The role of socio-emotional factors for cognitive health in later life

Abstract: With increasing life expectancies in most parts of the world, the prevalence of dementia and other age-related chronic diseases is growing. Several factors affect future projections and are discussed in this thesis, including possible limits to a continued growth of life expectancy. A related question is to what extent healthy ageing per se affects cognitive functions in old persons. Previous studies have generally exaggerated ageing effects on cognition, by applying study designs that did not account for common confounders, such as birth cohort differences, and the effects of terminal decline and subclinical dementia. In contrast to healthy ageing, dementia neuropathologies dramatically reduce cognitive performance, and proposed mechanisms behind dementia are briefly discussed with focus on Alzheimer’s disease (AD), on the role of genetic factors and on life course exposures. Three studies (study 1-3) investigated how cohabitant status and feelings of loneliness and hopelessness in midlife were associated with cognitive health in later life. Neurotrophic factors could potentially be involved in the biological mechanisms behind these and other associations between life-style factors and cognitive health. The fourth study aimed to explore how levels of brain-derived neurotrophic factor (BDNF), measured in serum, were affected by performing different activities; physical exercise, cognitive training, and mindfulness. THE FOUR STUDIES Study 1-3 were epidemiological association studies based on the Cardiovascular Risk Factor, Ageing and Dementia (CAIDE) Study, a population based cohort study on 1511 persons in eastern Finland, who at baseline were 50.4 years. Two re-examinations have been performed in the CAIDE Study, in 1998 when the participants were between 65 and 80 years, and between 2005-2008, averagely 25.3 years after the baseline examinations. The first two studies were based on the 1409 persons who fully participated in the first re-examination and the third study on the 1511 persons who participated in one or both re-examinations. In the first two studies logistic regression was the main statistical method with any cognitive impairment versus no cognitive impairment as outcome. In addition we performed analyses with mild cognitive impairment and Alzheimer’s disease as separate outcomes. In Study 1 and 2 we also analysed how apolipoprotein epsilon 4 (ApoE4) status affected the associations with Alzheimer’s disease. The statistical method in Study 3 was survival model analysis (Kaplan-Meyer and Cox regression) and the outcome variable was dementia, without subtyping. We compared the results from the analysis on the 1511 participants with the results when we used the total sample (by including register linked data on dementia diagnoses). We adjusted the associations for several potential confounding variables in all three studies. In Study 4 we used 19 elderly healthy volunteers who were between 65 and 80 years (mean = 70.8 years). They performed three different activities during 35 minutes on separate occasions, i.e. a within-subject cross-over experimental design where we randomized the order of the three conditions between the participants. We sampled blood from a suitable lower arm vein directly before and after each activity session and in addition at 20 and 60 minutes after the session had ended. After the serum had been analysed for BDNF levels, we used repeated measures ANOVA to calculate the differences in the effect of BDNF levels between the three conditions. MAIN RESULTS We found that living alone in midlife was associated with approximately a doubled risk of cognitive impairment during the re-examination. Among the non-cohabitants the risk increase was especially high for persons who were widowed in midlife and who had continued to live alone until the re-examination (odds ratio (OR) 7.67, 95% confidence interval (CI) 1.6 – 40.0). Feelings of loneliness were common both among cohabitants and non-cohabitants, but we found that such feelings were only associated with an increased dementia risk if these persons had also been living alone. Feelings of hopelessness in midlife, but not at follow-up, were associated with increased risk of cognitive impairment at the re-examination, especially of Alzheimer’s disease (OR 2.90, CI 1.4 – 5.9). When we adjusted the association from midlife also for depression and hopelessness at the re-examination, this association was still statistically significant. Participants with a diagnosis of cognitive impairment had higher feelings of hopelessness at the re-examination, compared to the cognitively healthy group, but this difference between the groups existed already when they were in midlife. When we stratified the participants with reference to ApoE4 status, we found that participants who were also ApoE4 carriers had a dramatically increased risk of Alzheimer’s disease compared to non-carriers without feelings of hopelessness, even after final adjustment for depression (OR 6.48, CI 2.4 –17.5). A similar stratification for ApoE4 status in Study 1 showed an even more dramatic increase in the association for persons who had lost their partner (widowed or divorced/separated) if they in addition were ApoE4 carriers. In Study 4 we found that physical exercise, but not cognitive training or mindfulness, led to a statistically significant increase in BDNF levels of around 25%, compared to baseline. We also found that the individual differences in BDNF levels after the physical exercise correlated with working memory performance, measured on a separate occasion. CONCLUSIONS Social and emotional factors can have long-term consequences for cognitive health in later life. The long follow-up time in Study 1-3 suggests that the associations we found with dementia could reflect a causal, rather than a prodromal, relation. As other studies have found a range of adverse ill health consequences from both living alone and from depressive feelings, a possible mechanism behind the associations we found could be related to a systemic biological impact, and that the specific ill health outcome could be a result of individual vulnerability where genetic dispositions could play an important role. This conclusion seems consistent with the dramatic risk increases we found for AD when ApoE4 status was combined with the social factor of living alone and with the emotional dimension of hopelessness. At the micro level, as synaptic dysfunction and loss is characteristic of Alzheimer’s disease, and as BDNF has a central role for synaptogenesis, impaired BDNF functionality could play a role in the development of Alzheimer’s disease. More research is needed to further explore the role of BDNF in Alzheimer’s disease and if the disease can be prevented, or the disease process halted, by activities that stimulate BDNF expression in the brain.