Genetic Studies of Cognition and AD Risk

Genome-wide association studies of late-onset Alzheimer's disease (LOAD) have identified many risk variants. The lab has assessed the association of the top nine GWAS variants and the apolipoprotein ε4 (APOE ε4) allele with memory, as well as progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD).

For this study over 2,000 older Caucasians, cognitively normal at baseline and longitudinally, were evaluated at Mayo Clinic's campus in Rochester, Minnesota, and Mayo Clinic, Jacksonville, Florida. They were assessed for associations of genetic variants with memory decline using linear mixed models and for incident MCI/LOAD with Cox proportional hazards models.

Each variant was tested both individually and collectively using a single weighted risk score. The findings showed:

  • APOE ε4 was significantly associated with worse memory at baseline and an increased rate of five-year decline, with highly significant overall effect on memory
  • The CLU-locus risk allele rs11136000-G was associated with worse memory at baseline, but not with increased rate of decline
  • The CLU allele was also associated with incident MCI/LOAD in sensitivity analysis
  • The MS4A6A-locus risk allele rs610932-C was associated with increased incident MCI/LOAD in primary analysis and had suggestive association with lower baseline memory
  • The PICALM-locus risk allele rs3851179-G had significant HR in both primary and sensitivity analysis, but with a protective estimate

Further, risk scores excluding APOE were not significant, whereas APOE-inclusive risk scores were associated with worse memory and incident MCI/LOAD.

The lab is now analyzing the effect on memory decline in a similar fashion. This includes MCI and AD of variants at an additional 11 novel AD risk loci that were recently identified by the International Genomics of Alzheimer's Project consortium via meta-analysis of the largest LOAD genome-wide association studies.