Stress and Alzheimer’s Disease

Because older age, hypercortisolemia, and hippocampal atrophy are all associated with AD, the role of stress in AD pathology and memory dysfunction has logically attracted some attention. According to the glucocorticoid cascade hypothesis, hippocampal degeneration in AD might result in increased cortisol secretion, due to the loss of normal negative hippocampal feedback to the HPA axis. In turn, the overactive HPA system evident in AD could lead to additional neuronal degeneration, thereby inducing progressive cognitive impairment - potentially a vicious circle.

Memory deficits have also been found in the presence of other disorders that are associated with persistent HPA activation and high cortisol levels, such as Cushing’s disease and major depressive disorder. One investigator found that, compared to matched controls, women with histories of recurrent major depression had smaller hippocampal volumes, the size of which were correlated with their lifetime duration of depression, and did more poorly on tests of verbal memory.

Most studies of individuals with AD have found them to have elevated post-DST cortisol levels compared to healthy controls. Increased HPA activity, as evidenced by elevated basal cortisol levels, elevated glucocorticoid activity, increased CSF cortisol levels, and hippocampal atrophy, have also been usually found to be positively associated with the degree of cognitive impairment in elderly individuals with AD.

A relevant variable also appears to be the presence of agitation, found to be more frequent in DST nonsuppressors. In one small study that followed AD patients for up to 3 years, increased basal plasma cortisol levels were found to linearly correlate with decline in cognitive functioning.

A recent study demonstrated a relationship between APOE genotype and CSF cortisol levels in individuals with AD. Specifically, in analyses controlling for age, it was found that individuals with AD who had the APOE є4 genotype had significantly higher cortisol levels than did individuals without the e4 allele.

Similar analyses performed with nondemented elderly individuals revealed only a trend for individuals with the є4 allele to have higher CSF cortisol levels. These findings suggest that the APOE є4 genotype might contribute to HPA axis dysfunction. However, CSF cortisol levels were not significantly correlated with measures of global cognitive status, although it is possible that CSF cortisol levels might be associated with more subtle changes in cognitive functioning.