Lessons from genetic studies in Alzheimer disease

Research 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 the clinic, neither individually, nor in genetic risk scores. In the category of rare variants, two novel genes, ABCA1 and ATP8B4 now add to the three main ones, TREM2, SORL1, and ABCA7. The study of such rare variants suggests oligogenic inheritance in some families, as also suggested by digenic penetrance curves for SORL1 loss-of-function variants with APOE-ɛ4. Cumulate frequencies of definite (so-called) rare risk factors are 2.3% to 3.6% (depending on thresholds on odds ratios) in control databases and many more remain to be classified and identified, showing how important these risk factors may be as part of the complex determinism of AD. A better understanding of these rare risk factors and their combined effects on each other, with common variants, and with environmental factors, should allow for a prediction of AD risk and, eventually, preventive medicine. Taken together, most genetic determinants of AD, in monogenic and in complex forms, point toward the aggregation of Aβ as a pivotal triggering factor, such that targeting it may be efficient as prevention in at-risk individuals. The role of neuroinflammation, microglia, and Tau pathology modulation are important sources of research for disease modification.