**1. Introduction: Human Brain Aging and Inositols**

The aging process in humans is associated with physical decline and impairment of metabolic homeostasis [1]. The dysregulation of the metabolic network leads to an age-related elevated risk of suffering from chronic metabolic disorders, especially insulin resistance-related pathologies. In addition to the well-known peripheral role of insulin on glucose and energy storage, insulin also regulates a series of cognitive processes, such as memory formation, through its effects on glial–neuronal metabolic coupling. Central insulin resistance is a common feature linked to premature aging and is observed in neurological disorders, including early stages of Alzheimer's disease (AD) and Down's syndrome (DS) [2].

Currently, 16% of the EU population is over 65, and this figure is expected to rise to 25% by 2030. Taking this trend into consideration and the prevalence of dementia, including AD, the World Health Organization estimates that population aging will lead to a dramatic increase in dementia prevalence. By 2050, more than 131.5 million people are expected to be affected. AD leads to a loss of memory and neurodegenerative cognitive functions and affects 10% of the population aged over 65 years. Delaying a cognitive decline in AD is a major research challenge and a clinical need, considering the incidence of this disease in the elderly. Common features of AD are the aggregation of β-amyloid (Aβ) plaques and tau protein hyperphosphorylation, leading to neural damage. An approach for slowing down the progress of the disease is targeting the factors that might accelerate neural damage. Present results suggest that unhealthy dietary habits, microbiota changes, and oxidative stress favor the development of brain insulin resistance, which could contribute to a neuroinflammatory profile, directly activating both the resident immune cells of the brain (microglia) and astrocytes, promoting an adverse environment for neuronal survival in the context of AD [3,4]. Accordingly, a more detailed in-depth analysis of central insulin resistance contribution to cognitive impairment is discussed later in this review. A relevant issue on the clinical approach to AD and related pathologies that lead to cognitive impairment is the fact that most of the research efforts on therapeutics have focused on either fighting the symptoms by boosting certain deteriorated transmission pathways (e.g., anti-acetylcholinesterase drugs to enhance cholinergic transmission) or reducing Aβ load via immunotherapy. However, there is a clear lack of therapeutic development designed to restore metabolic impairments associated with these neurodegenerative disorders.

The lack of a "metabolic approach to AD therapeutics" might offer an opportunity to inositols, since in the past years they have gained close attention regarding treatment of pathologies associated with altered insulin signaling. Inositols are sugar-like cyclic alcohols constituent of cells, which are normally incorporated as part of the human diet. Given their structure, there are at least eight isomers of inositols that occur in nature (*myo-*, *muco-*, *neo-*, *scyllo-*, l*-chiro-*, d*-chiro-*, *epi-*, and *allo-*inositol) and one non-occurring in nature (*cis-*inositol) (Figure 1A) [5]. Inositols act as second messengers of the insulin-signaling pathway and their administration exerts insulin-sensitizing and mimetic effects, lowering blood glucose and promoting hepatic glycogen synthesis. d-chiro-inositol has been widely used as a treatment for pathologies associated with insulin resistance, e.g., polycystic ovary syndrome (PCOS) and diabetes [6,7]. Given their polar structure, other inositols show different properties, such as scyllo-inositol, which stabilizes soluble Aβ oligomers and is being tested under clinical trials as a promising therapy for AD [8]. The use of inositols for medical purposes is closely related to their "nutraceutical" nature, although the definition of the term is still debated. Since inositols are acquired through the diet, inositol extracts can be considered a nutraceutical under the definition of an isolated or purified product from natural sources, with specific health benefits against diseases or medical conditions or a protective effect against chronic diseases. Hence, these natural compounds arise as alternatives to treatments for central and peripheral insulin resistance-related disorders.

In the present review, we provide a short description of the structure and pharmacology of inositols. However, it is not the scope of this review to describe the particular chemical characteristics of inositols or to compile their application for metabolic disorders in peripheral tissues, since several works have already elegantly described these concepts previously [5,9–11]. The further sections herein try to establish a descriptive line, detailing the importance of inositols and their derivatives, such as inositol-(phospho)glycans (IPGs or simply IGs) in physiological processes, highlighting their role in insulin signaling, as well as their function in the central nervous system and the perspective of their use in the treatment of neurodegenerative diseases, with a special emphasis on AD and behavioral disorders here.

**Figure 1.** Structure in the chair conformation of inositol stereoisomers (**A**), inositol methyl derivatives (**B**), natural and synthetic inositol phosphoglycan cores, and insulin-mimicking inositol phosphoglycans (**C**). Glycophosphatidyl inositol phospholipase D (GPI-PLC) hydrolyzes phosphate inositol-lipid linkage, releasing unphosphorylated inositol. Phosphatidylinositol phospholipase C (PI-PLC) hydrolyzes phosphate inositol-lipid linkage in <sup>α</sup>(1→6) myo-inositol (but not <sup>α</sup>(1→2) <sup>d</sup>-chiro-inositol) structures when the C2 position is not occupied by an acyl-lipid chain, promoting cyclic (1,2) phosphate linkage to myo-inositol.
