Late-onset Alzheimer disease genetic variants in posterior cortical atrophy and posterior AD

Abstract

Objective: To investigate association of genetic risk factors for late-onset Alzheimer disease (LOAD) with risk of posterior cortical atrophy (PCA), a syndrome of visual impairment with predominant Alzheimer disease (AD) pathology in posterior cortical regions, and with risk of "posterior AD" neuropathology. Methods:We assessed 81 participants with PCA diagnosed clinically and 54 with neuropathologic diagnosis of posterior AD vs 2,523 controls for association with 11 significant single nucleotide polymorphisms (SNPs) from published LOAD risk genome-wide association studies.Results: There was highly significant association with APOE e4 and increased risk of PCA (p 5 0.0003, odds ratio [OR] 5 3.17) and posterior AD (p 5 1.11 3 10 217 , OR 5 6.43). No other locus was significant after corrections for multiple testing, although rs11136000 near CLU (p 5 0.019, OR 5 0.60) and rs744373 near BIN1 (p 5 0.025, OR 5 1. 63) associated nominally significantly with posterior AD, and rs3851179 at the PICALM locus had significant association with PCA (p 5 0.0003, OR 5 2.84). ABCA7 locus SNP rs3764650, which was also tested under the recessive model because of Hardy-Weinberg disequilibrium, also had nominally significant association with PCA risk. The direction of association at APOE, CLU, and BIN1 loci was the same for participants with PCA and posterior AD. The effects for all SNPs, except rs3851179, were consistent with those for LOAD risk. Conclusions:We identified a significant effect for APOE and nominate CLU, BIN1, and ABCA7 as additional risk loci for PCA and posterior AD. Our findings suggest that at least some of the genetic risk factors for LOAD are shared with these atypical conditions and provide effect-size estimates for their future genetic studies. Neurology ® 2014;82:1455-1462 GLOSSARY AD 5 Alzheimer disease; BA 5 Brodmann area; CI 5 confidence interval; GWAS 5 genome-wide association study; LOAD 5 late-onset Alzheimer disease; MAF 5 minor allele frequency; NFT 5 neurofibrillary tangle; OR 5 odds ratio; PCA 5 posterior cortical atrophy; SNP 5 single nucleotide polymorphism.

A Set-Based Mixed Effect Model for Gene-Environment Interaction and Its Application to Neuroimaging Phenotypes

“…ABCA7 is involved in lipid metabolism and transport, and is a possible link between cardiovascular risk factors and AD (Stampfer, 2006; Jones et al, 2010; Reitz et al, 2013). Furthermore, ABCA7 has been shown to be nominally associated with the brain atrophy in the posterior portion of the cerebral cortex (Carrasquillo et al, 2014), which is consistent with the significant cluster identified in this study.…”

Early-Onset Alzheimer Disease

“…Clinically, they all relatively spare memory, and pathologically, they may all have hippocampal sparing with greater posterior cortical NFTs 44 . There is additionally specific involvement of left hemisphere language areas in lvPPA 80,91 and the visual neocortex in PCA 92,93 . Neuroimaging data also suggest posterior neocortical rather than mesotemporal cortical overlap of these phenotypes 78,94,9578,94,95 .…”

Case Studies Illustrating Focal Alzheimer’s, Fluent Aphasia, Late-Onset Memory Loss, and Rapid Dementia

“…Amyloid PET scan is abnormal in PCA patients with AD but the distribution is hard to distinguish from AD[5] however tau PET scan shows disproportionate tau deposits in the visual areas[6]. Recently Carrasquillo and colleagues[7] found ApoE to be related to PCA and indicated that, CLU, BIN1 and ABCA7 may be related but further study is needed.…”