An Ironic Tragedy: Are Spouses of Persons with Dementia at Higher Risk for Dementia than Spouses of Persons without Dementia?
Year: 2010
Type: article
Abstract: This issue of JAGS includes an article by Norton and colleagues1 that reports a 600% greater risk of dementia in spouses of persons with dementia than in spouses of persons without dementia even after controlling for important risk factors for dementia. The authors explain their provocative finding using three arguments previously employed to understand the higher risks of health problems seen in spouses of persons with dementia than in spouses of persons without dementia. These include assortative mating, a shared lifestyle, and caregiving.2 However, no caregiver data are presented to support their argument (e.g., hours of care, length of care, caregiver distress, health habits, and health problems), and this study was not designed to test the hypothesis that caregiving is a risk factor for dementia. Despite these limitations, many of the spouses of persons with dementia were probably caregivers, and although it is not possible to conduct mediation analyses to interpret this study's results, the literature includes several caregiver outcomes that may be postulated as reasons for the observed higher dementia risk in spouses of persons with dementia. Thousands of articles have reported greater psychological and physical health problems in caregivers than in noncaregivers,2, 3 although it was not until 2003 that cognition of caregivers and noncaregivers was compared. Norton and colleagues1 present much of this research to support their finding. Two of these articles observed greater cognitive decline in caregivers than in demographically similar noncaregivers; variables salient to dementia mediated these differences. Caregivers having higher composite scores for obesity, fasting insulin, and fasting glucose than noncaregivers mediated greater 2-year decline in vocabulary in caregivers than in noncaregivers, and higher depressed mood in caregivers than noncaregivers mediated a 4.5 times faster 2-year decline in processing speed in caregivers than in noncaregivers. Caregivers in these samples also declined 85% faster on self-rated physical functioning than did noncaregivers after controlling for functioning at study entry and important covariates. Processing speed at study entry, processing speed decline from study entry to 1 year later, psychological distress at study entry, C-reactive protein (CRP), and increases in CRP from study entry to 2 years later mediated this.4 Several other putative intervening variables between caregiving and incident dementia should be considered. The first domain includes psychosocial and behavioral risk factors. Spouse caregivers of persons with dementia are more likely to have greater depressed mood than demographically similar spouse noncaregivers3 and to report poorer sleep quality than noncaregivers.5 Depressed mood is a potential risk factor for dementia,6 as are sleep problems.7 Caregivers may also be more socially isolated and lonelier than noncaregivers,8 and these experiences are associated with less social engagement and less-stimulating cognitive activities, which may increase the risk for dementia.9 Caregivers also report greater daily calorie and fat intake,2 less physical activity,10 and less time to exercise11 than do noncaregivers. Poor diet and less physical activity may increase the risk for dementia.12, 13 The second domain of putative mediators includes interrelated physiological risk factors. In a meta-analysis of family caregivers of persons with dementia and noncaregivers who were similar in age, sex, and type of relationship, stress hormones had the largest mean effect size (correlation coefficient=0.23) of 11 health categories.2 This is important because high levels of cortisol are associated with less hippocampus volume and brain glucose metabolism.14 Insulin is critical to brain regions involved in learning and memory,15, 16 and hyperinsulinemia is associated with greater dementia risk.17-19 Similarly, caregivers have greater weight gain, waist size, and obesity than noncaregivers.20-22 Seventy-three caregivers of persons with AD had higher fasting insulin levels at study entry and 15 to 18 months later than did 69 demographically similar noncaregivers, even after obesity, exercise, sex, age, alcoholic drinks, hormone replacement therapy, lipids, and hypertension were controlled for in the analyses.23 Higher fasting insulin levels were also observed in another study of 123 spouse caregivers of persons with Alzheimer's disease (AD) than in 117 spouse noncaregivers at study entry and 1 and 2 years later, after adjusting for covariates.21 These results may be noteworthy because insulin resistance is associated with greater cerebral inflammation and amyloid-beta protein levels, which form the "plaques" seen in AD.24 Alternatively, reductions in stressors may decrease proinflammatory cytokine levels (interleukin-6 (IL-6)),25 and depression and stressful experiences may increase pro-inflammatory cytokines.26 In response to circulating proinflammatory cytokines, the liver releases CRP, which harms artery linings. High CRP levels may also increase the risk of dementia.25 Insulin resistance can damage blood vessels, diminish cerebral blood flow, and promote inflammation.27 The results of these studies are important for dementia risk in caregivers because IL-6 serum levels increased over 6 years in caregivers at a rate 400% higher than in age-matched noncaregivers.28 Also, over 2 years, CRP levels increased in caregivers significantly more than in noncaregivers despite them having had similar levels at study entry.4 Caregivers of persons with AD also have significantly higher plasma D-dimer levels (intravascular thrombosis) than noncaregivers.29 Finally, over 6 years of follow-up, caregivers who provided the most assistance to their spouses with AD had greater risk of reaching at least one frank cardiovascular event than other caregivers and noncaregivers.30 Another major finding of the current study is that "the association between spousal dementia and subsequent dementia in the caregiver was stronger for husbands 'caring for' wives with dementia than for wives 'caring for' husbands with dementia." Although this was contrary to what Norton and colleagues1 predicted, it is what one would have predicted given the literature. Men have higher rates of chronic illnesses and less longevity than women, and widowers have more illnesses and higher rates of mortality than widows. Men also have greater physiological reactivity to laboratory stressors than do women, which may be exacerbated when faced with caregiving.2 Male caregivers are more physiological reactive to laboratory stressors than female caregivers or male noncaregivers.2 Male caregivers also have lower high-density lipoprotein levels than male noncaregivers, but this is not true for female caregivers and noncaregivers.2 This may be important because high cholesterol is a risk factor for dementia. Given this literature, one would have expected the difference in hazard rate ratios (HRRs) between caregivers and noncaregivers to be significantly different for men and women, but Norton and colleagues1 reported them as not significantly different using the method of overlapping confidence intervals. Unfortunately, when the null hypothesis is false, this method mistakenly fails to reject it (e.g., no sex differences in HHRs) more frequently than a formal test. As the authors note, replications with larger samples of men are in order. In conclusion, to interpret and extend the current results, future work should address several things. First, during this study's follow-up, incident dementia was 14.8% for spouses of persons with dementia and 10.0% for spouses of persons without dementia, but when the authors incorporated into their analysis the amount of time that spouses were exposed to their spouses' dementia, the added risk increased from 48% to 600%. This occurred even after adjusting for age, sex, education, socioeconomic status, and the presence of at least one apolipoprotein E ɛ4 allele (vs no ɛ4 allele). We need to understand how length of exposure and its interactions with demographic, psychosocial, behavioral, and physiological variables serve to increase the risk of dementia so dramatically. For example, age may exacerbate dementia risk in caregivers, because it is associated with increases in cortisol levels, chronic inflammation, and dementia incidence. Caregivers who are older before exposure may be at greater risk for chronic diseases, neurological problems, and acute events (e.g., strokes) than older noncaregivers, but such differences may not be as great for younger caregivers and noncaregivers. Hence, length of exposure may be more serious for older than younger spouse caregivers. Such differences could have major implications for preventing dementia in younger caregivers. Ethnicity is also relevant to caregiver dementia risk, because it is related to health disparities and caregiver distress.2 In Norton's article, the ethnic composition of the Cache County sample is not provided, but the county is reported to be 92% white, with small percentages of Asian, Native, and African Americans. As such, it is unclear to what degree the added dementia risk for spouses of persons with dementia versus spouses of persons without dementia exists for other Americans. Finally, several factors may confer a higher dementia risk in spouse caregivers than spouse noncaregivers, but many of them probably share similar pathological processes and are predictive of similar illnesses. Hence, repeated associations between putative risk factors and incident dementia are only necessary and not sufficient conditions for causality. It may be difficult to distinguish prognostic factors, causal intervening variables, and symptoms of preclinical dementia (e.g., inflammation is associated with dementia, depression, diabetes mellitus, coronary disease, obesity, and AD).31 Research must determine whether inflammation before dementia is an early independent predictor, a contributing factor, or simply a preclinical effect of slowly evolving dementia.32 To better understand such relationships it may be necessary to perform doubly prospective studies. These could examine several potential intervening variables simultaneously before and after the incidence of caregiving and the incidence of dementia and test for mediation by examining changes in putative intervening variables relative to incident caregiving and incident dementia. Despite potential confounding of risk factors with actual causes of dementia, these factors are presented here because data suggest that they are more likely to occur in spouse caregivers than spouse noncaregivers and they may be predictive of dementia. In sum, rather than being alarmed by the results reported here,1 stakeholders, policy-makers, clinicians, and researchers should be motivated to support and design appropriate studies that, if proved positive, can be used to plan interventions and preventions to prepare for the projected increases in dementia expected in the decades ahead. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. This work was supported by National Institutes of Health Grants 5R01MH057663-05 and 5R01MH043267-05. Author Contributions: Sole author. Sponsor's Role: None.
Author: Peter P. Vitaliano
Institution: University of Washington
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2087065717