Two recently postulated risk factors for the expression of Alzheimer's disease (AD) include: a) enhanced HPA axis activity in normal aging, and b) the presence of the apolipoprotein-E (apoE) epsilon4 allele. Studies in the rodent suggest that aging enhances hypothalamic-pituitary- adrenocortical (HPA) axis responsivity and that the resultant increase in glucocorticoid (GC) secretion lowers the threshold for aging-associated hippocampal neuronal damage and cognitive decline. The relevance to old humans of the provocative findings in old rodents has not been explored. Studies in late onset familial AD suggest that the presence of an isoform of apoE, epsilon4, lowers the age of expression of dementia in these families. Furthermore, epidemiologic studies demonstrate a significantly although variably higher frequency of the epsilon4 allele in sporadic late onset AD than in normal older persons. To explore HPA axis activity and apoE genotype as risk factors for cognitive decline in older humans, we propose the following Specific Aims: 1) To address the hypothesis that high HPA axis activity and/or presence of the apoE-epsilon allele increases cognitive decline in older humans, we will measure longitudinally the effects of HPA activity as estimated by urinary and salivary cortisol measurements on cognitive function within two groups of older subjects at high risk for cognitive decline: very elderly (over age 80) nondemented subjects and patients with AD. In addition, all subjects will be genotyped for apoE alleles. 2) To address the hypothesis that mechanism for enhanced HPA axis activity in older humans (as in older rats) is decreased sensitivity of the HPA axis to GC feedback inhibition, we will compare sensitivity of the HPA axis to GC feedback inhibition among nondemented very old persons, normal young persons, and patients with AD. If elevated circulating GC levels contribute to hippocampal neuronal degeneration in the nonhuman primate, and if enhanced HPA axis responsivity and/or the presence of the apoE- epsilon4 allele in human aging and AD is associated with increased cognitive decline, such findings would be relevant to designing treatment strategies to delay the onset or slow the progression of Alzheimer's disease.

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