Psychological Stress and the Hypothalamic-Pituitary-Adrenal Axis in Alzheimer’s Disease

The evidence of a direct role of stress in AD onset remains limited and inconclusive. As previously noted, there are many studies reporting a significant association between acute and chronic stress with memory impairment, yet few studies have considered the role of elevated stress levels in the development of AD. In a longitudinal analysis of subjects’ proneness to psychological distress and AD onset, investigators found that in analyses that accounted for depressive symptoms, for each 1-point increase on the distress-proneness scale there was a corresponding 6% greater risk of AD onset.

Proneness to psychological distress was measured with a well-established index of neuroticism. Furthermore, greater proneness to psychological distress was associated with poorer levels of, and a greater decline in, global cognitive functioning. Additional analyses revealed an association between greater psychological distress and greater decline in episodic memory functioning. Specifically, decline was 16% greater for each 1-point increase on the distress proneness scale in episodic memory functioning. However, proneness to psychological distress was not associated with pathological AD as examined postmortem.

In a similar analysis examining distress-proneness and AD onset in a community sample of Caucasian and African American (49.8%) elderly individuals, it was found that individuals who scored in the ninetieth percentile or higher on a neuroticism index were 2.4 times more likely to develop AD over the course of 3-6 years. Additional analyses accounting for depressive symptoms or excluding individuals with depression at baseline did not alter the results.

Although the researchers did not have postmortem data for AD pathology, the APOE genotype (a potential risk factor for AD) was available; and the researchers found no significant association between APOE genotype and distress-proneness in the full sample. Interestingly, the magnitude of the association between distress-proneness and AD onset was significantly different in Caucasian versus African American individuals.

In the Caucasian sample, with each 1-point increase on the distress-proneness scale the odds of developing AD increased 12%. In contrast, the odds of developing AD in the African American sample increased only 2% for every 1-point increase on the distress-prone scale. These findings highlight the possibility of sociocultural differences in the association between stress and AD onset.

Other studies examining psychosocial stressors and AD onset have reported similar findings. For example, in a longitudinal analysis of psychosocial stressors and AD onset, when accounting for demographic factors, including education, individuals who reported psychosocial stressors as far back as childhood were found to have significantly higher rates of AD onset relative to individuals with fewer or no psychosocial stressors.

Specifically, the incidence rate of AD over 9 years in individuals reporting no psychosocial stressors was 1.7%, and this rose to 5% in individuals reporting one or two and to 8.3% for individuals reporting three or more psychosocial stressors. The psychosocial stressors or risk factors that were considered included events from childhood (i.e., death of a parent and poverty), adulthood (i.e., death of a spouse, arduous manual labor, and serious illness in a child), and old age (i.e., deterioration in financial status and physical illness).

Psychosocial stressors that were significantly associated with AD onset included the death of a parent during childhood, arduous manual labor, physical illness in a spouse during old age, and serious illness in a child (offspring). Possibly relevant to this finding is an earlier study reporting that, when accounting for education and alcohol consumption, men who had occupations involving manual labor were 5.3 times more likely to be diagnosed with late-onset AD than were men in nonarduous occupations.

The finding that psychosocial stressors earlier in the life span might contribute to dysfunction in later life is also congruent with research using animal models in which earlier experiences altered noradrenergic and serotonergic functions in adulthood and the rate of aging.