Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study

Alzheimer's disease (AD) is one of the most common causes of dementia and is the fourth leading cause of death in the United States. ^[1,2] The prevalence of AD varies across decades, from about 3% of individuals 65 years old to nearly 50% of people 85 years old. ^[3,4] AD occurring at ages younger than 65 years, often referred to as early-onset AD, is rare but is still one of the most common causes for declining cognitive function in late middle age. The average length of time from onset of symptoms to death is approximately 7 to 8 years. ^[5,6] At present, there is no cure, and only minor palliative treatment is available.

Family, epidemiologic, and molecular studies have implicated genetic factors in the etiology of AD. ^[7] Some familial cases with age at onset in the fourth and fifth decades have defects in genes recently identified on chromosomes 1 and 14. ^[8,9] The frequency of these mutations in the population is not yet known. Manifestation of early-onset AD is also associated with mutations in the beta-amyloid precursor protein (APP) gene on chromosome 21, but this is a very rare cause of AD. ^[10-13] A genomic search localized a gene for familial late-onset AD to chromosome 19, ^[14] and association studies of loci in this region subsequently implicated the apolipoprotein E (ApoE) gene as a likely susceptibility locus. ^[15] The element 4 allele of ApoE is several times more frequent in sporadic patients with late-onset disease than in cognitively normal persons in the general population. ^[16] This finding has been replicated in numerous clinic-based and cross-sectional patient populations including those enriched for early-onset disease ^[17-22] (for a review see reference 23).

In spite of the remarkable dose-dependent effect of element 4 on risk and age at onset of AD, ^{[24,25] …}