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CDH6 and HAGH protein levels in plasma associate with Alzheimer's disease in APOE ?4 carriers.

ABSTRACT: Many Alzheimer's disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD?=?161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (A?) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N?=?441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (??=?0.638, P?=?3.33?×?10-4) and HAGH (??=?0.481, P?=?7.20?×?10-4), were significantly elevated in APOE ?4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (??=?1.365, P?=?3.97?×?10-3) and HAGH proteins (??=?0.506, P?=?9.31?×?10-7) when comparing cases and controls in APOE ?4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ?4 stratum (P?

SUBMITTER: Ahmad S

PROVIDER: S-EPMC7237496 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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CDH6 and HAGH protein levels in plasma associate with Alzheimer's disease in APOE ε4 carriers.

Ahmad Shahzad S Milan Marta Del Campo MDC Hansson Oskar O Demirkan Ayse A Agustin Ruiz R Sáez Maria E ME Giagtzoglou Nikolaos N Cabrera-Socorro Alfredo A Bakker Margot H M MHM Ramirez Alfredo A Hankemeier Thomas T Stomrud Erik E Mattsson-Carlgren Niklas N Scheltens Philip P van der Flier Wiesje M WM Ikram M Arfan MA Malarstig Anders A Teunissen Charlotte E CE Amin Najaf N van Duijn Cornelia M CM

Scientific reports 20200519 1

Many Alzheimer's disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER s ...[more]

PMID: 32427856

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Project description:BackgroundLeukocyte telomere length (LTL) has been shown to predict Alzheimer's disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor.MethodsWe analyzed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards.ResultsAfter follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1-24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404-7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947-2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD.ConclusionsOur findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.

Dataset Information

CDH6 and HAGH protein levels in plasma associate with Alzheimer's disease in APOE ?4 carriers.

Publications

CDH6 and HAGH protein levels in plasma associate with Alzheimer's disease in APOE ε4 carriers.

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