*4.4. Evidence in AD Patients*

Numerous works have studied ABCA7 as a risk gene in patients with mild cognitive impairment (MCI), or in AD individuals. All these studies are summarized elsewhere [57], and Table 1 gives an overview of AD-associated ABCA7 (epi-) genetic variation. Recently, an analysis of cerebrospinal fluid (CSF) from AD patients bearing the protective rs3764650 allele reported a decrease of CSF Aβ1-42 although total tau and phosphorylated tau levels remained unchanged [63]. Another recent study investigating genetic associations correlating with Aβ deposition found a strong association with ABCA7 among 1600 investigated genes [88]. These observations confirmed the link between ABCA7 and Aβ peptides in

humans but do not explain if this is mainly due to a decrease in Aβ production, or an increase of the clearance mediated by microglia across the BBB. A recent and elegant study from Lyssenko et al. investigated ABCA7 protein level in different Braak stages in AD patients and controls [23]. They observed that patients with low levels of ABCA7 are more prone to develop early AD than patients with the highest ABCA7 levels. Therefore, authors suggested that ABCA7 acts like a blocker of AD in the early stage of disease, particularly by removing toxic lipids from cellular membranes. As largely demonstrated now, lipid composition of cellular membranes can influence secretase activities and then APP processing and Aβ synthesis [89], therefore it might be hypothesized that ABCA7 levels and functioning can directly modulate APP processing and then, Aβ production. Another recent study performed in the frame of the Alzheimer's Disease Neuroimaging Initiative (ADNI) suggests also that ABCA7 acts very early in amyloid deposition [76]. Authors analyzed 18F-florbetapir positron emission tomographic data from 322 cognitively normal control individuals, 496 patients with mild cognitive impairment (MCI), and 159 individuals with AD. These results were compared with genetic data obtained in GWAS. They clearly observed that several AD risk variants of ABCA7 are highly associated with increased amyloid deposition, in particular in the cognitively healthy and MCI populations, but not in AD patients [76].

However, the impact of these variants on ABCA7 expression is still unclear since some studies report that deleterious alleles such as rs4147929 downregulates ABCA7 expression in AD patients [57], whereas other studies report contradictory results [58]. Studies investigating the association between rs3764650 and ABCA7 expression also reported inconsistent findings [65,90]. Therefore, there is a need of further studies that should address how ABCA7 is regulated and how this transporter is involved in brain functioning as well in Aβ peptide clearance or deposition in AD brains. Use of iPSCs cells from patients bearing SNPs of ABCA7 should open new avenues for investigating this transporter in AD. These cells can be differentiated into neurons to investigate not only neurogenesis but also Aβ production. It would be also possible to generate in vitro models of the BBB [91] or microglial cells [92] to further study Aβ clearance from CNS, and therefore to gain insight into the molecular role of ABCA7 in AD.
