Genome-wide interaction study of brain beta-amyloid burden and cognitive impairment in Alzheimer's disease.

Mol Psychiatry
Authors
Abstract

The lack of strong association between brain beta-amyloid deposition and cognitive impairment has been a challenge for the Alzheimer's disease (AD) field. Although beta-amyloid is necessary for the pathologic diagnosis of AD, it is not sufficient to make the pathologic diagnosis or cause dementia. We sought to identify the genetic modifiers of the relation between cortical beta-amyloid burden (measured using [(18)F]Florbetapir-PET) and cognitive dysfunction (measured using ADAS-cog) by conducting a genome-wide interaction study on baseline data from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) phases GO/2 (n=678). Near genome-wide significant interaction effect was observed for rs73069071 within the IAPP (amylin) and SLCO1A2 genes (P=6.2 × 10(-8)). Congruent results were found using data from participants followed up from ADNI-1 (Pone-tailed=0.028, n=165). Meta-analysis across ADNI-GO/2 and ADNI-1 revealed a genome-wide significant interaction effect (P=1.1 × 10(-8)). Our results were further supported by similar interaction effects on temporal lobe cortical thickness (whole-brain voxelwise analysis: familywise error corrected P=0.013) and longitudinal changes in ADAS-cog score and left middle temporal thickness and amygdalar volume (Pone-tailed=0.026, 0.019 and 0.003, respectively). Using postmortem beta-amyloid immunohistochemistry data from 243 AD participants in the Religious Orders Study and Memory and Aging Project, we also observed similar rs73069071-by-beta-amyloid deposition interaction effect on global cognitive function (Pone-tailed=0.005). Our findings provide insight into the complexity of the relationship between beta-amyloid burden and AD-related cognitive impairment. Although functional studies are required to elucidate the role of rs73069071 in AD pathophysiology, our results support the recently growing evidence on the role of amylin in AD.

Year of Publication
2017
Journal
Mol Psychiatry
Volume
22
Issue
2
Pages
287-295
Date Published
2017 Feb
ISSN
1476-5578
URL
DOI
10.1038/mp.2016.35
PubMed ID
27021820
PubMed Central ID
PMC5042808
Links
Grant list
RF1 AG015819 / AG / NIA NIH HHS / United States
R01 MH102324 / MH / NIMH NIH HHS / United States
R01 MH099167 / MH / NIMH NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States