S.A.A.; writing—original draft preparation, N.S.; writing—review and editing, N.S., S.S.A.A. and S.Y.K.; funding acquisition, S.S.A.A. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (Grant number RS-2023-00251396 and 2021R1A6A1A03038996).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Acknowledgments

We used napkin.ai (to generate the figures) and ChemDraw (for the chemical structures) in the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Dementia, A.s.a. 2024 Alzheimer’s Disease Facts and Figures Report: Executive Summary Alzheimer’s Association: Chicago, USA, 2024. Available online: https://www.alz.org/alzheimers-dementia/facts-figures?utm_source=google&utm_medium=paidsearch&utm_campaign=google_grants&utm_content=alzheimers&gad_source=1&gclid=Cj0KCQiAo5u6BhDJARIsAAVoDWvZr_lVukNLQ2UWXS-xPBYpa67lV99gFNLybrdHl9FcWJ6iOD4iG78aAkQKEALw_wcB (accessed on 10 September 2024).
  2. Anderson, P. Alzheimer’s Prevalence Predicted to Double by 2050. Available online: https://www.medscape.com/viewarticle/alzheimers-prevalence-predicted-double-2050-2024a10005o1?form=fpf (accessed on 15 September 2024).
  3. WHO. Dementia; WHO: Geneva, Switzerland, 2023. [Google Scholar]
  4. United Nations. World Social Report 2023: Leaving No One Behind in an Ageing World. 2023. Available online: https://desapublications.un.org/publications/world-social-report-2023-leaving-no-one-behind-ageing-world (accessed on 15 September 2024).
  5. Park, H.Y.; Park, J.W.; Song, H.J.; Sohn, H.S.; Kwon, J.W. The Association between Polypharmacy and Dementia: A Nested Case-Control Study Based on a 12-Year Longitudinal Cohort Database in South Korea. PLoS ONE 2017, 12, e0169463. [Google Scholar] [CrossRef] [PubMed]
  6. Grossi, C.M.; Richardson, K.; Fox, C.; Maidment, I.; Steel, N.; Loke, Y.K.; Arthur, A.; Myint, P.K.; Campbell, N.; Boustani, M. Anticholinergic and benzodiazepine medication use and risk of incident dementia: A UK cohort study. BMC Geriatr. 2019, 19, 1–10. [Google Scholar] [CrossRef] [PubMed]
  7. Chase, A. Anticholinergic medications might increase the risk of AD. Nat. Rev. Neurol. 2015, 11, 125. [Google Scholar] [CrossRef] [PubMed]
  8. Joyce, G.; Ferido, P.; Thunell, J.; Tysinger, B.; Zissimopoulos, J. Benzodiazepine use and the risk of dementia. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2022, 8, e12309. [Google Scholar] [CrossRef]
  9. Fallahzadeh, M.; Borhani Haghighi, A.; Namazi, M. Proton pump inhibitors: Predisposers to Alzheimer disease? J. Clin. Pharm. Ther. 2010, 35, 125–126. [Google Scholar] [CrossRef]
  10. Song, Y.Q.; Li, Y.; Zhang, S.L.; Gao, J.; Feng, S.Y. Proton pump inhibitor use does not increase dementia and Alzheimer’s disease risk: An updated meta-analysis of published studies involving 642305 patients. PLoS ONE 2019, 14, e0219213. [Google Scholar] [CrossRef]
  11. Marttinen, M.K.; Kautiainen, H.; Haanpää, M.; Pohjankoski, H.; Hintikka, J.; Kauppi, M.J. Analgesic purchases among older adults—A population-based study. BMC Public Health 2021, 21, 256. [Google Scholar] [CrossRef]
  12. Frenk, S.M.; Gu, Q.; Bohm, M.K. Prevalence of Prescription Opioid Analgesic Use Among Adults: National Center for Health Statistics, United States, 2013–2016. 2019. Available online: https://www.cdc.gov/nchs/data/hestat/prescription-opioid/prescription-opioid.htm (accessed on 7 October 2024).
  13. Pisarska, A. Przyjmowanie leków przeciwbólowych przez podopiecznych młodzieżowych ośrodków socjoterapii i młodzieżowych ośrodków wychowawczych. Paediatr. Fam. Med. Pediatr. I Med. Rodz. 2023, 19, 87–91. [Google Scholar] [CrossRef]
  14. Yin, L.; Wang, K.; Zhang, T.; Liu, H.; Li, Y.; Luo, J. The survey on adolescents’ cognition, attitude, and behavior of using analgesics: Take Sichuan and Chongqing as an example. Front. Public Health 2022, 10, 744685. [Google Scholar] [CrossRef]
  15. Norling, A.M.; Bennett, A.; Crowe, M.; Long, D.L.; Nolin, S.A.; Myers, T.; Del Bene, V.A.; Lazar, R.M.; Gerstenecker, A. Longitudinal associations of anticholinergic medications on cognition and possible mitigating role of physical activity. J. Am. Geriatr. Soc. 2023, 71, 1937–1943. [Google Scholar] [CrossRef]
  16. Cebron Lipovec, N.; Jazbar, J.; Kos, M. Anticholinergic burden in children, adults and older adults in Slovenia: A Nationwide database study. Sci. Rep. 2020, 10, 9337. [Google Scholar] [CrossRef] [PubMed]
  17. Lukačišinová, A.; Reissigová, J.; Ortner-Hadžiabdić, M.; Brkic, J.; Okuyan, B.; Volmer, D.; Tadić, I.; Modamio, P.; Mariño, E.L.; Tachkov, K.; et al. Prevalence, country-specific prescribing patterns and determinants of benzodiazepine use in community-residing older adults in 7 European countries. BMC Geriatr. 2024, 24, 240. [Google Scholar] [CrossRef] [PubMed]
  18. Carrasco-Garrido, P.; Jiménez-Trujillo, I.; Hernández-Barrera, V.; Lima Florencio, L.; Palacios-Ceña, D. Patterns of non-medical use of benzodiazepines and Z-Drugs among adolescents and young adults: Gender differences and related factors. J. Subst. Use 2021, 26, 190–196. [Google Scholar] [CrossRef]
  19. Shanika, L.G.T.; Reynolds, A.; Pattison, S.; Braund, R. Proton pump inhibitor use: Systematic review of global trends and practices. Eur. J. Clin. Pharmacol. 2023, 79, 1159–1172. [Google Scholar] [CrossRef]
  20. Jing, R.; Yao, H.; Yan, Q.; Xue, Y.; Sun, W.; Lu, P.; Zhang, Z.; Xie, R.; Cui, B.; Feng, B. Trends and gaps in statin use for cardiovascular disease prevention in type 2 diabetes: A real-world study in Shanghai, China. Endocr. Pract. 2023, 29, 747–753. [Google Scholar] [CrossRef]
  21. Saeed, A.; Mehta, L. Statin therapy in older adults for primary prevention of atherosclerotic cardiovascular disease: The balancing act. Am. Coll. Cardiol. 2020, 20. [Google Scholar]
  22. Thompson-Paul, A.M.; Gillespie, C.; Wall, H.K.; Loustalot, F.; Sperling, L.; Hong, Y. Recommended and observed statin use among US adults–National Health and Nutrition Examination Survey, 2011–2018. J. Clin. Lipidol. 2023, 17, 225–235. [Google Scholar] [CrossRef]
  23. Novakova, I.; Subileau, E.A.; Toegel, S.; Gruber, D.; Lachmann, B.; Urban, E.; Chesne, C.; Noe, C.R.; Neuhaus, W. Transport rankings of non-steroidal antiinflammatory drugs across blood-brain barrier in vitro models. PLoS ONE 2014, 9, e86806. [Google Scholar] [CrossRef]
  24. Ghossein, N.; Kang, M.; Lakhkar, A.D. Anticholinergic Medications; StatPearls Publishing: Treasure Island, FL, USA, 2020. [Google Scholar]
  25. Golovenko, N.Y.; Larionov, V. Pharmacodynamical and neuroreceptor analysis of the permeability of the blood-brain barrier for derivatives of 1,4-benzodiazepine. Neurophysiology 2014, 46, 199–205. [Google Scholar] [CrossRef]
  26. Ortiz-Guerrero, G.; Amador-Muñoz, D.; Calderón-Ospina, C.A.; López-Fuentes, D.; Nava Mesa, M.O. Proton Pump Inhibitors and Dementia: Physiopathological Mechanisms and Clinical Consequences. Neural Plast. 2018, 2018, 5257285. [Google Scholar] [CrossRef]
  27. Sodero, A.O.; Barrantes, F.J. Pleiotropic effects of statins on brain cells. Biochim. Biophys. Acta (BBA)—Biomembr. 2020, 1862, 183340. [Google Scholar] [CrossRef] [PubMed]
  28. FMI. Analgesics Market Outlook for 2024 to 2034. 2024. Available online: https://www.futuremarketinsights.com/reports/analgesics-market (accessed on 11 October 2024).
  29. Li, H.X.; Li, B.L.; Wang, T.H.; Zheng, H.; Yan, T. Double-edged sword of opioids in the treatment of cancer pain: Hyperalgesia. Zhonghua Yi Xue Za Zhi 2022, 102, 3073–3079. [Google Scholar] [CrossRef] [PubMed]
  30. Borjkhani, M.; Bahrami, F.; Janahmadi, M. Assessing the Effects of Opioids on Pathological Memory by a Computational Model. Basic. Clin. Neurosci. 2018, 9, 275–288. [Google Scholar] [CrossRef] [PubMed]
  31. Vaughan, C.W.; Ingram, S.L.; Connor, M.A.; Christie, M.J. How opioids inhibit GABA-mediated neurotransmission. Nature 1997, 390, 611–614. [Google Scholar] [CrossRef] [PubMed]
  32. Freye, E.; Levy, J.V. Mechanism of Action of Opioids and Clinical Effects. Opioids Med. 2008, 85–187. [Google Scholar] [CrossRef]
  33. Eisch, A.J.; Barrot, M.; Schad, C.A.; Self, D.W.; Nestler, E.J. Opiates inhibit neurogenesis in the adult rat hippocampus. Proc. Natl. Acad. Sci. USA 2000, 97, 7579–7584. [Google Scholar] [CrossRef]
  34. Yuan, S.; Ling, Y.; Huang, X.; Tan, S.; Li, W.; Xu, A.; Lyu, J. Associations between the use of common nonsteroidal anti-inflammatory drugs, genetic susceptibility and dementia in participants with chronic pain: A prospective study based on 194,758 participants from the UK Biobank. J. Psychiatr. Res. 2024, 169, 152–159. [Google Scholar] [CrossRef]
  35. Zhang, Y.; Zhou, C.; Yang, S.; Zhang, Y.; Ye, Z.; He, P.; Liu, M.; Wu, Q.; Qin, X. Association of regular use of ibuprofen and paracetamol, genetic susceptibility, and new-onset dementia in the older population. Gen. Hosp. Psychiatry 2023, 84, 226–233. [Google Scholar] [CrossRef]
  36. Jobbé-Duval, A.; Bézard, M.; Moutereau, S.; Kharoubi, M.; Oghina, S.; Zaroui, A.; Galat, A.; Chalard, C.; Hugon-Vallet, E.; Lemonnier, F. Prevalence and determinants of iron deficiency in cardiac amyloidosis. ESC Heart Fail. 2022, 9, 1314–1327. [Google Scholar] [CrossRef]
  37. Qin, T.; Yan, M.; Fu, Z.; Song, Y.; Lu, W.; Fu, A.d.; Yin, P. Association between anemia and cognitive decline among Chinese middle-aged and elderly: Evidence from the China health and retirement longitudinal study. BMC Geriatr. 2019, 19, 305. [Google Scholar] [CrossRef]
  38. Tan, X.-x.; Qiu, L.-L.; Sun, J. Research progress on the role of inflammatory mechanisms in the development of postoperative cognitive dysfunction. BioMed Res. Int. 2021, 2021, 3883204. [Google Scholar] [CrossRef] [PubMed]
  39. Abd El-Ghffar, E.A.; El-Nashar, H.A.; Eldahshan, O.A.; Singab, A.N.B. GC-MS analysis and hepatoprotective activity of the n-hexane extract of Acrocarpus fraxinifolius leaves against paracetamol-induced hepatotoxicity in male albino rats. Pharm. Biol. 2017, 55, 441–449. [Google Scholar] [CrossRef] [PubMed]
  40. Oh, T.K.; Song, I.-A. Impact of prescribed opioid use on development of dementia among patients with chronic non-cancer pain. Sci. Rep. 2024, 14, 3313. [Google Scholar] [CrossRef] [PubMed]
  41. Levine, S.Z.; Rotstein, A.; Goldberg, Y.; Reichenberg, A.; Kodesh, A. Opioid exposure and the risk of dementia: A national cohort study. Am. J. Geriatr. Psychiatry 2023, 31, 315–323. [Google Scholar] [CrossRef]
  42. AAIC. New Use of Opioids Increases Risk of Death Elevenfold in Older Adults with Dementia. 2024 Alzheimer’s Association International Conference|28 July–1 August 2024|Philadelphia, USA. Available online: https://aaic.alz.org/releases_2023/opioids-increase-risk-death-older-adults-dementia.asp (accessed on 3 October 2024).
  43. Gao, Y.; Su, B.; Ding, L.; Qureshi, D.; Hong, S.; Wei, J.; Zeng, C.; Lei, G.; Xie, J. Association of Regular Opioid Use with Incident Dementia and Neuroimaging Markers of Brain Health in Chronic Pain Patients: Analysis of UK Biobank. Am. J. Geriatr. Psychiatry 2024, 32, 1154–1165. [Google Scholar] [CrossRef]
  44. Breitner, J.C.; Haneuse, S.; Walker, R.; Dublin, S.; Crane, P.; Gray, S.; Larson, E. Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. Neurology 2009, 72, 1899–1905. [Google Scholar] [CrossRef]
  45. Sonnen, J.A.; Larson, E.B.; Walker, R.; Haneuse, S.; Crane, P.K.; Gray, S.L.; Breitner, J.C.; Montine, T.J. Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques. Neurology 2010, 75, 1203–1210. [Google Scholar] [CrossRef]
  46. Dublin, S.; Walker, R.L.; Gray, S.L.; Hubbard, R.A.; Anderson, M.L.; Yu, O.; Montine, T.J.; Crane, P.K.; Sonnen, J.A.; Larson, E.B. Use of Analgesics (Opioids and Nonsteroidal Anti-Inflammatory Drugs) and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort. J. Alzheimers Dis. 2017, 58, 435–448. [Google Scholar] [CrossRef]
  47. Flanagan, M.E.; Larson, E.B.; Walker, R.L.; Keene, C.D.; Postupna, N.; Cholerton, B.; Sonnen, J.A.; Dublin, S.; Crane, P.K.; Montine, T.J. Associations between Use of Specific Analgesics and Concentrations of Amyloid-β 42 or Phospho-Tau in Regions of Human Cerebral Cortex. J. Alzheimers Dis. 2018, 61, 653–662. [Google Scholar] [CrossRef]
  48. Gasparini, L.; Ongini, E.; Wenk, G. Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer’s disease: Old and new mechanisms of action. J. Neurochem. 2004, 91, 521–536. [Google Scholar] [CrossRef]
  49. McGeer, P.L.; Schulzer, M.; McGeer, E.G. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: A review of 17 epidemiologic studies. Neurology 1996, 47, 425–432. [Google Scholar] [CrossRef] [PubMed]
  50. Stewart, W.F.; Kawas, C.; Corrada, M.; Metter, E.J. Risk of Alzheimer’s disease and duration of NSAID use. Neurology 1997, 48, 626–632. [Google Scholar] [CrossRef] [PubMed]
  51. Rogers, J.; Kirby, L.; Hempelman, S.; Berry, D.; McGeer, P.; Kaszniak, A.; Zalinski, J.; Cofield, M.; Mansukhani, L.; Willson, P. Clinical trial of indomethacin in Alzheimer’s disease. Neurology 1993, 43, 1609. [Google Scholar] [CrossRef] [PubMed]
  52. Etminan, M.; Gill, S.; Samii, A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: Systematic review and meta-analysis of observational studies. BMJ 2003, 327, 128. [Google Scholar] [CrossRef]
  53. Puhl, A.C.; Milton, F.A.; Cvoro, A.; Sieglaff, D.H.; Campos, J.C.; Bernardes, A.; Filgueira, C.S.; Lindemann, J.L.; Deng, T.; Neves, F.A.; et al. Mechanisms of peroxisome proliferator activated receptor γ regulation by non-steroidal anti-inflammatory drugs. Nucl. Recept. Signal 2015, 13, e004. [Google Scholar] [CrossRef]
  54. Khan, M.A.; Alam, Q.; Haque, A.; Ashafaq, M.; Khan, M.J.; Ashraf, G.M.; Ahmad, M. Current progress on peroxisome proliferator-activated receptor gamma agonist as an emerging therapeutic approach for the treatment of Alzheimer’s disease: An update. Curr. Neuropharmacol. 2019, 17, 232–246. [Google Scholar] [CrossRef]
  55. Dublin, S.; Walker, R.L.; Gray, S.L.; Hubbard, R.A.; Anderson, M.L.; Yu, O.; Crane, P.K.; Larson, E.B. Prescription Opioids and Risk of Dementia or Cognitive Decline: A Prospective Cohort Study. J. Am. Geriatr. Soc. 2015, 63, 1519–1526. [Google Scholar] [CrossRef]
  56. Taipale, H.; Hamina, A.; Lampela, P.; Tanskanen, A.; Tiihonen, J.; Karttunen, N.; Tolppanen, A.-M.; Hartikainen, S. Is Alzheimer’s Disease Associated with Previous Opioid Use? Pain. Med. 2017, 19, 2115–2121. [Google Scholar] [CrossRef]
  57. Zhang, C.; Wang, Y.; Wang, D.; Zhang, J.; Zhang, F. NSAID Exposure and Risk of Alzheimer’s Disease: An Updated Meta-Analysis From Cohort Studies. Front. Aging Neurosci. 2018, 10, 83. [Google Scholar] [CrossRef]
  58. Veld, B.A.i.t.; Ruitenberg, A.; Hofman, A.; Launer, L.J.; Duijn, C.M.v.; Stijnen, T.; Breteler, M.M.B.; Stricker, B.H.C. Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer’s Disease. N. Engl. J. Med. 2001, 345, 1515–1521. [Google Scholar] [CrossRef]
  59. Shim, K.H.; Kang, M.J.; Sharma, N.; An, S.S.A. Beauty of the beast: Anticholinergic tropane alkaloids in therapeutics. Nat. Prod. Bioprospect 2022, 12, 33. [Google Scholar] [CrossRef] [PubMed]
  60. Grossi, C.M.; Richardson, K.; Savva, G.M.; Fox, C.; Arthur, A.; Loke, Y.K.; Steel, N.; Brayne, C.; Matthews, F.E.; Robinson, L. Increasing prevalence of anticholinergic medication use in older people in England over 20 years: Cognitive function and ageing study I and II. BMC Geriatr. 2020, 20, 267. [Google Scholar] [CrossRef] [PubMed]
  61. Fox, C.; Richardson, K.; Maidment, I.D.; Savva, G.M.; Matthews, F.E.; Smithard, D.; Coulton, S.; Katona, C.; Boustani, M.A.; Brayne, C. Anticholinergic medication use and cognitive impairment in the older population: The medical research council cognitive function and ageing study. J. Am. Geriatr. Soc. 2011, 59, 1477–1483. [Google Scholar] [CrossRef] [PubMed]
  62. Gerretsen, P.; Pollock, B.G. Drugs with anticholinergic properties: A current perspective on use and safety. Expert. Opin. Drug Saf. 2011, 10, 751–765. [Google Scholar] [CrossRef]
  63. Gray, S.L.; Anderson, M.L.; Dublin, S.; Hanlon, J.T.; Hubbard, R.; Walker, R.; Yu, O.; Crane, P.K.; Larson, E.B. Cumulative use of strong anticholinergics and incident dementia: A prospective cohort study. JAMA Intern. Med. 2015, 175, 401–407. [Google Scholar] [CrossRef]
  64. Ancelin, M.L.; Artero, S.; Portet, F.; Dupuy, A.-M.; Touchon, J.; Ritchie, K. Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: Longitudinal cohort study. BMJ 2006, 332, 455–459. [Google Scholar] [CrossRef]
  65. Carrière, I.; Fourrier-Reglat, A.; Dartigues, J.-F.; Rouaud, O.; Pasquier, F.; Ritchie, K.; Ancelin, M.-L. Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: The 3-city study. Arch. Intern. Med. 2009, 169, 1317–1324. [Google Scholar] [CrossRef]
  66. Jessen, F.; Kaduszkiewicz, H.; Daerr, M.; Bickel, H.; Pentzek, M.; Riedel-Heller, S.; Wagner, M.; Weyerer, S.; Wiese, B.; van den Bussche, H. Anticholinergic drug use and risk for dementia: Target for dementia prevention. Eur. Arch. Psychiatry Clin. Neurosci. 2010, 260, 111–115. [Google Scholar] [CrossRef]
  67. Richardson, K.; Fox, C.; Maidment, I.; Steel, N.; Loke, Y.K.; Arthur, A.; Myint, P.K.; Grossi, C.M.; Mattishent, K.; Bennett, K.; et al. Anticholinergic drugs and risk of dementia: Case-control study. BMJ 2018, 361, k1315. [Google Scholar] [CrossRef]
  68. Joung, K.-i.; Kim, S.; Cho, Y.H.; Cho, S.-i. Association of Anticholinergic Use with Incidence of Alzheimer’s Disease: Population-based Cohort Study. Sci. Rep. 2019, 9, 6802. [Google Scholar] [CrossRef]
  69. Andrade, C. Anticholinergic drug exposure and the risk of dementia: There is modest evidence for an association but not for causality. J. Clin. Psychiatry 2019, 80, 831. [Google Scholar] [CrossRef] [PubMed]
  70. Coupland, C.A.; Hill, T.; Dening, T.; Morriss, R.; Moore, M.; Hippisley-Cox, J. Anticholinergic drug exposure and the risk of dementia: A nested case-control study. JAMA Intern. Med. 2019, 179, 1084–1093. [Google Scholar] [CrossRef] [PubMed]
  71. Zheng, Y.B.; Shi, L.; Zhu, X.M.; Bao, Y.P.; Bai, L.J.; Li, J.Q.; Liu, J.J.; Han, Y.; Shi, J.; Lu, L. Anticholinergic drugs and the risk of dementia: A systematic review and meta-analysis. Neurosci. Biobehav. Rev. 2021, 127, 296–306. [Google Scholar] [CrossRef] [PubMed]
  72. Cancelli, I.; Gigli, G.L.; Piani, A.; Zanchettin, B.; Janes, F.; Rinaldi, A.; Valente, M. Drugs with anticholinergic properties as a risk factor for cognitive impairment in elderly people: A population-based study. J. Clin. Psychopharmacol. 2008, 28, 654–659. [Google Scholar] [CrossRef] [PubMed]
  73. Weigand, A.J.; Bondi, M.W.; Thomas, K.R.; Campbell, N.L.; Galasko, D.R.; Salmon, D.P.; Sewell, D.; Brewer, J.B.; Feldman, H.H.; Delano-Wood, L. Association of anticholinergic medications and AD biomarkers with incidence of MCI among cognitively normal older adults. Neurology 2020, 95, e2295–e2304. [Google Scholar] [CrossRef]
  74. Taylor-Rowan, M.; Edwards, S.; Noel-Storr, A.H.; McCleery, J.; Myint, P.K.; Soiza, R.; Stewart, C.; Loke, Y.K.; Quinn, T.J. Anticholinergic burden (prognostic factor) for prediction of dementia or cognitive decline in older adults with no known cognitive syndrome. Cochrane Database Syst. Rev. 2021, 5, Cd013540. [Google Scholar] [CrossRef]
  75. Heath, L.; Gray, S.L.; Boudreau, D.M.; Thummel, K.; Edwards, K.L.; Fullerton, S.M.; Crane, P.K.; Larson, E.B. Cumulative Antidepressant Use and Risk of Dementia in a Prospective Cohort Study. J. Am. Geriatr. Soc. 2018, 66, 1948–1955. [Google Scholar] [CrossRef]
  76. Wang, Y.C.; Chen, Y.L.; Huang, C.C.; Ho, C.H.; Huang, Y.T.; Wu, M.P.; Ou, M.J.; Yang, C.H.; Chen, P.J. Cumulative use of therapeutic bladder anticholinergics and the risk of dementia in patients with lower urinary tract symptoms: A nationwide 12-year cohort study. BMC Geriatr. 2019, 19, 380. [Google Scholar] [CrossRef]
  77. Mur, J.; Russ, T.C.; Cox, S.R.; Marioni, R.E.; Muniz-Terrera, G. Association between anticholinergic burden and dementia in UK Biobank. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2022, 8, e12290. [Google Scholar] [CrossRef]
  78. Poonawalla, I.B.; Xu, Y.; Gaddy, R.; James, A.; Ruble, M.; Burns, S.; Dixon, S.W.; Suehs, B.T. Anticholinergic exposure and its association with dementia/Alzheimer’s disease and mortality in older adults. BMC Geriatr. 2023, 23, 401. [Google Scholar] [CrossRef]
  79. Heser, K.; Luck, T.; Röhr, S.; Wiese, B.; Kaduszkiewicz, H.; Oey, A.; Bickel, H.; Mösch, E.; Weyerer, S.; Werle, J. Potentially inappropriate medication: Association between the use of antidepressant drugs and the subsequent risk for dementia. J. Affect. Disord. 2018, 226, 28–35. [Google Scholar] [CrossRef] [PubMed]
  80. Yoshiyama, Y.; Kojima, A.; Itoh, K.; Uchiyama, T.; Arai, K. Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model. Neurobiol. Dis. 2012, 45, 329–336. [Google Scholar] [CrossRef] [PubMed]
  81. Liu, Y.-P.; Chien, W.-C.; Chung, C.-H.; Chang, H.-A.; Kao, Y.-C.; Tzeng, N.-S. Are anticholinergic medications associated with increased risk of dementia and behavioral and psychological symptoms of dementia? A nationwide 15-year follow-up cohort study in Taiwan. Front. Pharmacol. 2020, 11, 30. [Google Scholar] [CrossRef] [PubMed]
  82. Low, L.F.; Anstey, K.J.; Sachdev, P. Use of medications with anticholinergic properties and cognitive function in a young-old community sample. Int. J. Geriatr. Psychiatry 2009, 24, 578–584. [Google Scholar] [CrossRef]
  83. Holm, H.; Ricci, F.; Di Martino, G.; Bachus, E.; Nilsson, E.D.; Ballerini, P.; Melander, O.; Hansson, O.; Nägga, K.; Magnusson, M.; et al. Beta-blocker therapy and risk of vascular dementia: A population-based prospective study. Vasc. Pharmacol. 2020, 125–126, 106649. [Google Scholar] [CrossRef]
  84. Schroevers, J.L.; Hoevenaar-Blom, M.P.; Busschers, W.B.; Hollander, M.; Van Gool, W.A.; Richard, E.; Van Dalen, J.W.; Moll van Charante, E.P. Antihypertensive medication classes and risk of incident dementia in primary care patients: A longitudinal cohort study in the Netherlands. Lancet Reg. Health—Eur. 2024, 42, 100927. [Google Scholar] [CrossRef]
  85. Beaman, E.E.; Bonde, A.N.; Larsen, S.M.U.; Ozenne, B.; Lohela, T.J.; Nedergaard, M.; Gíslason, G.H.; Knudsen, G.M.; Holst, S.C. Blood–brain barrier permeable β-blockers linked to lower risk of Alzheimer’s disease in hypertension. Brain 2022, 146, 1141–1151. [Google Scholar] [CrossRef]
  86. He, Q.; Chen, X.; Wu, T.; Li, L.; Fei, X. Risk of dementia in long-term benzodiazepine users: Evidence from a meta-analysis of observational studies. J. Clin. Neurol. 2019, 15, 9–19. [Google Scholar] [CrossRef]
  87. Shash, D.; Kurth, T.; Bertrand, M.; Dufouil, C.; Barberger-Gateau, P.; Berr, C.; Ritchie, K.; Dartigues, J.F.; Bégaud, B.; Alpérovitch, A. Benzodiazepine, psychotropic medication, and dementia: A population-based cohort study. Alzheimer’s Dement. 2016, 12, 604–613. [Google Scholar] [CrossRef]
  88. Bierman, E.; Comijs, H.; Gundy, C.; Sonnenberg, C.; Jonker, C.; Beekman, A. The effect of chronic benzodiazepine use on cognitive functioning in older persons: Good, bad or indifferent? Int. J. Geriatr. Psychiatry J. Psychiatry Late Life Allied Sci. 2007, 22, 1194–1200. [Google Scholar] [CrossRef]
  89. Tapiainen, V.; Taipale, H.; Tanskanen, A.; Tiihonen, J.; Hartikainen, S.; Tolppanen, A.M. The risk of Alzheimer’s disease associated with benzodiazepines and related drugs: A nested case–control study. Acta Psychiatr. Scand. 2018, 138, 91–100. [Google Scholar] [CrossRef] [PubMed]
  90. Lee, J.; Jung, S.J.; Choi, J.-w.; Shin, A.; Lee, Y.J. Use of sedative-hypnotics and the risk of Alzheimer’s dementia: A retrospective cohort study. PLoS ONE 2018, 13, e0204413. [Google Scholar] [CrossRef] [PubMed]
  91. De Gage, S.B.; Moride, Y.; Ducruet, T.; Kurth, T.; Verdoux, H.; Tournier, M.; Pariente, A.; Bégaud, B. Benzodiazepine use and risk of Alzheimer’s disease: Case-control study. BMJ 2014, 349, g5205. [Google Scholar] [CrossRef] [PubMed]
  92. Islam, M.M.; Iqbal, U.; Walther, B.; Atique, S.; Dubey, N.K.; Nguyen, P.-A.; Poly, T.N.; Masud, J.H.B.; Li, Y.-C.; Shabbir, S.-A. Benzodiazepine use and risk of dementia in the elderly population: A systematic review and meta-analysis. Neuroepidemiology 2017, 47, 181–191. [Google Scholar] [CrossRef]
  93. Saarelainen, L.; Tolppanen, A.M.; Koponen, M.; Tanskanen, A.; Tiihonen, J.; Hartikainen, S.; Taipale, H. Risk of death associated with new benzodiazepine use among persons with Alzheimer disease: A matched cohort study. Int. J. Geriatr. Psychiatry 2018, 33, 583–590. [Google Scholar] [CrossRef]
  94. Gomm, W.; von Holt, K.; Thomé, F.; Broich, K.; Maier, W.; Weckbecker, K.; Fink, A.; Doblhammer, G.; Haenisch, B. Regular benzodiazepine and Z-substance use and risk of dementia: An analysis of German claims data. J. Alzheimer’s Dis. 2016, 54, 801–808. [Google Scholar] [CrossRef]
  95. Lucchetta, R.C.; da Mata, B.P.M.; Mastroianni, P.d.C. Association between development of dementia and use of benzodiazepines: A systematic review and meta-analysis. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2018, 38, 1010–1020. [Google Scholar] [CrossRef]
  96. Penninkilampi, R.; Eslick, G.D. A systematic review and meta-analysis of the risk of dementia associated with benzodiazepine use, after controlling for protopathic bias. CNS Drugs 2018, 32, 485–497. [Google Scholar] [CrossRef]
  97. Ettcheto, M.; Olloquequi, J.; Sánchez-López, E.; Busquets, O.; Cano, A.; Manzine, P.R.; Beas-Zarate, C.; Castro-Torres, R.D.; García, M.L.; Bulló, M.; et al. Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer’s Disease Dementia. Front. Aging Neurosci. 2019, 11, 344. [Google Scholar] [CrossRef]
  98. Zhong, G.; Wang, Y.; Zhang, Y.; Zhao, Y. Association between benzodiazepine use and dementia: A meta-analysis. PLoS ONE 2015, 10, e0127836. [Google Scholar] [CrossRef]
  99. Mura, T.; Proust-Lima, C.; Akbaraly, T.; Amieva, H.; Tzourio, C.; Chevassus, H.; Picot, M.-C.; Jacqumin-Gadda, H.; Berr, C. Chronic use of benzodiazepines and latent cognitive decline in the elderly: Results from the Three-city study. Eur. Neuropsychopharmacol. 2013, 23, 212–223. [Google Scholar] [CrossRef] [PubMed]
  100. Pietrzak, R.H.; Lim, Y.Y.; Neumeister, A.; Ames, D.; Ellis, K.A.; Harrington, K.; Lautenschlager, N.T.; Restrepo, C.; Martins, R.N.; Masters, C.L. Amyloid-β, anxiety, and cognitive decline in preclinical Alzheimer disease: A multicenter, prospective cohort study. JAMA Psychiatry 2015, 72, 284–291. [Google Scholar] [CrossRef] [PubMed]
  101. Burke, S.L.; Hu, T.; Spadola, C.E.; Li, T.; Naseh, M.; Burgess, A.; Cadet, T. Mild cognitive impairment: Associations with sleep disturbance, apolipoprotein e4, and sleep medications. Sleep Med. 2018, 52, 168–176. [Google Scholar] [CrossRef] [PubMed]
  102. Biétry, F.A.; Pfeil, A.M.; Reich, O.; Schwenkglenks, M.; Meier, C.R. Benzodiazepine use and risk of developing Alzheimer’s disease: A case-control study based on Swiss claims data. CNS Drugs 2017, 31, 245–251. [Google Scholar] [CrossRef]
  103. Imfeld, P.; Bodmer, M.; Jick, S.S.; Meier, C.R. Benzodiazepine use and risk of developing Alzheimer’s disease or vascular dementia: A case–control analysis. Drug Saf. 2015, 38, 909–919. [Google Scholar] [CrossRef]
  104. Aldaz, P.; Garjón, J.; Beitia, G.; Beltrán, I.; Librero, J.; Ibáñez, B.; Arroyo, P.; Ariz, M.J. Association between benzodiazepine use and development of dementia. Med. Clin. (Engl. Ed.) 2021, 156, 107–111. [Google Scholar]
  105. Wu, C.C.; Liao, M.H.; Su, C.H.; Poly, T.N.; Lin, M.C. Benzodiazepine Use and the Risk of Dementia in the Elderly Population: An Umbrella Review of Meta-Analyses. J. Pers. Med. 2023, 13, 1485. [Google Scholar] [CrossRef]
  106. Gerlach, L.B.; Myra Kim, H.; Ignacio, R.V.; Strominger, J.; Maust, D.T. Use of benzodiazepines and risk of incident dementia: A retrospective cohort study. J. Gerontol. Ser. A 2022, 77, 1035–1041. [Google Scholar] [CrossRef]
  107. Phan, T.X.; Malkani, R.G. Sleep and circadian rhythm disruption and stress intersect in Alzheimer’s disease. Neurobiol. Stress 2019, 10, 100133. [Google Scholar] [CrossRef]
  108. Calvo-Flores Guzmán, B.; Vinnakota, C.; Govindpani, K.; Waldvogel, H.J.; Faull, R.L.; Kwakowsky, A. The GABAergic system as a therapeutic target for Alzheimer’s disease. J. Neurochem. 2018, 146, 649–669. [Google Scholar] [CrossRef]
  109. Fastbom, J.; Forsell, Y.; Winblad, B. Benzodiazepines may have protective effects against Alzheimer disease. Alzheimer Dis. Assoc. Disord. 1998, 12, 14–17. [Google Scholar] [CrossRef] [PubMed]
  110. Castellana, C.; Pecere, S.; Furnari, M.; Telese, A.; Matteo, M.V.; Haidry, R.; Eusebi, L.H. Side effects of long-term use of proton pump inhibitors: Practical considerations. Pol. Arch. Med. Wewn. 2021, 131, 541–549. [Google Scholar] [CrossRef] [PubMed]
  111. Luo, H.; Fan, Q.; Xiao, S.; Chen, K. Changes in proton pump inhibitor prescribing trend over the past decade and pharmacists’ effect on prescribing practice at a tertiary hospital. BMC Health Serv. Res. 2018, 18, 537. [Google Scholar] [CrossRef] [PubMed]
  112. Yibirin, M.; De Oliveira, D.; Valera, R.; Plitt, A.E.; Lutgen, S. Adverse Effects Associated with Proton Pump Inhibitor Use. Cureus 2021, 13, e12759. [Google Scholar] [CrossRef]
  113. Cheng, F.; Ho, Y.-F.; Hung, L.; Chen, C.; Tsai, T. Determination and pharmacokinetic profile of omeprazole in rat blood, brain and bile by microdialysis and high-performance liquid chromatography. J. Chromatogr. A 2002, 949, 35–42. [Google Scholar] [CrossRef]
  114. Kumar, R.; Kumar, A.; Nordberg, A.; Långström, B.; Darreh-Shori, T. Proton pump inhibitors act with unprecedented potencies as inhibitors of the acetylcholine biosynthesizing enzyme—A plausible missing link for their association with incidence of dementia. Alzheimer’s Dement. 2020, 16, 1031–1042. [Google Scholar] [CrossRef]
  115. Batchelor, R.; Gilmartin, J.F.M.; Kemp, W.; Hopper, I.; Liew, D. Dementia, cognitive impairment and proton pump inhibitor therapy: A systematic review. J. Gastroenterol. Hepatol. 2017, 32, 1426–1435. [Google Scholar] [CrossRef]
  116. Li, M.; Luo, Z.; Yu, S.; Tang, Z. Proton pump inhibitor use and risk of dementia: Systematic review and meta-analysis. Medicine 2019, 98, e14422. [Google Scholar] [CrossRef]
  117. Gomm, W.; von Holt, K.; Thomé, F.; Broich, K.; Maier, W.; Fink, A.; Doblhammer, G.; Haenisch, B. Association of proton pump inhibitors with risk of dementia: A pharmacoepidemiological claims data analysis. JAMA Neurol. 2016, 73, 410–416. [Google Scholar] [CrossRef]
  118. Welu, J.; Metzger, J.; Bebensee, S.; Ahrendt, A.; Vasek, M. Proton pump inhibitor use and risk of dementia in the veteran population. Fed. Pract. 2019, 36, S27. [Google Scholar]
  119. Chen, L.-Y.; Lin, H.-J.; Wu, W.-T.; Chen, Y.-C.; Chen, C.-L.; Kao, J.; You, S.-L.; Chou, Y.-C.; Sun, C.-A. Clinical Use of Acid Suppressants and Risk of Dementia in the Elderly: A Pharmaco-Epidemiological Cohort Study. Int. J. Environ. Res. Public Health 2020, 17, 8271. [Google Scholar] [CrossRef] [PubMed]
  120. Haenisch, B.; von Holt, K.; Wiese, B.; Prokein, J.; Lange, C.; Ernst, A.; Brettschneider, C.; König, H.-H.; Werle, J.; Weyerer, S. Risk of dementia in elderly patients with the use of proton pump inhibitors. Eur. Arch. Psychiatry Clin. Neurosci. 2015, 265, 419–428. [Google Scholar] [CrossRef] [PubMed]
  121. de Wilde, M.C.; Vellas, B.; Girault, E.; Yavuz, A.C.; Sijben, J.W. Lower brain and blood nutrient status in Alzheimer’s disease: Results from meta-analyses. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2017, 3, 416–431. [Google Scholar] [CrossRef] [PubMed]
  122. Tai, S.-Y.; Chien, C.-Y.; Wu, D.-C.; Lin, K.-D.; Ho, B.-L.; Chang, Y.-H.; Chang, Y.-P. Risk of dementia from proton pump inhibitor use in Asian population: A nationwide cohort study in Taiwan. PLoS ONE 2017, 12, e0171006. [Google Scholar] [CrossRef] [PubMed]
  123. Reynolds, E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006, 5, 949–960. [Google Scholar] [CrossRef]
  124. Majumdar, A.; Cruz, D.; Asamoah, N.; Buxbaum, A.; Sohar, I.; Lobel, P.; Maxfield, F.R. Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils. Mol. Biol. Cell 2007, 18, 1490–1496. [Google Scholar] [CrossRef]
  125. Nighot, M.; Nighot, P.; Ma, T. Proton Pump Inhibitors (PPI) induces colonic Tight Junction barrier (TJ) dysfunction via an upregulation of TJ pore forming Caludin-2 protein. Gastroenterology 2021, 160, S36. [Google Scholar] [CrossRef]
  126. Thongon, N.; Chamniansawat, S. Hippocampal synaptic dysfunction and spatial memory impairment in omeprazole-treated rats. Metab. Brain Dis. 2022, 37, 2871–2881. [Google Scholar] [CrossRef]
  127. Taipale, H.; Tolppanen, A.-M.; Tiihonen, M.; Tanskanen, A.; Tiihonen, J.; Hartikainen, S. No association between proton pump inhibitor use and risk of Alzheimer’s disease. Off. J. Am. Coll. Gastroenterol. ACG 2017, 112, 1802–1808. [Google Scholar] [CrossRef]
  128. Goldstein, F.C.; Steenland, K.; Zhao, L.; Wharton, W.; Levey, A.I.; Hajjar, I. Proton pump inhibitors and risk of mild cognitive impairment and dementia. J. Am. Geriatr. Soc. 2017, 65, 1969–1974. [Google Scholar] [CrossRef]
  129. Cooksey, R.; Kennedy, J.; Dennis, M.S.; Escott-Price, V.; Lyons, R.A.; Seaborne, M.; Brophy, S. Proton pump inhibitors and dementia risk: Evidence from a cohort study using linked routinely collected national health data in Wales, UK. PLoS ONE 2020, 15, e0237676. [Google Scholar] [CrossRef] [PubMed]
  130. Ahn, N.; Nolde, M.; Krause, E.; Güntner, F.; Günter, A.; Tauscher, M.; Gerlach, R.; Meisinger, C.; Linseisen, J.; Baumeister, S.E. Do proton pump inhibitors increase the risk of dementia? A systematic review, meta-analysis and bias analysis. Br. J. Clin. Pharmacol. 2023, 89, 602–616. [Google Scholar] [CrossRef] [PubMed]
  131. Gray, S.L.; Walker, R.L.; Dublin, S.; Yu, O.; Aiello Bowles, E.J.; Anderson, M.L.; Crane, P.K.; Larson, E.B. Proton Pump Inhibitor Use and Dementia Risk: Prospective Population-Based Study. J. Am. Geriatr. Soc. 2018, 66, 247–253. [Google Scholar] [CrossRef] [PubMed]
  132. Torres-Bondia, F.; Dakterzada, F.; Galván, L.; Buti, M.; Besanson, G.; Gill, E.; Buil, R.; de Batlle, J.; Piñol-Ripoll, G. Proton pump inhibitors and the risk of Alzheimer’s disease and non-Alzheimer’s dementias. Sci. Rep. 2020, 10, 21046. [Google Scholar] [CrossRef]
  133. Wang, H.; Tian, L.; Yan, X. No association between acid suppressant use and risk of dementia: An updated meta-analysis. Eur. J. Clin. Pharmacol. 2022, 78, 375–382. [Google Scholar] [CrossRef]
  134. Moayyedi, P.; Eikelboom, J.W.; Bosch, J.; Connolly, S.J.; Dyal, L.; Shestakovska, O.; Leong, D.; Anand, S.S.; Störk, S.; Branch, K.R. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology 2019, 157, 682–691.e2. [Google Scholar] [CrossRef]
  135. Caetano, C.; Veloso, M.; Borda, S. Proton pump inhibitors and dementia: What association? Dement. Neuropsychol. 2023, 17, e20220048. [Google Scholar] [CrossRef]
  136. Wagstaff, L.R.; Mitton, M.W.; Arvik, B.M.; Doraiswamy, P.M. Statin-associated memory loss: Analysis of 60 case reports and review of the literature. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2003, 23, 871–880. [Google Scholar] [CrossRef]
  137. Sizar, O.; Khare, S.; Patel, P.; Talati, R. Statin medications. In StatPearls [Internet]; StatPearls Publishing: Treasure Island, FL, USA, 2024. [Google Scholar]
  138. FDA. FDA Drug Safety Communication: Important Safety Label Changes to Cholesterol-Lowering Statin Drugs; US Food and Drug Administration: Rockville, MD, USA, 2012. [Google Scholar]
  139. Nielsen, S.F.; Nordestgaard, B.G. Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: A nationwide prospective cohort study. Eur. Heart J. 2016, 37, 908–916. [Google Scholar] [CrossRef]
  140. Li, G.; Higdon, R.; Kukull, W.A.; Peskind, E.; Van Valen Moore, K.; Tsuang, D.; van Belle, G.; McCormick, W.; Bowen, J.D.; Teri, L.; et al. Statin therapy and risk of dementia in the elderly: A community-based prospective cohort study. Neurology 2004, 63, 1624–1628. [Google Scholar] [CrossRef]
  141. Zandi, P.P.; Sparks, D.L.; Khachaturian, A.S.; Tschanz, J.; Norton, M.; Steinberg, M.; Welsh-Bohmer, K.A.; Breitner, J.C. Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch. Gen. Psychiatry 2005, 62, 217–224. [Google Scholar] [CrossRef] [PubMed]
  142. Zhou, Z.; Ryan, J.; Ernst, M.E.; Zoungas, S.; Tonkin, A.M.; Woods, R.L.; McNeil, J.J.; Reid, C.M.; Curtis, A.J.; Wolfe, R.; et al. Effect of Statin Therapy on Cognitive Decline and Incident Dementia in Older Adults. J. Am. Coll. Cardiol. 2021, 77, 3145–3156. [Google Scholar] [CrossRef] [PubMed]
  143. Kemp, E.C.; Ebner, M.K.; Ramanan, S.; Godek, T.A.; Pugh, E.A.; Bartlett, H.H.; McDonald, J.W.; Mecca, M.C.; van Dyck, C.H.; Mecca, A.P. Statin Use and Risk of Cognitive Decline in the ADNI Cohort. Am. J. Geriatr. Psychiatry 2020, 28, 507–517. [Google Scholar] [CrossRef] [PubMed]
  144. Ott, B.R.; Daiello, L.A.; Dahabreh, I.J.; Springate, B.A.; Bixby, K.; Murali, M.; Trikalinos, T.A. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J. Gen. Intern. Med. 2015, 30, 348–358. [Google Scholar] [CrossRef]
  145. Bagheri, H.; Ghasemi, F.; Barreto, G.E.; Sathyapalan, T.; Jamialahmadi, T.; Sahebkar, A. The effects of statins on microglial cells to protect against neurodegenerative disorders: A mechanistic review. Biofactors 2020, 46, 309–325. [Google Scholar] [CrossRef]
  146. Bukiya, A.N.; Blank, P.S.; Rosenhouse-Dantsker, A. Cholesterol intake and statin use regulate neuronal G protein-gated inwardly rectifying potassium channels. J. Lipid Res. 2019, 60, 19–29. [Google Scholar] [CrossRef]
  147. Jeong, S.M.; Shin, D.W.; Yoo, T.G.; Cho, M.H.; Jang, W.; Lee, J.; Kim, S. Association between statin use and Alzheimer’s disease with dose response relationship. Sci. Rep. 2021, 11, 15280. [Google Scholar] [CrossRef]
  148. Poly, T.N.; Islam, M.M.; Walther, B.A.; Yang, H.C.; Wu, C.C.; Lin, M.C.; Li, Y.C. Association between Use of Statin and Risk of Dementia: A Meta-Analysis of Observational Studies. Neuroepidemiology 2020, 54, 214–226. [Google Scholar] [CrossRef]
  149. Adhikari, A.; Tripathy, S.; Chuzi, S.; Peterson, J.; Stone, N.J. Association between statin use and cognitive function: A systematic review of randomized clinical trials and observational studies. J. Clin. Lipidol. 2021, 15, 22–32.e12. [Google Scholar] [CrossRef]
  150. Cramer, C.; Haan, M.N.; Galea, S.; Langa, K.M.; Kalbfleisch, J.D. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology 2008, 71, 344–350. [Google Scholar] [CrossRef]
  151. Haag, M.D.; Hofman, A.; Koudstaal, P.J.; Stricker, B.H.; Breteler, M.M. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J. Neurol. Neurosurg. Psychiatry 2009, 80, 13–17. [Google Scholar] [CrossRef] [PubMed]
  152. Chou, C.Y.; Chou, Y.C.; Chou, Y.J.; Yang, Y.F.; Huang, N. Statin use and incident dementia: A nationwide cohort study of Taiwan. Int. J. Cardiol. 2014, 173, 305–310. [Google Scholar] [CrossRef] [PubMed]
  153. Olmastroni, E.; Molari, G.; De Beni, N.; Colpani, O.; Galimberti, F.; Gazzotti, M.; Zambon, A.; Catapano, A.L.; Casula, M. Statin use and risk of dementia or Alzheimer’s disease: A systematic review and meta-analysis of observational studies. Eur. J. Prev. Cardiol. 2021, 29, 804–814. [Google Scholar] [CrossRef] [PubMed]
  154. Li, H.H.; Lin, C.L.; Huang, C.N. Neuroprotective effects of statins against amyloid β-induced neurotoxicity. Neural Regen. Res. 2018, 13, 198–206. [Google Scholar] [CrossRef]
  155. Mendoza-Oliva, A.; Zepeda, A.; Arias, C. The complex actions of statins in brain and their relevance for Alzheimer’s disease treatment: An analytical review. Curr. Alzheimer Res. 2014, 11, 817–833. [Google Scholar] [CrossRef]
  156. Ren, Q.-w.; Katherine Teng, T.-H.; Tse, Y.-K.; Wei Tsang, C.T.; Yu, S.-Y.; Wu, M.-Z.; Li, X.-l.; Hung, D.; Tse, H.-F.; Lam, C.S.P.; et al. Statins and risks of dementia among patients with heart failure: A population-based retrospective cohort study in Hong Kong. Lancet Reg. Health—West. Pac. 2024, 44, 101006. [Google Scholar] [CrossRef]
  157. Cobos-Palacios, L.; Sanz-Cánovas, J.; Muñoz-Ubeda, M.; Lopez-Carmona, M.D.; Perez-Belmonte, L.M.; Lopez-Sampalo, A.; Gomez-Huelgas, R.; Bernal-Lopez, M.R. Statin therapy in very old patients: Lights and shadows. Front. Cardiovasc. Med. 2021, 8, 779044. [Google Scholar] [CrossRef]
  158. Rea, F.; Biffi, A.; Ronco, R.; Franchi, M.; Cammarota, S.; Citarella, A.; Conti, V.; Filippelli, A.; Sellitto, C.; Corrao, G. Cardiovascular outcomes and mortality associated with discontinuing statins in older patients receiving polypharmacy. JAMA Netw. Open 2021, 4, e2113186. [Google Scholar] [CrossRef]
  159. O’Mahony, D.; O’Sullivan, D.; Byrne, S.; O’Connor, M.N.; Ryan, C.; Gallagher, P. STOPP/START criteria for potentially inappropriate prescribing in older people: Version 2. Age Ageing 2014, 44, 213–218. [Google Scholar] [CrossRef]
  160. Panel, A.G.S.B.C.U.E.; Fick, D.M.; Semla, T.P.; Steinman, M.; Beizer, J.; Brandt, N.; Dombrowski, R.; DuBeau, C.E.; Pezzullo, L.; Epplin, J.J. American Geriatrics Society 2019 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J. Am. Geriatr. Soc. 2019, 67, 674–694. [Google Scholar] [CrossRef]
  161. The American Geriatrics Society 2012 Beers Criteria Update Expert Panel; Campanelli, C.M. American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J. Am. Geriatr. Soc. 2012, 60, 616–631. [Google Scholar] [CrossRef]
Ijms 25 12850 g001
Figure 1. Broad classification and structures of some analgesics.
Figure 1. Broad classification and structures of some analgesics.
Ijms 25 12850 g001
Ijms 25 12850 g002
Figure 2. Increased risk of AD/dementia associated with the use of analgesics. Frequent use of opioids (>20 prescriptions) was associated with the highest risk of AD/dementia in comparison to NSAIDs. The graph was plotted using data reported by Gao et al., 2024 [43].
Figure 2. Increased risk of AD/dementia associated with the use of analgesics. Frequent use of opioids (>20 prescriptions) was associated with the highest risk of AD/dementia in comparison to NSAIDs. The graph was plotted using data reported by Gao et al., 2024 [43].
Ijms 25 12850 g002
Ijms 25 12850 g003
Figure 3. Evaluating cognitive impacts of opioids vs. NSAIDs.
Figure 3. Evaluating cognitive impacts of opioids vs. NSAIDs.
Ijms 25 12850 g003
Ijms 25 12850 g004
Figure 4. Some common examples and applications of anticholinergic drugs.
Figure 4. Some common examples and applications of anticholinergic drugs.
Ijms 25 12850 g004
Ijms 25 12850 g005
Figure 5. Association between anticholinergic use and AD/dementia risk. In this category, antipsychotics pose a higher risk of AD/dementia in comparison to others. The graph was plotted using data reported by Coupland et al., 2024 [70].
Figure 5. Association between anticholinergic use and AD/dementia risk. In this category, antipsychotics pose a higher risk of AD/dementia in comparison to others. The graph was plotted using data reported by Coupland et al., 2024 [70].
Ijms 25 12850 g005
Ijms 25 12850 g006
Figure 6. Common effects, uses, and examples of benzodiazepines.
Figure 6. Common effects, uses, and examples of benzodiazepines.
Ijms 25 12850 g006
Ijms 25 12850 g007
Figure 7. Summary and structures of some common proton pump inhibitors.
Figure 7. Summary and structures of some common proton pump inhibitors.
Ijms 25 12850 g007
Ijms 25 12850 g008
Figure 8. Proton pump inhibitor pathways linked to AD risk.
Figure 8. Proton pump inhibitor pathways linked to AD risk.
Ijms 25 12850 g008
Ijms 25 12850 g009
Figure 9. Structures of some statins.
Figure 9. Structures of some statins.
Ijms 25 12850 g009
Ijms 25 12850 g010
Figure 10. Statin use reduces dementia and AD risk. The graph was plotted using data reported by Ren et al., 2024 [156].
Figure 10. Statin use reduces dementia and AD risk. The graph was plotted using data reported by Ren et al., 2024 [156].
Ijms 25 12850 g010
Table 1. A generalized view on medication use in adult (<60 years) and elderly (60+) groups.
Table 1. A generalized view on medication use in adult (<60 years) and elderly (60+) groups.
Medication TypeYoung Adults (%)Elderly
(%)		Ref.
Analgesics20–6070–85[11,12,13,14]
Anticholinergics20–2530–50[15,16]
Benzodiazepines5–1030–40[17,18]
Proton pump inhibitors2–535–50[19]
Statins15–2535–60[20,21,22]
Table 2. Drugs, their targets, protein expression, and location of these targets in different cells and tissues.
Table 2. Drugs, their targets, protein expression, and location of these targets in different cells and tissues.
DrugTarget1 Protein Expression
and Location		1 Tissue RNA Expression 1 Cell-Type RNA Expression
AnalgesicsCox 1 and 2, opioid receptors (μκ
Others (BACE1, PPARγ)		Cox1: Cytoplasmic expression at variable levels in several tissues, high expression in squamous epithelia, megakaryocytes, fallopian tube, brain, and subsets of cells in tissue stroma.
Localized to the Golgi apparatus, Vesicles		Tissue-enhanced (Intestine, Skin, Urinary bladder).
Skin—Cornification (mainly).
Low human brain regional specificity.
Macrophages and Microglia—Immune response (mainly)		Group-enriched (granulocytes, Glandular and luminal cells). Cell-type-enriched (Adrenal gland—Macrophages,
Heart muscle—Fibroblasts,
Skeletal muscle—Fibroblasts,
Skin—Keratinocyte (other),
Spleen—Platelets)
Cox 2: Cytoplasmic and membranous expression in selected tissues, including seminal vesicle, urinary bladder, and gall bladder.
Localized to the Vesicles, Cytosol		Tissue-enhanced
(Bone marrow, Seminal vesicle, Urinary bladder).
Tissue-enhanced
(Bone marrow, Seminal vesicle, Urinary bladder).
Low human brain regional specificity.
Neurons—Mixed function (mainly)		Group-enriched (Basal prostatic cells,
granulocytes,
Langerhans cells,
monocytes,
Macrophages,
Alveolar cells type 1). Cell-type-enriched (Heart muscle—Fibroblasts)
Opioid receptor μ: Membranous expression in seminiferous tubules. Soma, dendrite, axon, and synapse in neurons.Tissue-enhanced
(Brain, Testis).
Low human brain regional specificity.
Sub-cortical—Mixed function (mainly)		Cell-type-enhanced (Excitatory neurons,
Early spermatids,
Late spermatids,
Inhibitory neurons,
Microglial cells).
Cell-type-enriched (Adrenal gland—Adrenal medulla cells,
Testis—Early spermatids,
Testis—Late spermatids)
Opioid receptor κ: Cytoplasmic expression in CNS.
Localized to the Plasma membrane, Nucleoplasm,
Cytosol		Tissue-enhanced
(Brain, Prostate, Skeletal muscle),
Low human brain regional specificity,
Neurons—Mixed function (mainly)		Cell-type-enhanced (Prostatic glandular cells,
Inhibitory neurons,
Extravillous trophoblasts,
Glandular and luminal cells,
Excitatory neurons,
Leydig cells).
Cell-type-enriched (Colon—Colon enteroendocrine cells,
Minor Salivary Gland—Adipocytes (Minor salivary gland),
Prostate—Prostate glandular cells)
BACE1: Granular cytoplasmic expression in several tissues. Localized to the Plasma membraneGroup-enriched
(Brain, Pancreas).
Low human brain regional specificity.
White matter—Myelination (mainly)		Cell-type-enhanced (Late spermatids,
Cone photoreceptor cells,
Oligodendrocytes)
PPARγ: Cytoplasmic and nuclear expression in several tissues.
Localized to the Nucleoplasm, Vesicles		Tissue-enhanced
(Adipose tissue).
Low human brain regional specificity.
Neurons—Mixed function (mainly)		Cell-type-enhanced (Extravillous trophoblasts, Adipocytes,
Distal enterocytes,
Cytotrophoblasts,
Syncytiotrophoblasts)
AnticholinergicsmAChR (M1–M5)M1: Cytoplasmic expression in pyramidal neurons and Purkinje cells.
Soma, dendrite, and synapse in neurons.		Group-enriched
(Brain, Prostate, Salivary gland),
Group-enriched
(Amygdala, Basal ganglia, Cerebral cortex, Hippocampal formation, White matter), Neurons—Mixed function (mainly)		Cell-type-enriched (Prostatic glandular cells), Cell-type-enriched (Heart muscle—Cardiomyocytes,
Liver—Hepatic stellate cells,
Testis—Early spermatids, Testis—Late spermatids), Group-enriched
(Brain, Prostate, Salivary gland)
M2: Ubiquitous cytoplasmic expression in all tissues at variable levels.
Localized to the Plasma membrane, Nucleoli, Golgi apparatus, Primary cilium, Basal body		Tissue-enhanced
(Heart muscle, Intestine), Heart muscle—Heart development (mainly), Low human brain regional specificity,
Hindbrain—Mixed function (mainly)		Cell-type-enriched (Heart muscle—Cardiomyocytes, Liver—Hepatic stellate cells,
Testis—Early spermatids, Testis—Late spermatids) Group-enriched (Inhibitory neurons, Cardiomyocytes, Excitatory neurons)
M3: General cytoplasmic expression at variable levels.
Localized to the Plasma membrane		Tissue-enhanced (Salivary gland), Salivary gland—Salivary secretion (mainly) Low human brain regional specificity, Astrocytes—Astrocyte-neuron interactions (mainly)Cell-type-enriched (Heart muscle—Smooth muscle cells,
Minor Salivary Gland—Minor salivary glandular cells,
Skin—Eccrine sweat gland cells,
Thyroid gland—Endothelial cells),
Group-enriched (Excitatory neurons,
Inhibitory neurons)
M4: Cytoplasmic and membranous expression in several tissues, including the brain and intestines Localized to the Golgi apparatus and NucleoplasmTissue-enhanced
(Brain, Intestine, Lymphoid tissue), Human brain regional-enhanced (Basal ganglia), Neurons—Mixed function (mainly)		Cell-type-enriched (Colon—Colon enteroendocrine cells,
Skin—Keratinocyte (granular),
Testis—Early spermatids, Testis—Late spermatids)
M5: Tissue profile NA.
Membrane, Intracellular (different isoforms)		Tissue-enriched (Brain),
Low human brain regional specificity,
Oligodendrocytes—Mixed function (mainly)		Cell-type-enriched (Oligodendrocytes,
Testis—Early spermatids, Testis—Late spermatids)
BenzodiazepinesGABA-A receptorSelective expression in neuropil and subset of neurons, Localized to the Plasma membrane, Nucleoplasm,
Synapse in neurons		Group-enriched
(Brain, Retina)
Brain—Synaptic signal transduction (mainly)
Low human brain regional specificity
Neurons—Mixed function (mainly)		Cell-type-enriched (Adrenal gland—Adrenal medulla cells,
Stomach—Gastric enteroendocrine cells,
Testis—Early spermatids, Testis—Late spermatids)
Proton pump
inhibitors		 H/K-ATPaseMembranous expression in most tissues.
Localized to the Vesicles, Plasma membrane		Tissue-enhanced
(Parathyroid gland),
Parathyroid gland—Vesicular transport (mainly). Low human brain regional specificity,
Neurons and Synapses—Synaptic function (mainly)		Cell-type-enriched (Adrenal gland—Adrenal cortex cells,
Lung—Alveolar cells type 2,
Thyroid gland—Thyroid glandular cells)
StatinsHMG-CoA
reductase		Ubiquitous cytoplasmic expression.
Membrane, Intracellular (different isoforms)		Tissue-enhanced (Liver)
Liver and Intestine—Lipid metabolism (mainly);
Low human brain regional specificity.
Neurons—Mixed function		Cell-type-enriched (Adrenal gland—Adrenal cortex cells,
Lung—Alveolar cells type 2,
Minor Salivary Gland—Minor salivary gland basal cells)
BACE: β-secretase; COX: cyclooxygenase; GABA: γ-aminobutyric acid; H/K-ATPase: hydrogen-potassium adenosine triphosphatase; HMG CoA reductase: 3-hydroxy-3-methylglutaryl coenzyme A; mAChR: muscarinic acetylcholine receptors; PPARγ: peroxisome proliferator-activated receptor gamma. 1 The Human Protein Atlas.
Table 3. Association between use of analgesics and AD/dementia risk.
Table 3. Association between use of analgesics and AD/dementia risk.
StudyPopulation SampleAnalgesic TypeAD/Dementia Risk FactorStatisticsRef.
Prospective Study—UK Biobank n = 194,758
(aged ≥ 60)		Aspirin, Paracetamol,
2–3 NSAIDs		Frequent use of paracetamol, as opposed to ibuprofen, was linked to a notably increased likelihood of developing dementia in elderly Aspirin HR: 1.12 (CI: 1.01–1.24, p < 0.05)
Paracetamol HR: 1.15 (CI:1.05–1.27, p < 0.01)
2–3 NSAIDs HR: 1.2 (CI:1.08–1.33, p < 0.05)		[35]
Prospective national cohort study—Israeln = 91,307
(aged ≥ 60)		OpioidsLinked with an increased dementia riskaHR = 1.39, 95% CI = 1.01–1.92, p < 0.05 in opioid exposed group aged 75+ yrs[41]
Community-based cohort—West King County, USn = 3392
(aged ≥ 65)		NSAIDsHeavy NSAID users had increased incidence of dementia and ADDementia: aHR 1.66 95% CI: 1.24–2.24
AD: aHR:1.57 95% CI: 1.10–2.23		[44]
Population Cohort Study-
Korean patients 		n = 1,261,682OpioidsIncreased AD and dementia riskDementia: 15%;
AD: 15%;
Unspecified Dementia: 16%		[40]
Longitudinal Study—Baltimore n = 1686 NSAIDsNo association was found between AD risk and use of acetaminophen
AD risk decreased with increasing duration of NSAID use 		RR = 1.35; 95% CI: 0.79–2.30
2 or more years NSAID use, RR:0.40 95% CI: 0.19–0.84; less than 2 years RR: 0.65 95% CI: 0.33–1.29		[50]
Population-based
autopsy cohort—ACT Study		n = 257 NSAIDsIncreased dementia risk1000–2000 SDD [RR] 2.16, 95% [CI] 1.02–4.25;
>2000 SDD [aRR] 2.37, 95% CI 1.24–4.67		[45]
Nested Case–Control Study
UK Biobank 		n = 500,000
(age 40–69 yrs)		OpioidsIncreased dementia risk
Risk increased with more opioid prescriptions		OR (1–5 prescriptions): 1.21 (CI: 1.07–1.37, p: 0.003);
OR (6–20 prescriptions): 1.27 (CI: 1.08–1.50, p: 0.003);
OR (>20 prescriptions): 1.43 (CI: 1.23–1.67, p < 0.001)		[43]
Community-based autopsy cohort—ACT Studyn = 420Opioids
NSAIDs		The use of prescription opioids does not have a connection with dementia-related neuropathological alterations, although frequent use of NSAIDs may be linkedFor neuritic plaques, the aRR [95% CI] was 0.99 [0.64–1.47] for 91+ TSDDs of opioids;
heavy NSAID use had a higher risk of neuritic plaques (RR 1.39 [1.01–1.89]) 		[46]
Systematic Review and Meta-Analysis
(6 cohort; 3 case–controls)		n = 13,211 (cohorts)
n = 1443 (case–controls)
(age > 55 yrs)		NSAIDsDecreased AD riskPooled RR for AD:0.72 95% CI: 0.56–0.94
(<1 month)
RR: 0.95 CI: 0.70–1.29;
(<24 months)
RR:0.83 CI: 0.65–1.06;
(>24 months) RR: 0.27 CI: 0.13–0.58		[52]
Systematic Review and Meta-Analysis (17 epidemiological studies from 8 countries—US, Australia, Canada, China, Finland, Italy, Netherlands, UK) NSAIDsDecreased AD riskCombined OR: 0.55, p < 0.0001 [49]
A Finnish nationwide nested case–control study MEDALZ n = 70,718
(mean age 80 yrs)		OpioidsNo increased AD risk even for longer duration or higher doseaOR: 1.00 95% CI: 0.98–1.03
cumulative use for >365 days: aOR = 1.02, 95% CI = 0.96–1.08
>90 TSDs: aOR = 1.02, 95% CI = 0.98–1.07		[56]
Meta-analysis (16 cohort studies) n = 236,022NSAIDsReduced AD riskGlobal RR: 0.81 CI: 0.70–0.94;
Europe: RR: 0.72; Asia: no association		[57]
Prospective Cohort Study-Northwest USn = 3434 (median age 74 yrs)NSAIDs
Opioids		Individuals who had high levels of opioid or NSAID consumption were found to have a slightly elevated risk of dementia compared to those with minimal or no usageCumulative opioid use: HRs for dementia: 1.06 95% CI = 0.88–1.26
for 11 to 30 TSDs; HR: 0.88 (95% CI = 0.70–1.09) for 31 to 90 TSDs; and
HR:1.29 (95% CI = 1.02–1.62) for 91 or more TSDs. A similar pattern was seen for NSAID use		[55]
Clinical trial
double-blind, placebo-controlled study—Northwest Phoenix metropolitan area		n = 44NSAID (indomethacin)Protective against cognitive decline in mild to moderately impaired ADImproved cognitive tests p < 0.003 [51]
Prospective, population-based cohort study—Rotterdam, Netherlands n = 6989
(age ≥ 50)		NSAIDsNo association with a reduction in the risk of VDAD: RR: 0.95 95% CI: 0.70–1.29 (short-term use);
RR: 0.83 95% CI: 0.62–1.11 (intermediate-term use); and
RR:0.20 95% CI: 0.05–0.83 (long-term use) 		[58]
AD: Alzheimer’s disease; aHR: Adjusted hazard ratio; aOR: Adjusted odds ratio; aRR: Adjusted risk ratio; CI: confidence interval; HR: Hazard ratio; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs; RR: Risk ratio; OR: Odds ratio; SDDs: Standard daily doses; TSD: Total standardized daily dose; VD: Vascular dementia.
Table 4. Association between anticholinergics use and AD/dementia risk.
Table 4. Association between anticholinergics use and AD/dementia risk.
Study TypePopulation SampleEffect on Dementia/AD RiskStatistical DataRef.
German Cohort Studyn = 2605,
(age > 75 ± 4.5 yrs)		Increased risk of dementiaDementia: HR: 2.08;
AD: HR: 1.63		[66]
UK Case–control study n = 40,770
(age ≥ 65 yrs)		Dementia was associated with an increasing average ACB scoreaOR for any anticholinergic drug with an ACB score of 3 was 1.11 (95% confidence interval 1.08 to 1.14)[67]
Population-based Cohort Study—
South Korea 		n = 550,000
(age ≥ 60 yrs)		AD risk was higher in subjects with an increased number of prescriptionsHR (95% confidence interval (95% CI)) 0.99 (0.95–1.03), 1.19 (1.12–1.26), 1.39 (1.30–1.50); in the 10–49 doses/year, 50–119 doses/year, and ≥120 doses/year groups
HR higher in the young-old subgroup (60–64 years old)
[HR (95% CI) 1.11 (1.04–1.22), 1.43 (1.25–1.65), 1.83 (1.56–2.14); in the 10–49 doses/year, 50–119 doses/year, and ≥120 doses/year groups		[68]
Nested Case–Control Study—UKn = 284,343Higher dementia riskAntidepressants: aOR, 1.29; 95% CI, 1.24–1.34,
Anti-Parkinson’s drugs: aOR, 1.52; 95% CI, 1.16–2.00,
Antipsychotics: aOR, 1.70; 95% CI, 1.53–1.90,
Bladder antimuscarinic drugs: aOR, 1.65; 95% CI, 1.56–1.75, and
Antiepileptic drugs: aOR, 1.39; 95% CI, 1.22–1.57
all for more than 1095 TSDDs		[70]
Population-based cohort recruited from 3 French citiesn = 6912
(age > 65 yrs)		Increased risk of cognitive decline and dementiaHR: 1.65; 95% CI, 1.00–2.73[65]
Systematic Review and Meta-Analysis
(France, UK, Germany, US, Nigeria, Turkey, Netherlands, China, Taiwan)		n = 1,564,18Increased risk of ACD and AD (anti-Parkinson’s, urological, antidepressants)
Negative association with dementia (anticholinergic cardiovascular and gastrointestinal drugs)
No association (antipsychotic, analgesic, and respiratory anticholinergic)		Anti-Parkinson’s (RR = 1.39, 95% CI: 1.26–1.53, I2 = 0, 95% CI: 0–90%, p = 0.504), Urological drugs (RR = 1.27, 95% CI: 1.12–1.44, I2 = 94.4%, 95% CI: 87%–98%, p < 0.001), and
Antidepressants (RR = 1.19, 95% CI: 1.15–1.22, I2 = 52.6%, 95% CI: 0–83%, p = 0.077).
Anticholinergic cardiovascular (RR = 0.97, 95% CI: 0.95−0.996, I2 = 0, 95% CI: 0–90%, p = 0.721)
Gastrointestinal (RR = 0.95, 95% CI: 0.91−0.99, I2 = 48.1%, 95% CI: 0–85%, p = 0.146)		[72]
Population-Based Study—
Italy		n = 750,
(age > 65 yrs)		Cognitive impairmentOR: 3.18 95% CI: 1.93–5.23, p < 0.001[73]
ADNI cohortn = 688
(mean age 73.5 yrs)		Increased dementia riskHR:1.47, p = 0.02[75]
Prospective and retrospective longitudinal cohort and case–control observational studiesn = 968,428
(age ≥ 65 yrs)		Increased risk of cognitive decline or dementiaOR 1.47, 95% CI 1.09 to 1.96[76]
Longitudinal Study—England and Walesn = 13,004
(age ≥ 65 yrs)		Increased cumulative risk of cognitive impairment and mortalityA decline in MMSE score (95% confidence interval (CI) = 0.03–0.64, p = 0.03)[61]
A Nationwide 15-Year Follow-Up Cohort Study—Taiwann = 790,240
(age > 65 yrs)		No significant associationHR: 1.043 (95% CI: 0.958–1.212, p = 0.139)[83]
Retrospective cohort study used the Humana Research Database n = 12,209Increase AD and dementia risk1.6 (95% CI 1.4–1.9),
2.1 (95% CI 1.7–2.8),
2.6 (95% CI 1.5–4.4), and
2.6 (95% CI 1.1–6.3) times
increased risk		[80]
UK Biobank Cohort studyn = 171,775Increase dementia riskHR: 1.094; 95% CI: 1.068–1.119[79]
Prospective cohort study conducted within Kaiser Permanente Washington (KPWA)n = 3059Increase AD and dementia risk0–90 TSDDs: HR = 1.69, 95% CI = 1.18–2.42;
91–365 TSDDs: HR = 1.40, 95% CI = 0.88–2.23; 366–1095 TSDDs: HR = 2.13, 95% CI = 1.32–3.43;
≥1095 TSDDs: HR = 1.42, 95% CI = 0.82–2.46		[77]
Nationwide 12-year cohort study—Taiwann = 16,412
(age > 50 yrs)		Bladder anticholinergics
increased dementia risk		Dementia aHR 1.15 (95% CI = 0.97–1.37) in the 85–336 cDDD group,
and 1.40 (95% CI = 1.12–1.75) in the ≥337 cDDD group		[78]
Randomly selected community-based n = 2058
(age 60–64 yrs)		Anticholinergic medication is associated with lower level of complex attention in the young-old, but not with greater cognitive decline over time [84]
Prospective cohort study—Seattle, Washingtonn = 3434
(age ≥ 65 yrs)		Increased risk for
dementia		aHR: 0.92 (95% CI, 0.74–1.16)
for TSDDs of 1 to 90;
aHR:1.19 (95% CI, 0.94–1.51)
for TSDDs of 91 to 365;
aHR:1.23 (95% CI, 0.94–1.62)
for TSDDs of 366 to 1095; and
aHR: 1.54 (95% CI, 1.21–1.96)
for TSDDs greater than 1095.
A similar pattern for AD		[63]
Longitudinal cohort study—Montpellier region of southern Francen = 372
(age > 60 yrs)		Significant cognitive functioning impairments and high chances of being categorized as MCI impaired, with no higher risk of dementiaOR: 5.12, p = 0.001[64]
Population-based prospective study—Malmo, Swedenn = 18,063 (mean age 68.2 yrs)β-blockers not associated with increased risk ACD, AD, and mixed dementiaACD:HR:1.15; 95% CI 0.80–1.66; p = 0.44; AD:HR:0.85; 95%CI 0.48–1.54; p = 0.59 and Mixed dementia: HR:1.35; 95%CI 0.56–3.27; p = 0.50[86]
Longitudinal cohort study—Netherlandsn = 133,355AHM, ARBs, CCBs, and Ang-II-stimulating AHM were associated with lower dementia riskARBs [HR = 0.86 (95% CI = 0.80–0.92)], β-blockers [HR = 0.81 (95% CI = 0.75–0.87)],
CCBs [HR = 0.77 (95% CI = 0.71–0.84)], and diuretics [HR = 0.65 (95% CI = 0.61–0.70)] were associated with significantly lower dementia risks;
β-blockers [HR = 1.21 (95% CI = 1.15–1.27)] and
diuretics [HR = 1.69 (95% CI = 1.60–1.78)] were associated with higher,
CCBs with similar, and
ARBs with lower [HR = 0.83 (95% CI = 0.80–0.87)] mortality risk.
Dementia [HR = 0.88 (95% CI = 0.82–0.95)] and mortality risk [HR = 0.86 (95% CI = 0.82–0.91)] were lower for Ang-II-stimulating drugs		[87]
Danish Population-based study n = 69,081
(median age 64.4 yrs)		Highly permeable β-blockers protect against AD by promoting waste brain metabolite clearance.−0.45%, p < 0.036[88]
AD: Alzheimer’s disease; ACB: Anticholinergic cognitive burden; aHR: Adjusted hazard ratio; aOR: Adjusted odds ratio; ACD: All-cause dementia; cDDD: Cumulative defined daily dose; AHM: Antihypertensive medication; ANG-II: Angiotensin-II-receptor; ARBs: Angiotensin receptor blockers; CCBs: Calcium channel blockers; CI: confidence interval; HR: Hazard ratio; RR: Risk ratio; MCI: Mild cognitive decline; OR: Odds ratio; TSDDs: Total standardized daily doses.
Table 5. Association between benzodiazepine use and AD/dementia risk.
Table 5. Association between benzodiazepine use and AD/dementia risk.
Study TypePopulation SampleEffect on Dementia/AD RiskStatistical DataRef.
Meta-Analysisn = 45,391Long-term BZD users are at a higher risk of developing dementia in comparison to those who have never used the medicationRR: 1.49,95% CI: 1.30–1.72) forever user,
RR:1.55 (95% CI 1.31–1.83) for recent users, and
RR:1.55 (95% CI 1.17–2.03) for past users.		[101]
Longitudinal Studyn = 668
(aged ≥ 75)		Significantly lower incidence of AD in the BDZ+ group [110]
Population-based Study
German population		n = 105,725
(aged ≥ 60)		Increased dementia riskOR: 1.21 (95% CI: 1.13–1.29, p < 0.001)[97]
Three-city French population-based studyaged ≥ 65 yrsLinked to lower cognitive ability but not to faster cognitive deterioration as one agesChronic use significantly associated with a lower latent cognitive level (β = −1.79 SE = 0.25 p ≤ 0.001)
no association was found between chronic use and an acceleration of cognitive decline, (β × time = 0.010 SE = 0.04 p = 0.81),		[102]
Retrospective Cohort Study—USn = 528,006
(aged ≥ 65 yrs)		Slightly raised the risk of dementia compared to not using them, but the risk did not significantly increase with higher exposure levels.aHR: 1.06 (95% CI: 1.02–1.10) for low BZD exposure,
1.05 (95% CI 1.01–1.09) for medium BZD exposure, and
1.05 (95% CI 1.02–1.09) for high BZD exposure.		[109]
Umbrella Review of Meta-Analyses (5) and systematic review (15) Weak evidence of dementia linkaRR: 1.06 (low users),
1.05 (medium users),
1.05 (high users)		[108]
Case–control study
Canadian population		n = 38,741
(age ≥ 65 yrs)		Increased risk of ADaOR: 1.51, 95% CI: 1.36 to 1.69;[94]
A Systematic Review and Meta-Analysis (Asian, North American, European population) Increased risk of dementiaHigher association in Asian (OR 2.40; 95% CI 1.66–3.47); moderate association in North American
(OR 1.49; 95% CI 1.34–1.65) and
In European (OR 1.43; 95% CI 1.16–1.75)		[95]
Matched cohort study
Finnish population		n = 70,718Increased risk of deathaHR = 1.4, 95% CI: 1.2–1.6[96]
A Systematic Review and Meta-Analysisn = 981,133 (in the systematic review) and n = 980,860 (in the meta-analysis)Can be a risk factor for developing dementiaOR: 1.38, 95% CI: l 1.07–1.77[98]
A Systematic Review and Meta-Analysisn = 159,090Increase dementia riskOR: 1.39, 95%, CI: 1.21–1.59[99]
Case–Control Study Swiss populationn = 2876
(Mean age 80 ± 7.5 yrs)		No association with increased AD riskLong-term benzodiazepine use (≥30 prescriptions) aOR: 0.78 (0.53–1.14).[105]
UK-based case–control analysisn = 26,459
(aged ≥ 65 yrs)		No association with increased AD or VD riskAD: aOR: 0.69 (0.57–0.85) or VD: aOR: 1.11 (0.85–1.45).[106]
Analytical prospective nested case–control study Spanish populationn = 77,609Increased AD riskOR = 1.05, 95% CI: 1.01–1.10[107]
AD: Alzheimer’s disease; aHR: Adjusted hazard ratio; aOR: Adjusted odds ratio; aRR: Adjusted risk ratio; CI: confidence interval; HR: Hazard ratio; RR: Risk ratio; OR: Odds ratio; VD: Vascular dementia.
Table 6. Association between PPI use and AD/dementia risk.
Table 6. Association between PPI use and AD/dementia risk.
Study TypePopulation SampleEffect on Dementia/AD RiskStatistical DataRef.
Prospective cohort study—Germanyn = 73,679 (aged ≥ 75 yrs)Increased dementia riskHR: 1.44, 95% CI: 1.36–1.52;
p < 0.001		[120]
Prospective cohort study—US n = 3484
(aged ≥ 65 yrs)		Not associated with dementia risk, even for people with high cumulative exposureDementia (p = 0.66)
AD (p = 0.77)		[134]
Retrospective study—
Veteran population, US		n = 23,656Significant associationOR: 1.55[121]
Nationwide cohort study—Taiwann = 1,000,000
(aged ≥ 65 yrs)		Increased dementia riskaHR: 1.42; 95% CI, 1.07–1.84[122]
Meta-Analysisn = 642,305 No significant AD or
dementia risk		Dementia: HR: 1.04 (95% CI: 0.92–1.15)
AD: HR: 0.96 (95% CI: 0.83–1.09 p < 0.001)		[10]
Longitudinal, multicenter cohort study—
Germany		n = 3327
(aged ≥ 75 yrs)		Increased risk of dementia and ADDementia: HR: 1.38 (95% CI: 1.04–1.83)
AD: HR: 1.44 (95% CI: 1.01–2.06)		[123]
Comprehensive Review (8 systematic reviews, 1 clinical trial, 15 observational studies, 3 case–control studies, and 1 cross-sectional observational study) No link to cognitive decline or dementia [136]
A Nationwide Cohort Study—Taiwann = 15,726 (aged ≥ 40 yrs)Increased dementia riskaHR: 1.22; 95% CI: 1.05–1.42[125]
Finnish Nationwide nested case–control studyn = 282,858No clinically meaningful association between PPI use and the risk of AD
Higher dose was not associated with an increased risk 		1–3 years of use: aOR: 1.01, 95% CI: 0.97–1.06;
≥3 years OR: 0.99, 95% CI: 0.94–1.04.
≥1.5 defined daily doses: aOR: 1.03, 95% CI: 0.92–1.14		[130]
Observational, longitudinal studyn = 12,416 (aged ≥ 50 yrs)Not associated with a greater risk of dementia or ADDecline in cognitive function HR = 0.78, 95% CI = 0.66–0.93, p = 0.005
Conversion to MCI or AD (HR = 0.82, 95% CI = 0.69–0.98, p = 0.03).
Intermittent use was also associated with a lower risk of decline in cognitive function (HR = 0.84, 95% CI = 0.76–0.93, p = 0.001) and risk of conversion to MCI or AD (HR = 0.82, 95% CI = 0.74–0.91, p = 0.001)		[131]
Population-based study—UKn = 3,765,744 (aged ≥ 55 yrs)PPI use was associated with decreased dementia riskHR: 0.67, 95% CI: 0.65–0.67, p < 0.01.[132]
A systematic review, meta-analysis, and bias analysis from 9 observational cohortsn = 3,302,778 No clear evidence Dementia: RR: 1.15 (95% CI  =  1.00–1.31);
AD: RR: 1.13 (95% CI  =  0.93–1.38)		[133]
Community-based retrospective cohortsn = 135,722
(aged ≥ 45 yrs)		AD was not higher among PPI users, and a slight increase in the risk of non-AD dementia was observedAD: OR: 1.47; 95% CI: 1.18–1.83
non-AD dementias OR: 1.38; 95% CI: 1.12–1.70		[135]
Meta-analysis
location (European, North American, Asian) 		n = 1,251,562
(mean age ≥ 70 yrs)		No association foundHR = 0.98, 95% CI: 0.85–1.13[137]
Large placebo-controlled randomized trialn = 17,598
(mean age ≥ 65 yrs)		No negative effects related to the use of pantoprazole over 3 years, except for a potentially higher chance of contracting enteric infectionsOR: 1.15; 95% CI: 0.89–1.50; p = 0.28[138]
AD: Alzheimer’s disease; aHR: Adjusted hazard ratio; CI: confidence interval; HR: Hazard ratio; RR: Risk ratio; SHR: Sub-distribution hazard ratio; MCI: Mild cognitive impairment; OR: Odds ratio.
Table 7. Association between statin use and AD/dementia risk.
Table 7. Association between statin use and AD/dementia risk.
Study TypePopulation SampleEffect on Dementia/AD RiskStatistical DataRef.
Time-varying status of statin use along with the dose–response relationship
Korean population		n = 119,013
(≥60 years old)
Statin users duration < 540 days		Short-term use linked to increased AD risk; consistent use decreased AD riskaHR = 1.04; 95%, CI = [0.99–1.10].
Having at least 540 days of statin prescription and a cumulative defined daily dose of at least 540 were linked to a reduced risk of AD [aHR (95% CI) = 0.87 (0.80–0.95) and 0.79 (0.68–0.92), respectively].		[150]
Meta-Analysis (30 studies)n = 9,162,509Statin use is associated with reduced risks of dementia, AD, and vascular dementia (VD)Dementia risk: RR:0.83, 95% CI: 0.79–0.87
AD risk: RR: 0.69, 95% CI: 0.60–0.80, p < 0. 0001),
VD risk: RR: 0.93, 95% CI: 0.74–1.16, p = 0.54).		[151]
Systematic review of randomized clinical trials (3) and observational studies (21)n = 1,404,459 (aged ≥ 60 yrs)No adverse cognitive effectsOR: 1.03 [0.82–1.30] and
OR: 1.0 [0.61–1.65]		[152]
Nationwide Cohort Study
Taiwan		n = 33,398 (aged ≥ 60 yrs)Reduction in dementia risk in older adultsDementia: ([HR], 0.78; 95% CI, 0.72–0.85, p < 0.001).[155]
Population-based study—Rotterdam n = 6992Reduction in dementia risk for both lipophilic and hydrophilic statinsAD: HR: 0.57; 95% CI: 0.37–0.90),
HRs were equal for lipophilic (HR: 0.54; 95% CI: 0.32- 0.89) and hydrophilic statins (HR: 0.54; 95% CI: 0.26–1.11).		[151]
A cohort of older patients receiving polypharmacyn = 29,047 patients exposed to polypharmacy (mean age 76 yrs)Stopping statins while continuing other medications led to a rise in the long-term chances of experiencing cardiovascular events, both fatal and nonfatalIn contrast to those who continued the medication, patients who stopped taking it had a higher risk of hospitalizations due to heart failure (HR: 1.24; 95% CI: 1.07–1.43) and any cardiovascular events (HR: 1.14; 95% CI: 1.03–1.26), as well as all-cause mortality (HR: 1.15; 95% CI: 1.02–1.30) and emergency admissions for any reason (HR: 1.12; 95% CI: 1.05–1.19).[159]
Population-based retrospective cohort study—Hong Kongn = 104,295 (mean age 74.2 ± 13.6 yrs)Reduced AD, VD, and dementia riskDementia: (multivariable-adjusted SHR 0.80, 95% CI 0.76–0.84,
AD: (SHR 0.72, 95% CI 0.63–0.82), VD: (SHR 0.82, 95% CI 0.70–0.95), unspecified dementia: (SHR 0.80, 95% CI 0.75–0.85).		[160]
Nationwide Prospective cohort study—
Danish population		n = 674,900 (age > 40 yr)Increased CVD riskDuring follow-up, the Hazard ratios for individuals with vs. without early statin discontinuation were 1.26 (1.21–1.30) for myocardial infarction and 1.18 (1.14–1.23) for death from cardiovascular disease.[142]
Systematic review
(60 case reports)		Mean age 62 yrsConflicting results [141]
Community-based prospective cohort studyn = 2356
(age > 65 yrs)		No significant associationACD: HR:1.33, 95% CI: 0.95–1.85 AD: HR: 0.90, CI: 0.54–1.51
An analysis of a specific subset of participants who had at least one APOE-ε4 allele and joined the study before age 80 revealed aHR: of 0.33, CI: 0.10–1.04.		[143]
AD: Alzheimer’s disease; aHR: Adjusted hazard ratio; ACD: awareness of cognitive decline; CI: confidence interval; CVD: Cardiovascular disease; HR: Hazard ratio; RR: Risk ratio; SHR: Sub-distribution hazard ratio; OR: Odds ratio; VD: Vascular dementia.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Sharma, N.; An, S.S.A.; Kim, S.Y. Medication Exposure and Risk of Dementia and Alzheimer’s Disease. Int. J. Mol. Sci. 2024, 25, 12850. https://doi.org/10.3390/ijms252312850

AMA Style

Sharma N, An SSA, Kim SY. Medication Exposure and Risk of Dementia and Alzheimer’s Disease. International Journal of Molecular Sciences. 2024; 25(23):12850. https://doi.org/10.3390/ijms252312850

Chicago/Turabian Style

Sharma, Niti, Seong Soo A. An, and Sang Yun Kim. 2024. "Medication Exposure and Risk of Dementia and Alzheimer’s Disease" International Journal of Molecular Sciences 25, no. 23: 12850. https://doi.org/10.3390/ijms252312850

APA Style

Sharma, N., An, S. S. A., & Kim, S. Y. (2024). Medication Exposure and Risk of Dementia and Alzheimer’s Disease. International Journal of Molecular Sciences, 25(23), 12850. https://doi.org/10.3390/ijms252312850

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop