The escape from Alzheimer's disease underlies genetic variants involved into immune response and endocytosis pathways

The risk to develop and escape Alzheimer9s disease (AD) is influenced by a constellation of genetic variants, each associated with specific molecular pathways. Different pathways may differentially contribute to the modification of the AD-risk. We studied the molecular mechanisms that explain the extreme ends of the cognitive spectrum by comparing pathway-specific polygenic risk scores (pathway-PRS) in individuals with AD and those who escaped AD until old age. We used 29 genetic variants associated with AD to calculate pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in patients with AD (N=1,909), population controls (N=1,654), and cognitively healthy centenarians who escaped AD (N=293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with the modification of AD-risk (p<0.05). The pathway that contributed the most was β-amyloid metabolism (32%), driven mainly by APOE variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (p<0.05), while specifically immune response (p=3.1x10-3) and endocytosis (p=3.8x10-4) associated with escaping AD. These pathways were the main contributors to the genetic risk of AD (41.3% and 21.4%, respectively), and their effect on escaping AD was larger or comparable to that of developing AD. Our work suggests that immune response and endocytosis might be involved in general neuro-protective functions, and highlights the need to study these pathways, next to β-amyloid metabolism.