Genetics of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia. In contrast to monogenic and early-manifesting forms of AD resulting from highly penetrant mutations in APP, PSEN1, and PSEN2, susceptibility to the sporadic, often late-onset AD (LOAD) is determined by a complex interaction among genetic, epigenetic, and environmental-lifestyle-related factors. Although APOE ɛ4 is the strongest genetic risk factor for AD, its effect only accounts for ~27.3% of the estimated disease heritability of 58–79%. Through the continuing technical development of genome-wide association studies (GWAS) and next-generation automatic sequencing methods, scientists in large-scale collaborations have succeeded in gradually revealing the missing heritability. Important insights from GWAS and analyses of signaling pathways suggest that microglia, the resident immune cells of the CNS, play a decisive role in the pathogenesis of AD. A considerable number of risk genes identified in genetic studies indicate immune system-related functions and are expressed to a large extent by microglia. Through the description of risk variants in CR1, CLU, SPI1, CD33, MS4A, ABCA7, EPHA1, HLA-DRB5/1, INPP5D, TYROBP, TREM2, PLCG2, and ABI3 the microglia-mediated immune response takes on a central role in the pathogenesis of AD. Of note might be that the PLCγ2 variant, p.P522R, exerts a protective effect on LOAD and as an enzyme, PLCγ2 offers a classic target for the therapeutic modulation of complex forms of AD.