TY - JOUR
T1 - Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease
AU - Tesi, Niccolò
AU - van der Lee, Sven J.
AU - Hulsman, Marc
AU - Jansen, Iris E.
AU - Stringa, Najada
AU - van Schoor, Natasja M.
AU - Scheltens, Philip
AU - van der Flier, Wiesje M.
AU - Huisman, Martijn
AU - Reinders, Marcel J. T.
AU - Holstege, Henne
N1 - Funding Information: The following studies and consortia have contributed to this manuscript. Amsterdam dementia cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience (www.amsterdamresearch.org). The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stiching VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). 100-plus study: we are grateful for the collaborative efforts of all participating centenarians and their family members and/or relatives. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814) and Stichting VUmc Fonds. Genotyping of the 100-plus study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). The clinical database structure was developed with funding from Stichting Dioraphte. Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. This work was in part carried out on the Dutch national e-infrastructure with the support of SURF Cooperative. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - https://doi.org/10.1038/s41398-020-01018-7
DO - https://doi.org/10.1038/s41398-020-01018-7
M3 - Article
C2 - 32994401
SN - 2158-3188
VL - 10
SP - 1
EP - 12
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 332
ER -
