Abstract
Hippocampal atrophy rate has been correlated with cognitive decline and its genetic modifiers are still unclear. Here we firstly performed a genome-wide association study (GWAS) to identify genetic loci that regulate hippocampal atrophy rate. Six hundred and two non-Hispanic Caucasian elders without dementia were included from the Alzheimer’s Disease Neuroimaging Initiative cohort. Three single nucleotide polymorphisms (SNPs) (rs4420638, rs56131196, rs157582) in the TOMM40-APOC1 region were associated with hippocampal atrophy rate at genome-wide significance and 3 additional SNPs (in TOMM40 and near MIR302F gene) reached a suggestive level of significance. Strong linkage disequilibrium between rs4420638 and rs56131196 was found. The minor allele of rs4420638 (G) and the minor allele of rs157582 (T) showed associations with lower Mini-mental State Examination score, higher Alzheimer Disease Assessment Scale-cognitive subscale 11 score and smaller entorhinal volume using both baseline and longitudinal measurements, as well as with accelerated cognitive decline. Moreover, rs56131196 (P = 1.96 × 10-454) and rs157582 (P = 9.70 × 10-434) were risk loci for Alzheimer’s disease. Collectively, rs4420638, rs56131196 and rs157582 were found to be associated with hippocampal atrophy rate. Besides, they were also identified as genetic loci for cognitive decline.
Highlights
The hippocampus is a vulnerable and plastic structure buried deep in the medial temporal lobe of human body [1]
The atrophy rate was greater in subjects with normal cognition (NC) who converted to mild cognitive impairment (MCI) or Alzheimer’s disease (AD) than in those who remained www.aging-us.com stable; it was greater in MCI subjects who converted to AD than in those who remained stable; and it was greater in fast AD progressors than slow ones [11, 12]
After adjusting for age, gender, years of education, intracranial volume (ICV), magnetic resonance imaging (MRI) and the first three multidimensional scaling (MDS) components, 3 single nucleotide polymorphism (SNP) on chromosome 19, including rs4420638 in the APOC1 gene (minor allele frequencies (MAF) = 0.1510, P = 9.32 × 10-9), rs56131196 in the APOC1 gene (MAF = 0.1508, P = 1.10 × 10-8) and rs157582 in the TOMM40 gene (MAF = 0.2937, P = 2.78 × 10-8), exhibited genome-wide significant associations with hippocampal atrophy rate (Figure 1A and Table 2). Their association signals disappeared after including apolipoprotein E (APOE) ε4 dosage as a covariate (Supplementary Figure 2)
Summary
The hippocampus is a vulnerable and plastic structure buried deep in the medial temporal lobe of human body [1]. The atrophic hippocampus is often accompanied by poor memory performance, and changes in the hippocampus provide a neural substrate for cognitive impairment that may be associated with normal aging, post-traumatic stress disorder, recurrent depression, and Cushing's syndrome [2]. The atrophy rate was greater in subjects with normal cognition (NC) who converted to mild cognitive impairment (MCI) or AD than in those who remained www.aging-us.com stable; it was greater in MCI subjects who converted to AD than in those who remained stable; and it was greater in fast AD progressors than slow ones [11, 12]. The reduction in hippocampal volumes over time may be promising in predicting individuals at high risk of developing cognitive decline, monitoring disease trajectories at early stage, and assessing treatment efficacy in clinical practice or drug trials
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