Identifying families with likely genetic protective factors against Alzheimer disease

Elderly individuals who lived beyond the age of 90 years without dementia w ere hypothesized to have increased concentrations of genetic protective fac tors against Alzheimer disease (AD), conferring a reduced liability for thi s disease relative to less-aged nondemented elderly However, testing this h ypothesis is complicated by having to distinguish such a group from those w ho may lack genetic risk factors for AD, have had protective environmental exposures, or have escaped dementia for other reasons. Probands carrying ge netic protective factors, however, should have relatives with lower illness rates not only for earlier-onset disease, when genetic risk factors are a strong contributing factor to the incidence of AD, but also for later-onset disease, when the role of these factors appears to be markedly diminished. AD dementia was assessed through family informants in 6,660 first-degree r elatives of 1,049 nondemented probands aged 60-102 years. The probands were grouped by age (60-74, 75-89, and 90-102 years), and the cumulative surviv al from AD and 10-year-age-interval hazard rates of AD were calculated in t heir first-degree relatives. Cumulative survival from AD was significantly greater in the relatives of the oldest proband group (aged 90-102 years) th an it was in the two younger groups. In addition, the reduction in the rate of illness for this group was relatively constant across the entire late l ife span. The results suggest that genetic factors conferring a lifelong re duced liability of AD may be more highly concentrated among nondemented pro bands aged greater than or equal to 90 years and their relatives. Efforts t o identify protective allele-bearing genes that are associated with very la te-onset AD should target the families of nonagenarians and centenarians.