Late-onset Alzheimer's risk variants in memory decline, incident mild cognitive impairment, and Alzheimer's disease

Neurobiol Aging. 2015 Jan;36(1):60-7. doi: 10.1016/j.neurobiolaging.2014.07.042. Epub 2014 Aug 4.


We tested association of nine late-onset Alzheimer's disease (LOAD) risk variants from genome-wide association studies (GWAS) with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD) in older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville (n>2000). Each variant was tested both individually and collectively using a weighted risk score. APOE-e4 associated with worse baseline memory and increased decline with highly significant overall effect on memory. CLU-rs11136000-G associated with worse baseline memory and incident MCI/LOAD. MS4A6A-rs610932-C associated with increased incident MCI/LOAD and suggestively with lower baseline memory. ABCA7-rs3764650-C and EPHA1-rs11767557-A associated with increased rates of memory decline in subjects with a final diagnosis of MCI/LOAD. PICALM-rs3851179-G had an unexpected protective effect on incident MCI/LOAD. Only APOE-inclusive risk scores associated with worse memory and incident MCI/LOAD. The collective influence of the nine top LOAD GWAS variants on memory decline and progression to MCI/LOAD appears limited. Discovery of biologically functional variants at these loci may uncover stronger effects on memory and incident disease.

Keywords: Alzheimer's disease; Association; Cognitive decline; Genetic risk; Memory; Mild cognitive impairment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / psychology*
  • Apolipoprotein E4 / genetics
  • Clusterin / genetics
  • Cognitive Dysfunction / epidemiology
  • Cognitive Dysfunction / genetics*
  • Cognitive Dysfunction / psychology*
  • Disease Progression
  • Female
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Incidence
  • Male
  • Membrane Proteins / genetics
  • Memory*
  • Middle Aged
  • Monomeric Clathrin Assembly Proteins / genetics
  • Receptor, EphA1 / genetics
  • Risk
  • Whites


  • ABCA7 protein, human
  • ATP-Binding Cassette Transporters
  • Apolipoprotein E4
  • CLU protein, human
  • Clusterin
  • MS4A6A protein, human
  • Membrane Proteins
  • Monomeric Clathrin Assembly Proteins
  • PICALM protein, human
  • Receptor, EphA1