APOE-4 AND AGE AT ONSET OF ALZHEIMERS-DISEASE - THE NIMH GENETICS INITIATIVE

Objective: To explore the impact of apoE-4 on Alzheimer's disease (AD) and its age at onset. Design: A genetic linkage study using affected relative pairs, predominantly siblings. Setting: Three academic medica l centers ascertained subjects from memory disorder clinics, nursing h omes, and the local community. Subjects: 310 families including 679 su bjects with AD by NINCDS/ADRDA and/or Khachaturian criteria and 231 un affected subjects. Outcome measure: ApoE genotype. Analytic methods: A ssociation, affected pedigree member, sibling pair, and lod score anal yses. Results: ApoE-4 was strongly associated with AD in this sample ( allele frequency = 0.46 vs. 0.14 in controls, p < 0.000001). Results o f lod score, affected pedigree member analysis, and sib-pair analysis also supported apoE-4 as a risk factor for AD. When the sample was str atified on family mean age at onset, the risk conferred by apoE-4 was most marked in the 61 to 65 age group. Individuals with two copies of apoE-4 had a significantly lower age at onset than those with one or n o copies (66.4 vs. 72.0, p < 0.001), but individuals with one copy did not differ from those with none. Within families, the individual with the earliest age at onset had, on average, significantly more apoE-4 alleles (p < 0.0001) than the individual with the latest onset. Discus sion: This work supports previous reports of an association between ap oE-4 and the development of AD and demonstrates that apoE-4 exerts its maximal effect before age 70. These findings have important implicati ons for the potential use of apoE genotyping for diagnosis and predict ion of disease. They also underscore the need to identify additional g enetic factors involved in AD with onset beyond age 70 years.