Stress, the brain and cognition

In this thesis we investigated whether the experience of stressful life events and depression were related to early symptoms of Alzheimer’s disease and whether this relation could be explained by alterations in hypothalamic-pituitary adrenal (HPA) axis activity. To study this we used data from two large cohort studies, the Longitudinal Aging Study Amsterdam (LASA) and the Second Manifestation of ARTerial disease (SMART) study. First, we established the relation between stressful life events and long-term changes in HPA axis activity, by investigating the relation between life events and cortisol levels. Cortisol levels are a marker of HPA axis activity. In LASA, we found that early life stress was associated with lower levels of cortisol, whereas recent life events were associated with higher levels of cortisol. We found that older persons with high levels of cortisol had poorer memory performance, but that high levels of cortisol were not a risk factor for memory decline over a period of 4 years. However, in older persons with a genetic susceptibility for AD (apolipoprotein e4 carriers) we found that alterations in cortisol levels were associated with memory decline. In addition to the studies in LASA, we investigated in the SMART study whether stressful life events can lead to cognitive impairment via alterations in HPA-axis activity. We found no evidence for stress-related cognitive impairment, as the experience of life events was associated with better cognitive functioning. Moreover, the relation between stressful life events and cognitive functioning was not explained by HPA-axis activity. We further examined the relation between depression and hippocampal and entorhinal cortex volume and whether this relation could be explained by HPA-axis activity. We found a differential relation of age of onset of depression and hippocampal and entorhinal cortex volume; early-onset depression (before age of 50 years) was associated with smaller hippocampal volumes, whereas late-onset depression (after age of 50 years) was associated with smaller entorhinal cortex volume The relations between depression and brain atrophy were not explained by HPA axis activity. The findings of these thesis suggest that particularly late-onset depression is associated with smaller entorhinal cortex volume, which could be indicative of early symptoms of Alzheimer’s disease, whereas early-onset depression was only associated with moderate hippocampal volume decrease. We hypothesize that depression does not lead to brain volume loss; rather we think that late-onset depression and brain atrophy are both a result of a common causal factor, for instance Alzheimer’s disease. In case of early-onset depression, it is likely that smaller hippocampal volumes precede the onset of depression and could even be a risk factor for the onset of depression. To conclude, psychosocial stress and depression were related to alterations in HPA-axis activity and elevated cortisol levels were also associated with cognitive impairment and brain atrophy, but we found no proof that psychosocial stress and depression lead to cognitive decline and brain atrophy via alterations in HPA-axis activity.