Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect

N Engl J Med. 2009 Jul 16;361(3):255-63. doi: 10.1056/NEJMoa0809437.


Background: The APOE epsilon4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOE epsilon4 allele, those who are heterozygous for the allele, and noncarriers is unknown.

Methods: Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE epsilon4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOE epsilon4 allele, using a mixed model for longitudinal change with age.

Results: We analyzed 815 subjects: 317 APOE epsilon4 carriers (79 who were homozygous for the APOE epsilon4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 years; P<0.001) and were followed for a longer period (5.3 vs. 4.7 years, P=0.01), with an equivalent duration of formal education (15.4 years) and proportion of women (69%). Longitudinal decline in memory in carriers began before the age of 60 years and showed greater acceleration than in noncarriers (P=0.03), with a possible allele-dose effect (P=0.008). We observed similar although weaker effects on measures of visuospatial awareness and general mental status.

Conclusions: Age-related memory decline in APOE epsilon4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Apolipoprotein E4 / genetics*
  • Cross-Sectional Studies
  • Female
  • Heterozygote
  • Homozygote
  • Humans
  • Longitudinal Studies
  • Male
  • Memory
  • Memory Disorders / diagnosis
  • Memory Disorders / genetics*
  • Middle Aged
  • Neuropsychological Tests
  • Young Adult


  • Apolipoprotein E4