New insights on the genetic etiology of Alzheimer’s and related dementia

Abstract

Deciphering the genetic landscape of Alzheimer disease (AD) is essential to define the pathophysiological pathways involved and to successfully translate genomics to potential tailored medical care. To generate the most complete knowledge of the AD genetics, we developed through the European Alzheimer Disease BioBank (EADB) consortium a discovery meta-analysis of genome-wide association studies (GWAS) based on a new large case-control study and previous GWAS (in total 39,106 clinically diagnosed cases, 46,828 proxy-AD cases and 401,577 controls) with the most promising signals followed-up in independent samples (18,063 cases and 23,207 controls). In addition to 34 known AD loci, we report here the genome-wide significant association of 31 new loci with the risk of AD. Pathway-enrichment analyses strongly indicated the involvement of gene sets related to amyloid and Tau, but also highlighted microglia, in which increased gene expression corresponds to more significant AD risk. In addition, we successfully prioritized candidate genes in the majority of our new loci, with nine being primarily expressed in microglia. Finally, we observed that a polygenic risk score generated from this new genetic landscape was strongly associated with the risk of progression from mild cognitive impairment (MCI) to dementia (4,609 MCI cases of whom 1,532 converted to dementia), independently of age and the APOE e4 allele.

Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits

“…We detected three AD-associated loci with previously unknown pleiotropy for cardiometabolic traits and four loci that were pleiotropic and novel for both AD and the pertinent cardiometabolic trait, all of which we were able to map to one or more candidate causal genes. While our manuscript was under consideration, we note that a report was posted which indicated the DOC2A locus is a genome-wide significant AD locus supporting our results [38].…”

TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation

“…Moreover, the protective PLCγ2 variant seems to counteract the harmful effect of the APOE ε4 allele, as shown for a cognitively healthy centenarian carrying both the homozygous APOE ε4 and the PLCG2 protective polymorphism [9]. Additional haplotypes around PLCG2 have been recently found to be associated with AD [10][11][12]. However, the effects of TREM2 and PLCG2 polymorphisms might depend on the type of brain disease, stage of neurodegeneration [13] and on gene-dosage, or the level of enzymatic activity produced.…”

Sialometabolism in Brain Health and Alzheimer’s Disease

“…With failure of drugs targeting Aβ plaques and neurofibrillary tangles and identification of multiple AD risk genes exclusively expressed by microglia (Bellenguez et al, 2020), alternative microglia-based therapies have become a more recent focus of AD drug discovery (Spangenberg and Green, 2017). Such therapies, while facilitating phagocytotic clearance of Aβ plaques and hyperphosphorylated tau, could also restore microglial phenotype to a healthy and functional state.…”