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P4‐137: Age, APOE genotype, gender and serial position effects in healthy adults
Author(s) -
Pomara Nunzio,
Yi Linlin,
Schmeltz Amanda,
Sidtis John J.
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.805
Subject(s) - serial position effect , analysis of variance , psychology , recall , audiology , developmental psychology , free recall , medicine , cognitive psychology
Background: Cerebrospinal fluid (CSF) levels of tau protein are increased in Alzheimer’s disease (AD), and correlate with the presence of tangles in the brain suggesting they may be a useful biomarker for AD. Quantitative traits such as CSF tau levels offer more power than case-control tests in identifying genes influencing risk for AD. Objective: To identify SNPs in genes related to tau metabolism that are associated with CSF tau and phosphorylated tau181 (ptau181) levels that could be new risk factors for AD. Methods: We genotyped 384 SNPs in 35 genes related to tau posttranslational modification. CSF tau and ptau181 levels were available for 374 individuals from the Washington University ADRC and for 400 individuals from ADNI. ANCOVA was used to test for association between genotypes and CSF tau and ptau181 levels. False discovery rate was used for multiple test correction. PPP3R1 and PPP3CA mRNA levels in parietal lobe from 42 non-demented and 78 demented individuals were quantified by real-time PCR. Results: 15 SNPs in 11 genes were associated with either tau or ptau181 in the ADRC CSF series. Upon follow-up of the significant SNPs in the ADNI series only SNPs located in the regulatory (PPP3R1; rs1868402) and in the catalytic (PPP3CA; rs17030739) subunits of the phosphatase PP2B (calcineurin) replicated. In a combined analysis of the two series, rs1868402 (p1⁄46.28x10-05) and rs17030739 (p1⁄42.05x10-04) were the most significant SNPs. Gene expression analyses showed that PPP3R1 mRNA levels are higher in AD cases compared to controls (p1⁄40.0001) and that in controls the minor allele of rs1868402 is associated with lower PPP3R1 expression (p1⁄40.009). PPP3R1 and PPP3CA mRNA levels are highly correlated in the WU ADRC brains (Spearman correlation factor1⁄40.71; p1⁄41.33310-20) and in the publicly available GEO database (Series GSE8919) of 193 neuropathologically normal human brain samples (p1⁄46.35310-21). These results suggest the presence of common regulatory elements in both genes. Conclusions: Our results suggest genetic variants in both the catalytic and the regulatory subunits of calcineurin could increase tau pathology and be associated with risk for AD or earlier age at onset.