Genetics of Posterior Cortical Atrophy

This study investigated the association of genetic risk factors for late-onset Alzheimer's disease (LOAD) with risk of posterior cortical atrophy (PCA). PCA is a syndrome of visual impairment with predominant Alzheimer disease (AD) pathology in posterior cortical regions with risk of posterior AD neuropathology.

The lab assessed 81 participants with PCA diagnosed clinically and 54 with neuropathologic diagnosis of posterior AD, versus 2,523 controls for association with 11 significant single nucleotide polymorphisms (SNPs) from published LOAD risk genome-wide association studies.

The findings included:

  • A highly significant association with apolipoprotein ε4 (APOE) and increased risk of PCA and posterior AD
  • After corrections for multiple testing, no other locus was significant, although rs11136000 near the clusterin (CLU) gene and rs744373 near the bridging integrator 1 (BIN1) gene associated nominally significantly with posterior AD, and rs3851179 at the phosphatidylinositol binding clathrin assembly protein (PICALMI) locus had significant association with PCA
  • ATP-binding cassette, sub-family A (ABC1), member 7 (ABCA7) locus SNP rs3764650, which was also tested under the recessive model because of Hardy-Weinberg disequilibrium, likewise 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

Therefore, the lab identified a significant effect for APOE and nominated CLU, BIN1 and ABCA7 as additional risk loci for PCA and posterior AD. These 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.

This work has been published, and the lab is analyzing the effect on PCA and posterior AD of variants at an additional 11 novel AD risk loci identified by the International Genomics of Alzheimer's Project consortium via meta-analysis of the largest LOAD genome-wide association study.