Genetic risk for alzheimer disease is distinct from genetic risk for amyloid deposition

Leonenko, Ganna; Shoai, Maryam; Bellou, Eftychia; Sims, Rebecca; Williams, Julie; Hardy, John; Escott‐Price, Valentina

doi:10.1002/ana.25530

Cited by 83 publications

(94 citation statements)

References 37 publications

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“…In line with our findings, Ahmad et al 29 found that genes capturing endocytosis pathway significantly associated with AD and with the conversion to AD. Other studies used less variants 28 or less stringent selection for variants, and did not observe a differential involvement of pathways in AD etiology 57 .…”

Section: Discussionmentioning

confidence: 95%

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

et al. 2020

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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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Section: Discussionmentioning

confidence: 95%

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

et al. 2020

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“…[29] Other studies used less variants [28] or less stringent selection for variants, and did not observe a differential involvement of pathways in AD etiology. [54] The amyloid cascade hypothesis has been dominating AD-related research in the last two decades. However, treatments targeting amyloid have, so far, not been able to slow or stop disease progression.…”

Section: Discussionmentioning

confidence: 99%

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

Tesi

Lee

Hulsman

et al. 2019

Preprint

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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=1,895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N=1,654) 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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“…However, the definition of these disease pathways is based mostly on the different functional categories defined by Gene Ontology (46). This is problematic (46) as there is little expert scrutiny, inclusion thresholds are low and almost all AD genes are implicated in more than one pathway (12,47,48). It turns out that the AD predictability using such categories is low (47).…”

Section: Leveraging Polygenic Riskmentioning

confidence: 99%

Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets

Sierksma

Escott‐Price

Strooper

2020

Science

112

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To provide better prevention and treatment, we need to understand the environmental and genetic risks of Alzheimer’s disease (AD). However, the definition of AD has been confounded with dementia in many studies. Thus, overinterpretation of genetic findings with regard to mechanisms and drug targets may explain, in part, controversies in the field. Here, we analyze the different forms of genetic risk of AD and how these can be used to model disease. We stress the importance of studying gene variants in the right cell types and in the right pathological context. The lack of mechanistic understanding of genetic variation has become the major bottleneck in the search for new drug targets for AD.

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Genetic risk for alzheimer disease is distinct from genetic risk for amyloid deposition

Cited by 83 publications

References 37 publications

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

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

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

Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets

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