Lessons from genetic studies in Alzheimer disease

Rev Neurol (Paris). 2024 Feb 29:S0035-3787(24)00290-X. doi: 10.1016/j.neurol.2023.12.006. Online ahead of print.ABSTRACTResearch on Alzheimer disease (AD) genetics has provided critical advances to the knowledge of AD pathophysiological mechanisms. The etiology of AD can be divided into monogenic (autosomal dominant inheritance) and complex (multifactorial determinism). In monogenic AD, recent advances mainly concern mutation-associated mechanisms, presymptomatic clinical studies, and the search for modifiers of ages of onset that are still ongoing. In complex AD, genetic factors can be further categorized into three classes: (i) the APOE-ɛ4 and ɛ2 common alleles that represent a category by themselves as they are both common and with a strong impact on AD risk; (ii) common variants with a modest effect, identified in genome-wide association studies (GWAS); and (iii) rare variants with a moderate-to-strong effect, identified in case-control sequencing studies. Regarding APOE, odds ratios, available in multiple ethnicities, can now be converted into penetrance curves, although such curves remain to be performed in diverse ethnicities. In addition, advances in the understanding of mechanisms have been recently reported and rare APOE variants add to the complexity. In the GWAS category, novel loci have been discovered thanks to larger studies, doubling the number of hits as compared to the previous reference meta-analysis. However, such modest risk factors cannot be used in th...
Source: Revue Neurologique - Category: Neurology Authors: Source Type: research