Intermediate Phenotypes Identify Divergent Pathways to Alzheimer's Disease

Joshua M Shulman,Julie A Schneider,Philip L De Jager,Lori B Chibnik,Cristin Aubin,David A Bennett,Katharina Domschke

doi:10.1371/journal.pone.0011244

Abstract

BackgroundRecent genetic studies have identified a growing number of loci with suggestive evidence of association with susceptibility to Alzheimer's disease (AD). However, little is known of the role of these candidate genes in influencing intermediate phenotypes associated with a diagnosis of AD, including cognitive decline or AD neuropathologic burden.Methods/Principal FindingsThirty-two single nucleotide polymorphisms (SNPs) previously implicated in AD susceptibility were genotyped in 414 subjects with both annual clinical evaluation and completed brain autopsies from the Religious Orders Study and the Rush Memory and Aging Project. Regression analyses evaluated the relation of SNP genotypes to continuous measures of AD neuropathology and cognitive function proximate to death. A SNP in the zinc finger protein 224 gene (ZNF224, rs3746319) was associated with both global AD neuropathology (p = 0.009) and global cognition (p = 0.002); whereas, a SNP at the phosphoenolpyruvate carboxykinase locus (PCK1, rs8192708) was selectively associated with global cognition (p = 3.57×10−4). The association of ZNF224 with cognitive impairment was mediated by neurofibrillary tangles, whereas PCK1 largely influenced cognition independent of AD pathology, as well as Lewy bodies and infarcts.Conclusions/SignificanceThe findings support the association of several loci with AD, and suggest how intermediate phenotypes can enhance analysis of susceptibility loci in this complex genetic disorder.

Highlights

Alzheimer’s disease (AD), the most common cause of dementia, leads to progressive loss of memory and other cognitive domains, and is characterized pathologically by the accumulation of extracelluar amyloid plaques and intracellular neurofibrillary tangles
We initially tested for associations between each of the 34 polymorphisms and our two primary outcomes, intermediate phenotypes representing a measure of global AD pathologic burden on autopsy and a measure of global cognitive function proximate to death (Table 2)
apolipoprotein E locus (APOE) e4 was significantly associated with both cognition (p = 3.4610210) and AD pathology (p = 1.6610224) in our cohort, whereas an association with APOE e2 was only seen for the pathological phenotype (p = 9.161024)

Summary

Introduction

Alzheimer’s disease (AD), the most common cause of dementia, leads to progressive loss of memory and other cognitive domains, and is characterized pathologically by the accumulation of extracelluar amyloid plaques and intracellular neurofibrillary tangles. Linkage studies have identified rare gene mutations as causal in familial, early age-of-onset AD, but these Mendelian variants only explain a small fraction of disease burden in the general population [1]. The identification of susceptibility loci for sporadic, late age-of-onset AD has been more challenging, with numerous reports of candidate gene associations, most of which have not been consistently replicated in follow-up studies [2,3,4]. One notable exception is the apolipoprotein E locus (APOE): the e4 allele is common, increases AD susceptibility 3-fold, and is estimated to explain at least 10% of the populationattributable risk of disease [1]. Recent genetic studies have identified a growing number of loci with suggestive evidence of association with susceptibility to Alzheimer’s disease (AD). Little is known of the role of these candidate genes in influencing intermediate phenotypes associated with a diagnosis of AD, including cognitive decline or AD neuropathologic burden

Methods

Results

Conclusion