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Transmission and age-at-onset patterns in familial Alzheimer's disease

Evidence for heterogeneity

Department of Neurology (Drs. Farrer and Myers) and School of Public Health (Drs. Farrer and Cupples), Boston University School of Medicine, and Department of Neurology (Drs. Farrer, Myers, St. George-Hyslop, and Growdon) and Neurogenetics Laboratory (Dr. St. George-Hyslop), Harvard University School of Medicine, Boston, MA; Department of Neurology (Dr. Bird), University of Washington Medical School and Seattle Veterans Administration Medical Center, Seattle, WA Departments of Neurology, Biochemistry, and Molecular Biology (Drs. Rossor and Mullan), St. Mary's Hospital Medical School, London, England; National Institute of Neurological Diseases and Stroke (Dr. Polinsky and L. Nee), Bethesda, MD; Department of Psychiatry (Dr. Heston), University of Minnesota, Minneapolis, MN Departments of Biochemistry (Dr. Van Broeckhoven) and Neurology (Dr. Martin), University of Antwerp, Belgium; and Department of Neurology (Dr. Crapper-McLachlan), University of Toronto, Toronto, Ontario, Canada.

We evaluated age at onset and lifetime risk for Alzheimer's disease (AD) in 70 kindreds with familial AD (designated FAD) composed of 541 affected and 1,066 unaffected offspring of demented parents who were identified retrospectively. Using a survival analysis method which takes into account affected persons with unknown onset ages and unaffected persons with unknown censoring ages, we found lifetime risk of AD among at-risk offspring by age 87 to be 64%. Analysis of age at onset among kindreds showed evidence for a bimodal distribution: in this sample, families with a mean onset age of less than 58 years were designated as having early-onset, while late-onset families had a mean onset age greater than 58 years. At-risk offspring in early-onset families had an estimated lifetime risk for dementia of 53%, which is significantly less than the risk of 86% that was estimated for offspring in late-onset families. Men and women in early-onset families had equivalent risk of dementia. In late-onset families, the risk to female offspring was somewhat higher than to male offspring but this difference was marginally significant. Lifetime risk of dementia in early-onset FAD kindreds is consistent with an autosomal dominant inheritance model. Our results may suggest that late-onset FAD has at least 2 etiologies; AD in some families may be transmitted as a dominant trait, whereas a proportion of cases in these and other late-onset families may be caused by other genetic or shared environmental factors.

Address correspondence and reprint requests to Dr. Lindsay A. Farrer, Department of Neurology, Boston University School of Medicine, 720 Harrison Avenue, Suite 1105, Boston, MA 02118.

Supported by PHS grants AG06865, AG5136, and P50AG5134, Veterans Administration Medical Research Funds, and grants from the Massachusetts Department of Public Health and the American Health Assistance Foundation.

Received March 17,1989. Accepted for publication in final form August 22,1989.