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(Blacker, Haines) These authors have made an equal contribution to the work.
From Massachusetts General Hospital (Drs. Haines and Blacker, L. Rodes, H. Terwedow, and Drs. Albert and Tanzi), Harvard Medical School, Boston, MA; University of Alabama, School of Medicine (Drs. Go, Harrell, and Perry), Birmingham, AL; Johns Hopkins Medical School (Drs. Bassett, Chase, and Meyers), Baltimore, MD.
Supported by grants from the National Institute of Mental Health: U01 MH46281 (Dr. Albert), U01 MH51066 (Dr. Albert), K21 MH01118 (Dr. Blacker), U01 MH46290 (Dr. Bassett), U01 MH52042 (Dr. Meyers), U01 MH46373 (Dr. Go), U01 MH51024 (Dr. Go).
Received March 5, 1996. Accepted in final form June 7, 1996.
Address correspondence and reprint requests to Dr Albert, Massachusetts General Hospital, Psychiatry/Gerontology (149-9124), Bldg 149, 13th Street, Charlestown, MA 02129.
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 medical centers ascertained subjects from memory disorder clinics, nursing homes, and the local community. Subjects: 310 families including 679 subjects with AD by NINCDS/ADRDA and/or Khachaturian criteria and 231 unaffected subjects. Outcome measure: ApoE genotype. Analytic methods: Association, affected pedigree member, sibling pair, and lod score analyses. Results: ApoE-4 was strongly associated with AD in this sample (allele frequency = 0.46 vs. 0.14 in controls, p < 0.000001). Results of lod score, affected pedigree member analysis, and sib-pair analysis also supported apoE-4 as a risk factor for AD. When the sample was stratified 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 no 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. Discussion: This work supports previous reports of an association between apoE-4 and the development of AD and demonstrates that apoE-4 exerts its maximal effect before age 70. These findings have important implications for the potential use of apoE genotyping for diagnosis and prediction of disease. They also underscore the need to identify additional genetic factors involved in AD with onset beyond age 70 years.
NEUROLOGY 1997;48: 139-147
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