In a recent editorial, Lena Johansson outlines some current concepts and research trends related to the long terms effects of stress and their impact on risk and development of Alzheimer’s disease (AD) in women. Dr. Johansson has authored two population studies – perhaps the first in this area – on the role of midlife stressors and increased risk of dementia in late life.
What drives the stress and AD association is not entirely clear, but the author highlights two possible mechanisms.
The first mechanism discussed is related to glucocorticoids effects on brain and the ‘glucocorticoid cascade hypothesis’, introduced by Robert M. Sapolsky et al., in 1986 and based on two premises: first, that senescence is a form of decreased adaptiveness to stress, and, second, that chronic stress can accelerate the aging process.
Per data from experimental aged animals, it appears that in the aged organism, secretion of adrenocortical glucocorticoids persists even after the stress has ended. Degenerative changes in the region of the brain that normally inhibits glucocorticoid release may be caused by cumulative exposure to glucocorticoids, which in turn switch on feed-forward cascades leading to even higher cortisol secretion from the adrenal gland with further neuronal loss.
According to the ‘glucocorticoid cascade hypothesis’, high and longstanding levels of cortisol lead to shrink and loss of neurons, especially in some vulnerable areas in the medial temporal lobe because of the high amount of cortisol receptors. Loss of neurons in these areas can lead to inhibitory feedbacks to the HPA axis, which in turn result in even higher cortisol secretion from the adrenal gland with further neuronal loss. Several studies have found associations between severe stress and atrophy in brain, for example, in the hippocampus complex.
Interestingly, a number of studies have reported associations between stress-prone personality, that is, high neuroticism and development of AD. Personality is defined as characteristics stable over time, which influence an individual’s thinking and emotions, and the personality trait neuroticism refers to stress proneness, emotional instability and negative affectivity. The Baltimore Longitudinal Study of Aging assessed personality in a large sample of middle-aged men and women. During the 22 years of follow-up, it was found that high neuroticism was associated with increased risk of developing late-life AD.
The second mechanism is related to the association between chronic stress and hypertension, metabolic syndrome and a dysfunctional immune system, which in turn have been associated with dementia and AD.
Women specifically are more prone to stress-related disorders and have greater associated morbidity; they also react to stress with greater cortisol response, limbic system activation and cytokine activity as compared with men.
In addition, hypothalamic-pituitary-adrenal (HPA) axis responsiveness is greater in women than in men, mostly due to estrogen’s ability to induce corticotropin-releasing hormone gene expression and noradrenergic function (GP. Chrousos, DJ. Torpy and PW. Gold, MD; Ann Intern Med. 1998; 129:229-240).
Recent epidemiological studies have linked stress and AD compellingly. Via the Prospective Population Study of Women, a longitudinal cohort study from Sweden spanning over 30 years, Dr. Johansson and colleagues have shown that long-standing stress in midlife is associated with AD, temporal lobe atrophy and white matter lesions later on, and that experiencing a greater number of psychosocial life stressors is associated with higher incidence of AD.
Also linked to AD in other studies are: parental death during childhood, chronic work-related stress, post-traumatic stress disorder, high neuroticism and anxiety.
The association of stress and AD, while supported by recent evidence, is difficult to delineate well due to the paucity of longitudinal studies. The consequences of chronic stress are a particularly pertinent topic as the average life span increases and our overall population ages. In addition, it is important to recognize the existing gender disparities, in AD as in other illnesses, so as to better understand the neurohormonal processes involved therein.
In conclusion, the author discusses that despite evidence that longstanding stress has damaging effects on brain, little is known about stress as a risk factor for AD. Thus, importantly, longitudinal studies are lacking. It has been suggested that structural AD changes in brain appear already 20–30 years before the disease get clinically manifested, and the pathological levels of β-amyloids have been found to be fully altered 10 years before conversion to AD.