Genome-wide association study of CSF biomarkers Aβ _1-42 , t-tau, and p-tau _181p in the ADNI cohort

Abstract

Objectives: CSF levels of A␤ 1-42 , t-tau, and p-tau 181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (A␤ 1-42 , t-tau, p-tau 181p , p-tau 181p /A␤ 1-42 , and t-tau/A␤ GLOSSARY A␤ 1-42 ϭ amyloid-␤ 1-42 peptide; AD ϭ Alzheimer disease; ADNI ϭ Alzheimer's Disease Neuroimaging Initiative; GWAS ϭ genome-wide association study; LD ϭ linkage disequilibrium; LOAD ϭ late-onset Alzheimer disease; MAF ϭ minor allele frequency; MCI ϭ mild cognitive impairment; p-tau 181p ϭ tau phosphorylated at the threonine 181; QC ϭ quality control; SNP ϭ single nucleotide polymorphism; t-tau ϭ total tau.Alzheimer disease (AD) is the most common form of dementia, affecting an estimated 5.3 million Americans. Amyloid-␤ 1-42 peptide (A␤ 1-42 ), total tau (t-tau), and tau phosphorylated at the threonine 181 (p-tau 181p ), measured in CSF samples, are potential diagnostic biomarkers for AD. 1-3 A␤ 1-42 is decreased and t-tau and p-tau 181p are increased in the CSF of patients with AD. 4 Baseline A␤ 1-42 has been shown to be a good predictor of the 12-month change in e-Pub ahead of print on December 1, 2010, at www.neurology.org.*These authors contributed equally to this work.

APOE-TOMM40 in the Pharmacogenomics of Dementia

“…The 523 VL poly T resulted in significantly higher expression than the S poly T. These results suggest that the 523 locus may contribute to LOAD susceptibility by modulating the expression of TOMM40 and/or APOE transcription [55]. Recent studies also suggest that the TOMM40 gene rs10524523 ("523") variable length poly T repeat polymorphism is associated to a certain extent with similar AD phenotypes as those reported for APOE, such as brain white matter changes [56,57] or different biomarkers [58][59][60][61]. In addition, the TOMM40 rs2075650 G allele may be a risk factor for the development of depression [62] and sporadic inclusion body myositis [63].…”

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

“…Han et al [53] found CYP19A1 and NCAM2 to be associated with AD biomarkers in cerebrospinal fluid (CSF) including b-amyloid peptide (Ab 1-42 ), total tau protein, and phosphorylated tau (P-tau 181P ). Using the same AD biomarkers in CSF as Han et al, Kim et al [54] showed that APOE, LOC100129500, TOMM40, and EPC2 had genome-wide significance. By performing so far the largest GWAS using AD biomarkers in CSF, Cruchaga et al [55] revealed the association of GLIS3 and TREM with AD.…”

A REVIEW OF BIOCHEMICAL MARKERS FOR EARLY DIAGNOSIS OF ALZHEIMER’S DISEASE

“…Genetic variants of the neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or SORL A) have been found to be risk factors for the development of Alzheimer's Disease (AD). Significant relation between CSF Aβ (1-42) levels and the SORL1 SNPs 23 and 24 were identified in the AD group (Kim et al, 2011). In addition to known candidate genes, APOE, TOMM40 and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2 and certain other genes were associated with CSF biomarkers that are related to AD.…”