BACKGROUND: The clinical expression of @entity195 likely occurs when the accumulation of degeneration in specific brain regions leads to the descent below a critical threshold of "brain reserve" beyond which normal cognitive function cannot be maintained. The association between @entity135 ( @entity135 ), a measure of brain reserve, and the incidence of probable @entity195 was examined in a large nondemented cohort that has been followed since 1992 and its modification by @entity2204 epsilon 4 genotype. METHODS: Fifty-nine incident cases of probable @entity195 were identified from 1,869 initially nondemented individuals seen at the baseline examination (1992 to 1994) and followed for a mean of 3.8 years. Variables measured at baseline included age, education, gender, @entity135 , height, weight, and score on the National Adult Reading Test-Revised. @entity2204 was genotyped at the time of the first biennial examination (1994 to 1996) and was available for 1,111 individuals in the cohort. Cox proportional hazard regression was performed to estimate hazard ratios (HR) for probable @entity195 for @entity135 and other covariates. RESULTS: Incident cases were significantly older, less educated, shorter, and lighter, had lower estimated verbal IQ scores, and were more likely to have at least one @entity2204 epsilon 4 allele than unaffected individuals. The HR associated with the lowest tertile of @entity135 (<21.4 inches) adjusted for education, gender, and @entity2204 epsilon 4 was 2.3 (95% CI 0.7 to 6.9, p = 0.16). The HR for one or two @entity2204 epsilon 4 alleles was significant (HR = 4.8, 95% CI 1.8 to 12.9, p = 0.002). The combination of low @entity135 and @entity2204 epsilon 4 strongly predicted earlier onset of @entity195 with HR = 14.1 (95% CI 3.0 to 65, p = 0.0007). CONCLUSIONS: Smaller @entity135 , in the presence of the @entity2204 epsilon 4 allele, hastens the age at onset of @entity195 . These results support the brain reserve hypothesis and its importance in precipitating the clinical expression of @entity195 among genetically predisposed individuals.

Head circumference and incident XXXX : modification by @entity2204 .

@entity135 :: ('MESH:D006258', 'Disease') :: ['HC', 'head circumference'] @entity2204 :: ('348', 'Gene') :: ['APOE'] @entity195 :: ('MESH:D000544', 'Disease') :: ['AD']
@entity195 :: (MESH:D000544,Disease) :: ['Alzheimer's disease']
