Maria C. Norton

While age and the APOE ε4 allele are major risk factors for Alzheimer’s disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline. We used over 200 “AD resilient” individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs. Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value = 0.028, odds ratio = 0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value = 0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aβ42 (p value = 0.0003) and in the Aβ42/Aβ40 ratio (p value = 0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04). Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.

To address the worldwide epidemic of obesity, a sizable literature implicates sleep problems in the onset of obesity in younger populations. However, less is known about how this process may operate among older adults, which is of concern, given demographic shifts that have resulted in a much higher proportion of developed nations around the world reaching late life. We offer a current review of the literature studying older adults and examining associations between sleep quality and obesity in this population. We consider both subjective and objectively measured sleep as well as both cross-sectional and longitudinal studies offering stronger causal inference. We discuss seemingly contradictory literature showing that shorter sleep duration as well as longer sleep duration are associated with obesity risk, then review studies that tested for non-linear relationships and reported a U-shape pattern, suggesting that too much or too little sleep is detrimental. Besides sleep duration, we discuss evidence showing that other forms of sleep dysfunction related to night-time awakenings, REM sleep, slow-wave sleep, and daytime sleepiness, which are indicators of sleep quality, are also linked to obesity. Specific psychological and physiological mediators and moderators, suggesting possible mechanisms whereby sleep problems may affect obesity in older adults, are described. We conclude by discussing areas, where additional research could help clarify this association, considering such factors as medical comorbidities common in late life, and health-related behaviors that may stem from poor sleep (such as disordered eating behavior). Such insights will have great value for clinical practice. Level V, narrative review.

Biological and epidemiological evidence has linked early-life psychosocial stress with late-life health, with inflammation as a potential mechanism. We report here the association between familial death in childhood and adulthood and increased levels of high-sensitivity C-reactive protein (CRP), a marker of systemic inflammation. The Cache County Memory Study is a prospective study of persons initially aged 65 and older in 1995. In 2002, there were 1,955 persons in the study with data on CRP (42.3 percent male, mean [SD] age = 81.2 [5.8] years), linked with objective data on family member deaths. Using logistic regression, high (> 10 mg/L) versus low (≤ 10 mg/L) CRP was regressed on cumulative parental, sibling, spouse, and offspring deaths during childhood and during early adulthood, adjusted for family size in each period (percentage family depletion; PFD). Findings revealed PFD during childhood to be significantly associated with CRP (OR = 1.02, 95% CI [1.01, 1.04]). Individuals with two or more family deaths were 79 percent more likely to have elevated CRP than those with zero family deaths (OR = 1.79, 95% CI [1.07, 2.99]). Early adulthood PFD was not related to CRP. This study demonstrates a link between significant psychosocial stress in early life and immune-inflammatory functioning in late life, and suggests a mechanism explaining the link between early-life adversity and late-life health.

We determined the feasibility of accessing personal journals and correlating markers of linguistic complexity with all-cause dementia and Alzheimer’s disease (AD). A stratified random sample of 215 older adults reported on lifetime journal writing habits. From 66 of these participants (49% of those with journals), digital photographs of journal text were transcribed then subjected to the Linguistic Inquiry Word Count program to measure linguistic complexity markers: Words per Sentence, Percentage of 6+ Letter Words, Cognitive Mechanics, Percentage of Unique Words, and Percentage of Words that are Numerals. AD diagnosis was made via in-depth clinical protocol. In the larger sample, ever being a journal writer significantly predicted a 53% reduction in all-cause dementia risk. In the subsample with transcribed writings, Percentage of 6+ Letter Words predicted AD and all-cause dementia risk, with all logistic regression models controlling for age, education, gender, and Latter-Day Saints affiliation. These data suggest the potential viability of adulthood language use as a predictive tool for late-life AD risk, both in the linguistic features and the practice of journal writing itself.

Objectives: Parental death during childhood, and offspring and spouse death during adulthood have individually been associated with faster cognitive decline and higher Alzheimer's disease (AD) risk in late life. However, the cumulative effect of childhood and adulthood family deaths on AD risk among different age cohorts has not been studied.Methods: To examine these associations, this prospective cohort study uses a population‐based sample of 4545 initially non‐demented participants (56.7% female; age M = 75.0/SD = 6.9 years) observed at four triennial waves, linked with objective Utah Population Database data on cumulative mother, father, sibling, spouse, and offspring death experienced during childhood and adulthood. Cox regression modeled survival time from baseline interview to AD onset, as a function of family deaths during childhood or adulthood, among different age groups, along with gender and presence of ε4 allele at apolipoprotein E (APOE) polymorphic genetic locus.Results: Age group significantly moderated the relationship between family death and AD; among persons aged 65–69 years at baseline (children of the Great Depression), those exposed to 3–4 deaths and 5+ deaths during adulthood exhibited a doubling of AD risk (adjusted hazard ratio, aHR = 2.25, p = .038, and aHR = 2.72, p = .029), while among persons aged 80 years and older, those exposed to 3–4 deaths during adulthood exhibited lower AD risk (HR = 0.539, p = 0.014). In a combined model of childhood and adulthood deaths, these findings persisted.Conclusions: Results suggest a cohort effect in the link between family member deaths during adulthood and AD risk later in life. Copyright © 2015 John Wiley & Sons, Ltd.

Introduction: Most Alzheimer's disease (AD) prevention studies focus on older adults or persons with existing cognitive impairment. This study describes the design and progress of a novel pilot intervention, the Gray Matters study. Methods: This proof‐of‐concept randomized controlled trial tests an evidence‐based multidomain lifestyle intervention in 146 persons aged 40 to 64 years, in northern Utah. Data collectors were blinded to participants' randomization to treatment (n = 104) or control (n = 42). Intervention targeted physical activity, food choices, social engagement, cognitive simulation, sleep quality, and stress management, and uses a custom smartphone application, activity monitor, and educational materials. Secondary outcomes include biomarkers, body mass index, cognitive testing, and psychological surveys. Results: Midway through the study, achievements include a 98.7% retention rate, a 96% rate of compliance with app data entry, and positive trends in behavioral change. Discussion: Participants were empowered, learning that lifestyle might impact AD risk, exhibiting positive behavioral changes thus far.

Objectives: Prior research identifies that psychological outcomes among dementia caregivers are associated with their use of coping strategies. Few studies have tested the association of coping and health longitudinally. Method: This study examined factors associated with the use of coping strategies over time and their associations with physical and mental health outcomes in a population-based sample of 226 dementia caregivers in Cache County, Utah, USA. Caregivers annually completed the Ways of Coping Checklist-Revised, the Beck Anxiety Inventory, and a health interview. Care-recipient cognitive and functional abilities were obtained using the Mini-Mental State Exam and the Clinical Dementia Rating. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory. Results: Caregivers most frequently identified providing care as a problem (37.6%). Linear mixed models of caregiver coping strategies found that the use of most strategies were stable except for increasing Avoidance among adult child caregivers (β = 0.14, p = 0.048). On average, increased Wishful Thinking (β = 2.48, p < 0.001) or Blames Self (β = 1.06, p = 0.002) was associated with higher anxiety scores. Increased use of Blames Others among males (interaction, β = 0.28, p = 0.02) and greater use of Wishful Thinking among younger caregivers (interaction, β = −0.01, p = 0.01) were associated with more caregiver health conditions. Coping strategies were not associated with change in anxiety or health conditions over time. Conclusion: Our results emphasize the importance of caregiver coping strategies on caregiver health and well-being and may identify subgroups of persons at risk for worse outcomes.

Objective In recent decades, biological evidence has implicated chronic stress in the etiology of Alzheimer's disease (AD). As a result, the relationship between widowhood, one of the most stressful life events, and AD has also received attention. This study extends this literature by investigating whether depression, which may indicate proneness to distress, and antidepressant use, which can protect against hippocampal shrinkage, moderate the relationship between widowhood and increased risk for AD. Methods To investigate this, this study utilized data from the Cache County Memory Study, a large population-based epidemiological study of AD, and the Utah Population Database, one of the world's foremost linked genealogical databases, to regress AD on the interaction between widowhood and history of depression and antidepressant use. Results In Cox regression analyses, history of depression and antidepressant use moderated the association between widowhood and AD (p = 0.007 and p = 0.006, respectively), in that widowhood was associated with 73% and 94% increased hazard of AD among those reporting depression (hazard ratio [HR] = 1.73, 95% confidence interval [CI]: 1.001 to 2.99) and those reporting antidepressant use (HR = 1.94, 95% CI: 1.13 to 3.33). A significant three-way interaction between widowhood, depression, and antidepressant use was also found (p = 0.02), showing depression to moderate the association between widowhood and AD only among those not using antidepressants (p = 0.02). Conclusions These findings advance clinical and scientific knowledge concerning the effects of widowhood on risk for AD and underscore the importance of depression and antidepressant use in understanding vulnerability to and protection from these effects. Copyright © 2014 John Wiley & Sons, Ltd.