Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

Abstract

Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop 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 the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided 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 increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.

Polygenic Risk Score of Longevity Predicts Longer Survival Across an Age Continuum

“…Recently, increased parental life span was associated with a lower PRS of low-density lipoprotein cholesterol levels, systolic blood pressure, and body mass index ( 15 ). We previously showed that cognitively healthy centenarians have a significantly lower PRS of Alzheimer’s disease (AD) compared to population controls ( 43 ). The overlap between the variants that contribute to the AD PRS and our best longevity PRS is limited: Apart from APOE variants, the longevity-associated variant rs9665907 is in LD with the known AD variant rs11218343 (in/near SORL1 , R 2 = 0.39) ( 44 ), and the variant rs6558008 is in low LD with the known AD variant rs9331896 (in/near CLU , R 2 = 0.05) ( 45 ).…”

The effect of Alzheimer’s disease-associated genetic variants on longevity

“…In our study, groups sizes were also relatively small, but the centenarians had a relatively high level of cognitive health, which might have contributed to an increased effect size of AD-associated genetic variants in our comparison. 16,17…”

“…The copyright holder for this this version posted February 4, 2021. ; https://doi.org/10.1101/2021.02.02.21250991 doi: medRxiv preprint high level of cognitive health, which might have contributed to an increased effect size of AD-associated genetic variants in our comparison. 16,17…”

“…Their functional and cell-type annotations suggest that they contribute to the maintenance of regulatory stimuli in the immune and endosomal systems, which may be essential to maintain brain and overall physical health, necessary to reach extremely old ages in good cognitive health. 17 Variants associated with increased risk of AD and increased longevity risk: unexpected group.…”

“…We have previously shown that cognitively healthy centenarians are depleted with genetic variants that increased the risk of AD compared to a general population; however, the extent of depletion was variant specific, suggesting that a subset of AD-variants may be specifically beneficial to reach extremely old ages in good cognitive health. 16,17 There is, however, little evidence of an age-dependent effect for AD variants and the extent to which these variants affect other age-related diseases is mostly unknown. 18 Using the assumption of effect-size proportionality, we set out to investigate the relationship between AD- and longevity-risk for genetic variants associated with AD.…”