Rare variants in the endocytic pathway are associated with Alzheimer’s disease, its related phenotypes, and functional consequences.

Late-onset Alzheimer’s disease (LOAD) is the most common type of dementia
causing irreversible brain damage to the elderly and presents a major
public health challenge. Clinical research and genome-wide association
studies have suggested a potential contribution of the endocytic pathway to
AD, with an emphasis on common loci. However, the contribution of rare
variants in this pathway to AD has not been thoroughly investigated. In
this study, we focused on the effect of rare variants on AD by first
applying a rare-variant gene-set burden analysis using genes in the
endocytic pathway on over 3,000 individuals with European ancestry from
three large whole-genome sequencing (WGS) studies. We identified
significant associations of rare-variant burden within the endocytic
pathway with AD, which were successfully replicated in independent
datasets. We further demonstrated that this endocytic rare-variant
enrichment is associated with neurofibrillary tangles (NFTs) and
age-related phenotypes, increasing the risk of obtaining severer brain
damage, earlier age-at-onset, and earlier age-of-death. Next, by
aggregating rare variants within each gene, we sought to identify single
endocytic genes associated with AD and NFTs. Careful examination using NFTs
revealed one significantly associated gene, ANKRD13D. To identify
functional associations, we integrated bulk RNA-Seq data from over 600
brain tissues and found two endocytic expression genes (eGenes), HLA-A and
SLC26A7, that displayed significant influences on their gene expressions.
Differential expressions between AD patients and controls of these three
identified genes were further examined by incorporating scRNA-Seq data from
48 post-mortem brain samples and demonstrated distinct expression patterns
across cell types. Taken together, our results demonstrated strong
rare-variant effect in the endocytic pathway on AD risk and progression and
functional effect of gene expression alteration in both bulk and
single-cell resolution, which may bring more insight and serve as valuable
resources for future AD genetic studies, clinical research, and therapeutic
targeting.