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"Stress and the aging brain: the interplay between genetic susceptibility, aging and psychosocial stress on early symptoms of dementia"

Final Report Summary - STAGED (Stress and the aging brain: the interplay between genetic susceptibility, aging and psychosocial stress on early symptoms of dementia)

Currently, the lifetime cumulative risk for developing dementia is 20 % and with increasing life expectancy it is estimated that the percentage of affected people over the next half-century may be as high as 50 % in the developed countries. At present it is thought that dementia is caused by complex interactions of genetic susceptibility, biological factors and environmental exposures experienced over the life course. It is commonly accepted that psychosocial stress is a risk factor for several severe illnesses, including cardiovascular disease, immune disorders and dementia. Particularly old age encompasses powerful stressors due to important life changes such as retirement and frequent occurrence of negative events such as loss of loved ones and new diseases. Because the majority of people show resilience to stress, there is probably a vulnerable group of people who are more susceptible for the effects of stress; good examples of vulnerable people are elderly, and people with certain genetic susceptibilities. The general aim of this proposal was to explore the role of psychosocial stress on onset of dementia and early symptoms of dementia (e.g. development of cognitive decline, structural and functional brain abnormalities) by taking into account genetic susceptibility and telomere length shortening.
For this research I used data from five longitudinal studies of aging. Among which three studies which are part of the Swedish Twin Registry ( and two studies that are being managed by the Aging Research Center (
The main findings of this research are
1. Timing of stressful life event seems to be of great impact; stressful life events that are experienced before the age of 18 years old can have a lasting effect on the hippocampus, which is still visible in old age. The hippocampus is a brain structure that is related to memory and spatial functioning. Decreased volume of the hippocampus is one of the earliest signs in dementia. More recently experienced events in elderly are associated with increased volume of the amygdala, which is a part of the brain that plays a large role in emotions and stress sensitivity. Enlarged amygdala volume is a common finding in depression and anxiety disorders. However it is thought that this enlargement is only a temporary effect.

2. Stressful life events increase the risk for dementia. However mild stress (e.g. the experience of only one life event within the last few years) is protective for dementia, whereas the experience of two or more events is associated with increased risk for dementia. Particularly for dementia of the vascular type, and less so for Alzheimer’s disease. Stressful life events are also associated with increased risk for cardiovascular disease and hence this finding may mean that the experience of life events can lead to dementia via increased cardiovascular risk.

3. We found that two genes that have previously been shown to play a role in mood disorders and stress sensitivity, also play a role in cognitive decline and this effect is mediated by the experience of life events. When we took into account whole-gene variation we found that the genes FKBP5 and NR3C2, which play role in regulation of stress hormones, showed an interaction with the experience of life events. Individuals who had experienced life events and had the minor (e.g. risk) allele of the most significant genetic variation (SNP) within these genes showed more memory decline over time than persons without life events and/or without the risk allele of these genes.

4. Telomere length is a biomarker for accelerated aging. The experience of life events has previously been associated with shorter telomere length, and shorter telomere length is also related to dementia. In our preliminary analysis within a subsample of our data we found that individuals with shorter telomere length at baseline showed more memory decline over time if they also had experienced 2 or more life events. Whereas there was no main effect of telomere length nor life events on memory functioning over time.

Conclusions based on findings of this research
In all our studies we found that mild stress is not associated with detrimental outcomes. Life events like death of a spouse, a friend or financial problems are fairly common in society and fortunately most of the people are resilient. However if one experiences more than just one life event in a short period there may be increased risk for dementia and cognitive decline. For onset of dementia we found that everyone who experiences two or more life events has a 3 times higher risk of getting demented within the coming 15 years. For early symptoms of dementia, such as cognitive decline we however found that the effect is only seen in those individuals who are already susceptible, due to their genetic makeup.
This research could be relevant to health care providers and even policy makers, as it shows that older people who encounter stressful life events should be monitored better. It might well be that by providing more support and care to these people the onset of dementia could be prevented or at least the suffering from dementia could be reduced.