Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease
N. Tesi (TU Delft - Pattern Recognition and Bioinformatics, Vrije Universiteit Amsterdam, Amsterdam UMC)
S.J. van der Lee (Vrije Universiteit Amsterdam, Amsterdam UMC)
M. Hulsman (Amsterdam UMC, TU Delft - Pattern Recognition and Bioinformatics, Vrije Universiteit Amsterdam)
Iris E. Jansen (Amsterdam UMC, Vrije Universiteit Amsterdam)
N. Stringa (Amsterdam UMC, Amsterdam Public Health Research Institute)
Natasja M. van Schoor (Amsterdam UMC, Amsterdam Public Health Research Institute)
Philip Scheltens (Amsterdam UMC, Vrije Universiteit Amsterdam)
Wiesje M. van der Flier (Vrije Universiteit Amsterdam, Amsterdam UMC)
Martijn Huisman (Amsterdam UMC, Amsterdam Public Health Research Institute)
M.J.T. Reinders (TU Delft - Pattern Recognition and Bioinformatics)
H. Holstege (Amsterdam UMC, Vrije Universiteit Amsterdam, TU Delft - Intelligent Systems)
More Info
expand_more
Other than for strictly personal use, it is not permitted to download, forward or distribute the text or part of it, without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license such as Creative Commons.
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.
help_outline