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Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience.

ABSTRACT: While age and the APOE ?4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline.We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs.Rs142787485 in RAB10 confers significant protection against AD (p value?=?0.0184, odds ratio?=?0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value?=?0.028, odds ratio?=?0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value?=?0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in A?42 (p value?=?0.0003) and in the A?42/A?40 ratio (p value?=?0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value?=?0.04).Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.

SUBMITTER: Ridge PG

PROVIDER: S-EPMC5706401 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience.

Ridge Perry G PG Karch Celeste M CM Hsu Simon S Arano Ivan I Teerlink Craig C CC Ebbert Mark T W MTW Gonzalez Murcia Josue D JD Farnham James M JM Damato Anna R AR Allen Mariet M Wang Xue X Harari Oscar O Fernandez Victoria M VM Guerreiro Rita R Bras Jose J Hardy John J Munger Ronald R Norton Maria M Sassi Celeste C Singleton Andrew A Younkin Steven G SG Dickson Dennis W DW Golde Todd E TE Price Nathan D ND Ertekin-Taner Nilüfer N Cruchaga Carlos C Goate Alison M AM Corcoran Christopher C Tschanz JoAnn J Cannon-Albright Lisa A LA Kauwe John S K JSK

Genome medicine 20171129 1

<h4>Background</h4>While age and the APOE ε4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline.<h4>Methods</h4>We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resi ...[more]

PMID: 29183403

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Project description:BackgroundIn Alzheimer's disease (AD), the associations between tau pathology and brain atrophy and cognitive decline are well established, but imperfect. We investigate whether cerebrospinal fluid (CSF) biomarkers of biological processes (vascular, synaptic, and axonal integrity, neuroinflammation, neurotrophic factors) explain the disconnection between tau pathology and brain atrophy (brain resilience), and tau pathology and cognitive decline (cognitive resilience).MethodsWe included 428 amyloid positive participants (134 cognitively unimpaired (CU), 128 with mild cognitive impairment (MCI), 166 with AD dementia) from the BioFINDER-2 study. At baseline, participants underwent tau positron emission tomography (tau-PET), magnetic resonance imaging (MRI), cognitive testing, and lumbar puncture. Longitudinal data were available for MRI (mean (standard deviation) follow-up 26.4 (10.7) months) and cognition (25.2 (11.4) months). We analysed 18 pre-selected CSF proteins, reflecting vascular, synaptic, and axonal integrity, neuroinflammation, and neurotrophic factors. Stratifying by cognitive status, we performed linear mixed-effects models with cortical thickness (brain resilience) and global cognition (cognitive resilience) as dependent variables to assess whether the CSF biomarkers interacted with tau-PET levels in its effect on cortical atrophy and cognitive decline.ResultsRegarding brain resilience, interaction effects were observed in AD dementia, with vascular integrity biomarkers (VEGF-A (βinteraction = -0.009, pFDR = 0.047) and VEGF-B (βinteraction = -0.010, pFDR = 0.037)) negatively moderating the association between tau-PET signal and atrophy. In MCI, higher NfL levels were associated with more longitudinal cortical atrophy (β = -0.109, pFDR = 0.033) and lower baseline cortical thickness (β = -0.708, pFDR = 0.033) controlling for tau-PET signal. Cognitive resilience analyses in CU revealed interactions with tau-PET signal for inflammatory (GFAP, IL-15; βinteraction -0.073--0.069, pFDR 0.001-0.045), vascular (VEGF-A, VEGF-D, PGF; βinteraction -0.099--0.063, pFDR < 0.001-0.046), synaptic (14-3-3ζ/δ; βinteraction = -0.092, pFDR = 0.041), axonal (NfL; βinteraction = -0.079, pFDR < 0.001), and neurotrophic (NGF; βinteraction = 0.091, pFDR < 0.001) biomarkers. In MCI higher NfL levels (βmain = -0.690, pFDR = 0.025) were associated with faster cognitive decline independent of tau-PET signal.ConclusionsBiomarkers of co-existing pathological processes, in particular vascular pathology and axonal degeneration, interact with levels of tau pathology on its association with the downstream effects of AD pathology (i.e. brain atrophy and cognitive decline). This indicates that vascular pathology and axonal degeneration could impact brain and cognitive resilience.

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Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience.

Publications

Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience.

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