Scheltens ratings, clinical white matter hyperintensities and executive functioning in the Cache County Memory Study.

OBJECTIVE: Examine the association between neuropsychologically assessed executive function and clinically identifiable white matter burden from magnetic resonance imaging, using a visual rating system (Scheltens Rating System) applied to the Cache County Memory Study (CCMS) archival database. METHOD: We used the Scheltens Ratings Scale to quantify white matter lesion burden in the CCMS sample and used this metric as a predictor of executive function. The sample included 60 individuals with dementia and 13 healthy controls. RESULTS: Higher Scheltens ratings were associated with poorer task performance on an Executive Function composite score of common neuropsychological tests. This association held true for both controls and dementing cases. CONCLUSIONS: The current findings support extensive prior literature demonstrating the association between brain vascular health determined by white matter burden and clinical outcomes based on neuropsychological assessment of cognitive performance.

Malnutrition and neuropsychiatric symptoms in dementia: the Cache County Dementia Progression Study.

OBJECTIVES: Among people with dementia, poor nutritional status has been associated with worse cognitive and functional decline, but few studies have examined its association with neuropsychiatric symptoms (NPS). We examined this topic in a population-based sample of persons with dementia. DESIGN: Longitudinal, observational cohort study. SETTING: Community. PARTICIPANTS: Two hundred ninety-two persons with dementia (71.9% Alzheimer's disease, 56.2% women) were followed up to 6 years. MEASUREMENTS: We used a modified Mini-Nutritional Assessment (mMNA) and the Neuropsychiatric Inventory (NPI) to evaluate nutritional status and NPS, respectively. Individual linear mixed effects models examined the associations between time-varying mMNA total score or clinical categories (malnourishment, risk for malnourishment, or well-nourished) and NPI total score (excluding appetite domain) or NPI individual domain or cluster (e.g. psychosis) scores. Covariates tested were dementia onset age, type, and duration, medical comorbidities, sex, apolipoprotein E (APOE) genotype, and education. RESULTS: Compared to the well-nourished, those at risk for malnourishment and those malnourished had higher total NPI scores [b (95% CI) = 1.76 (0.04, 3.48) or 3.20 (0.62, 5.78), respectively], controlling for significant covariates. Higher mMNA total score (better nutritional status) was associated with lower total NPI [b (95% CI) = -0.58 (-0.86, -0.29)] and lower domain scores for psychosis [b (95% CI) = -0.08 (-0.16, .004)], depression [b (95% CI = -0.11 (-0.16, -0.05], and apathy [b (95% CI = -0.19 (-0.28, -0.11)]. CONCLUSIONS: Worse nutritional status is associated with more severe NPS. Dietary or behavioral interventions to prevent malnutrition may be beneficial for persons with dementia.

How good are medical and death records for identifying dementia?

INTRODUCTION: Retrospective studies using administrative data may be an efficient way to assess risk factors for dementia if diagnostic accuracy is known. METHODS: Within-individual clinical diagnoses of Alzheimer's disease (AD) and all-cause dementia in ambulatory (outpatient) surgery, inpatient, Medicare administrative records and death certificates were compared with research diagnoses among participants of Cache County Study on Memory, Health, and Aging (CCSMHA) (1995-2008, N = 5092). RESULTS: Combining all sources of clinical health data increased sensitivity for identifying all-cause dementia (71%) and AD (48%), while maintaining relatively high specificity (81% and 93%, respectively). Medicare claims had the highest sensitivity for case identification (57% and 40%, respectively). DISCUSSION: Administrative health data may provide a less accurate method than a research evaluation for identifying individuals with dementing disease, but accuracy is improved by combining health data sources. Assessing all-cause dementia versus a specific cause of dementia such as AD will result in increased sensitivity, but at a cost to specificity.

Neuropsychiatric Symptoms as Risk Factors for Cognitive Decline in Clinically Normal Older Adults: The Cache County Study.

INTRODUCTION: There has been considerable progress in identifying early cognitive and biomarker predictors of Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are common in AD and appear to predict progression after the onset of mild cognitive impairment or dementia. OBJECTIVES: The objective of the study is to examine the relationship between NPS in clinically normal older adults and subsequent cognitive decline in a population-based sample. METHODS: The Cache County Study on Memory in Aging consists of a population-based sample of 5,092 older adults. We identified 470 clinically normal adults who were followed for an average period of 5.73 years. NPS were evaluated at the baseline clinical assessment using the Neuropsychiatric Inventory (NPI). NPI domain scores were quantified as the product of frequency X severity in individual NPI domains, and then summed for the NPI-Total. Neuropsychological measures were collected at baseline and at each subsequent follow-up wave. Linear mixed-effects models assessed the association of NPI-Total, NPI-Depression, and NPI-Anxiety scores (obtained at baseline) on longitudinal change in neuropsychological performance, controlling for age, sex, and education. RESULTS: Baseline NPI-Total score was associated with a more rapid rate of decline in word list memory, praxis recall, and animal fluency. Baseline NPI-Depression was not associated with later decline on any of the cognitive tests, while baseline NPI-Anxiety was associated with decline in Symbol Digit Modality. CONCLUSION: In conclusion, among clinically normal older adults derived from this population-based study, total burden of NPS was associated with longitudinal cognitive decline. These results add to the evidence that NPS are risk factors for or clinical indicators of preclinical dementia syndrome. Our study was an exploratory study and we did not control for multiple comparisons.

Interaction Between Physical Activity and Genes Related to Neurotrophin Signaling in Late-Life Cognitive Performance: The Cache County Study.

Research indicates that lifestyle and genetic factors influence the course of cognitive impairment in aging, but their interactions have not been well-examined. This study examined the relationship between physical activity and genotypes related to brain-derived neurotrophic factor (BDNF) in predicting cognitive performance in a sample of older adults with up to 12 years of follow-up. Physical activity levels (sedentary, light, and moderate/vigorous) were determined for the sample of 3,591 participants (57% female) without dementia. The genotypes examined included BDNF gene single nucleotide polymorphisms (SNPs) (rs6265 and rs56164415) and receptor gene SNPs (NTRK2 rs2289656 and NGFR rs2072446). Cognition was assessed triennially using the Modified Mini-Mental State Exam. Unadjusted linear mixed models indicated that sedentary (ß = -5.05) and light (ß = -2.41) groups performed worse than moderate-vigorous (p < .001). Addition of interaction effects showed significant differences in rate of decline between activity levels, particularly among males (p = .006). A three-way interaction with sex, NGFR SNP rs2072446, and physical activity suggested that the C/C allele was associated with better cognitive performance among males engaging in light activity only (p = .004). Physical activity and sex, but not BDNF-related SNPs, predicted rate of cognitive decline in older adults, while NGFR rs2072446 may modify main effects.

Lifetime estrogen exposure and cognition in late life: the Cache County Study.

OBJECTIVE: Prevalence of Alzheimer's disease (AD) is higher for women, possibly influenced by sex-dependent effects of the estrogen. We examined the association between estrogen and cognitive decline in over 2,000 older adult women in a 12-year population-based study in Cache County, Utah. METHODS: The baseline sample included 2,114 women (mean age = 74.94 y, SD = 6.71) who were dementia-free at baseline and completed a women's health questionnaire, asking questions regarding reproductive history and hormone therapy (HT). Endogenous estrogen exposure (EEE) was calculated taking the reproductive window (age at menarche to age at menopause), adjusted for pregnancy and breastfeeding. HT variables included duration of use, HT type (unopposed; opposed), and time of HT initiation. A modified version of the Mini-Mental State Examination (3MS) was administered at four triennial waves to assess cognitive status. Linear mixed-effects models examined the relationship between estrogen exposure and 3MS score over time. RESULTS: EEE was positively associated with cognitive status (ß = 0.03, P = 0.054). In addition, longer duration of HT use was positively associated with cognitive status (ß = 0.02, P = 0.046) and interacted with age; older women had greater benefit compared with younger women. The timing of HT initiation was significantly associated with 3MS (ß = 0.55, P = 0.048), with higher scores for women who initiated HT within 5 years of menopause compared with those initiating HT 6-or-more years later. CONCLUSIONS: Our results suggest that longer EEE and HT use, especially in older women, are associated with higher cognitive status in late life.

Association study of rs3846662 with Alzheimer's disease in a population-based cohort: the Cache County Study.

3-Hydroxy-3-methylglutaryl coenzyme A reductase is associated with monitoring cholesterol levels. The presence of the single-nucleotide polymorphism rs3846662 introduces alternative splicing at exon 13; the exclusion of this exon leads to a reduction in total cholesterol levels. Lower cholesterol levels are linked to a reduction in Alzheimer's disease (AD) risk. The major allele of rs3846662, which encourages the splicing of exon 13, has recently been shown to act as a preventative allele for AD, especially in women. The purpose of our research was to replicate and confirm this finding. Using logistic regressions and survival curves, we found a significant association between AD and rs3846662, with a stronger association in individuals who carry the APOE e4 allele, supporting previously published work. The effect of rs3846662 on women is insignificant in our cohort. We confirmed that rs3846662 is associated with reduced risk for AD without gender differences; however, we failed to detect association between rs3846662 and delayed mild cognitive impairment conversion to AD for either of the APOE e4 allelic groups.

Neuropsychiatric symptoms in severe dementia: Associations with specific cognitive domains the Cache County Dementia Progression Study.

OBJECTIVES: To examine the prevalence of neuropsychiatric symptoms (NPS) and cognitive correlates in severe dementia. METHODS: A population-based sample of 56 individuals with severe dementia (85.7% Alzheimer's type; 67.9% female) were assessed with the Severe Cognitive Impairment Profile (SCIP) and the Neuropsychiatric Inventory (NPI). Descriptive statistics displayed the frequency of NPS and bivariate and multiple regression analyses examined the associations between cognitive domains on the SCIP and NPS total, domain, and cluster scores. RESULTS: NPS were common in severe dementia with 98% of the sample exhibiting at least one symptom. Most common were delusions, apathy, agitation/aggression, and aberrant motor behavior, affecting 50% or more of participants. SCIP comportment was significantly associated with NPI total score and apathy (r = -.350 and -.292, respectively). All SCIP domains except for arithmetic, visuospatial, comportment, and motor behavior were significantly associated with agitation/aggression (r = -.285 to -.350). These associations remained in individual multiple regression models. CONCLUSION: In severe dementia, impairment in specific cognitive domains was associated with more severe NPS. Environmental manipulations to reduce processing demands in persons with severe dementia may be a useful strategy to target agitation and aggressive behaviors.

Neuropsychiatric symptoms in patients with dementia and the longitudinal costs of informal care in the Cache County population.

INTRODUCTION: Severity of dementia and neuropsychiatric symptoms contribute to increasing informal care costs. We examined which neuropsychiatric symptoms subdomains (NPS-SD) were associated with informal costs in a population-based sample. METHODS: Dementia progression and informal costs (2015 dollars) were estimated from the Cache County Dementia Progression Study. Overall NPS and specific NPS-SD were assessed with the Neuropsychiatric Inventory. Generalized Estimating Equations (GEE with gamma-distribution/log-link) modeled the relationship between NPS-SDs and informal cost trajectories. RESULTS: Two hundred eighty participants (52.1% female; age M = 85.67, SD = 5.60) exhibited an adjusted cost increase of 5.6% (P = .005), 6.4% (P < .001), 7.6% (P = .030), and 13% (P = .024) for every increasing Neuropsychiatric Inventory unit in psychosis-SD, affective-SD, agitation/aggression-SD, and apathy-SD, respectively. An increase in each unit of apathy was associated with a 2% annual decrease in costs (P = .040). DISCUSSION: We extend our prior work on informal costs and dementia severity by identifying NPS-SD associated with informal costs. Interventions targeting NPS-SD may lower informal costs.

Caregiver-Care Recipient Relationship Closeness is Associated With Neuropsychiatric Symptoms in Dementia.

OBJECTIVE: Closer caregiver-care recipient (CG-CR) relationships are associated with better cognitive and functional abilities, activities of daily living (in persons with dementia), and lower informal care costs. METHODS: Due to the difficulty in treating neuropsychiatric symptoms (NPSs) and their detrimental effects on caregivers and care recipients, we examined whether closeness of CG-CR relationships was associated with overall NPS severity or with specific NPS symptom domains in care recipients. In a longitudinal population-based study in Cache County, Utah, the 12-item Neuropsychiatric Inventory (NPI-12) was assessed in 300 CG-CR dyads. Caregivers reported current relationship closeness using the Whitlatch Relationship Closeness Scale. Linear mixed models examined associations between CG-CR closeness and NPI-12 total score or selected symptom domains over time (observation period: 2002-2012). RESULTS: In unadjusted linear mixed models, higher closeness scores were associated with a five-point lower NPI-12 score and a one-point lesser increase in NPI-12 per year. NPI scores also showed lower affective cluster scores (two points) and lesser increase in psychosis cluster (approximately 0.5 points per year) and agitation/aggression (0.16 points per year) for each unit increase in closeness. When controlling for NPI caregiver distress, associations between closeness and NPSs diminished to a 0.5-point lesser increase in total NPI-12 score per year. Adjusted models for NPI domains/clusters showed -0.32 points per year for the psychosis cluster, -0.11 points per year for agitation/aggression, and -0.67 overall for the affective cluster. CONCLUSION: Higher CG-CR closeness, a potentially modifiable factor, is associated with lower NPS severity and may provide a target for intervention.

Nutritional Status is Associated With Severe Dementia and Mortality: The Cache County Dementia Progression Study.

PURPOSE: Studies have reported faster cognitive/functional decline in persons with dementia (PWD) with malnutrition. We investigated whether baseline nutritional status predicted severe dementia and mortality in a population-based sample. PATIENTS: A maximum of 300 PWD were assessed annually for up to 8.6 years. METHODS: Nutritional status was assessed using a modified Mini-Nutritional Assessment (mMNA). Severe dementia was defined as: "severe" rating on the Clinical Dementia Rating or Mini-Mental State Examination score ≤10. Using Cox proportional hazards models, we examined the association between baseline mMNA score (or its subcomponents) with each outcome. Covariates included demographics; dementia onset age, type, and duration; APOE genotype; and residency with caregiver. RESULTS: Compared with "well-nourished," "malnourished" PWD had 3-4 times the hazard of severe dementia [hazard ratio (HR), 4.31; P=0.014] and death (HR, 3.04; P<0.001). Those "at risk for malnutrition" had twice the hazard of severe dementia (HR, 1.98; P=0.064) and 1.5 times the hazard of death (HR, 1.46; P=0.015). mMNA subcomponents of food group intake, weight loss, body mass index, mobility, health status, protein consumption, and mid-arm circumference predicted one or both outcomes. CONCLUSIONS: Nutritional status is an important predictor of clinical outcomes in dementia and may provide an avenue for intervention.

Use of FDA approved medications for Alzheimer's disease in mild dementia is associated with reduced informal costs of care.

ABSTRACTBackground:The use of FDA approved medications for Alzheimer's disease [AD; FDAAMAD; (cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists)] has been associated with symptomatic benefit with a reduction in formal (paid services) and total costs of care (formal and informal costs). We examined the use of these medications and their association with informal costs in persons with dementia. METHOD: Two hundred eighty participants (53% female, 72% AD) from the longitudinal, population-based Dementia Progression Study in Cache County, Utah (USA) were followed up to ten years. Mean (SD) age at baseline was 85.6 (5.5) years. Informal costs (expressed in 2015 dollars) were calculated using the replacement cost method (hours of care multiplied by the median wage in Utah in the visit year) and adjusted for inflation using the Medical Consumer Price Index. Generalized Estimating Equations with a gamma log-link function were used to examine the longitudinal association between use of FDAAMAD and informal costs. RESULTS: The daily informal cost for each participant at baseline ranged from $0 to $318.12, with the sample median of $9.40. Within the entire sample, use of FDAAMAD was not significantly associated with informal costs (expß = 0.73, p = 0.060). In analyses restricted to participants with mild dementia at baseline (N = 222), use of FDAAMAD was associated with 32% lower costs (expß = 0.68, p = 0.038). CONCLUSIONS: Use of FDAAMAD was associated with lower informal care costs in those with mild dementia only.

Sex Differences in Risk for Alzheimer's Disease Related to Neurotrophin Gene Polymorphisms: The Cache County Memory Study.

Neurotrophins, including nerve-growth factor and brain-derived neurotrophic factor, have been implicated in Alzheimer's disease (AD). Associations between AD and neurotrophin signaling genes have been inconsistent, with few studies examining sex differences in risk. We examined four single-nucleotide polymorphisms (SNPs) involved in neurotrophin signaling (rs6265, rs56164415, rs2289656, rs2072446) and risk for AD by sex in a population-based sample of older adults. Three thousand four hundred and ninety-nine individuals without dementia at baseline [mean (standard deviation) age = 74.64 (6.84), 58% female] underwent dementia screening and assessment over four triennial waves. Cox regression was used to examine time to AD or right censoring for each SNP. Female carriers of the minor T allele for rs2072446 and rs56164415 had a 60% (hazard ratio [HR] = 1.60, 95% confidence interval [CI] = 1.02-2.51) and 93% (HR = 1.93, 95% CI = 1.30-2.84) higher hazard for AD, respectively, than male noncarriers of the T allele. Furthermore, male carriers of the T allele of rs2072446 had a 61% lower hazard (HR = 0.39, 95% CI = 0.14-1.06) than male noncarriers at trend-level significance (p = .07). The association between certain neurotrophin gene polymorphisms and AD differs by sex and may explain inconsistent findings in the literature.

The Empowering Role of Mobile Apps in Behavior Change Interventions: The Gray Matters Randomized Controlled Trial.

BACKGROUND: Health education and behavior change programs targeting specific risk factors have demonstrated their effectiveness in reducing the development of future diseases. Alzheimer disease (AD) shares many of the same risk factors, most of which can be addressed via behavior change. It is therefore theorized that a behavior change intervention targeting these risk factors would likely result in favorable rates of AD prevention. OBJECTIVE: The objective of this study was to reduce the future risk of developing AD, while in the short term promoting vascular health, through behavior change. METHODS: The study was an interventional randomized controlled trial consisting of subjects who were randomly assigned into either treatment (n=102) or control group (n=42). Outcome measures included various blood-based biomarkers, anthropometric measures, and behaviors related to AD risk. The treatment group was provided with a bespoke "Gray Matters" mobile phone app designed to encourage and facilitate behavior change. The app presented evidence-based educational material relating to AD risk and prevention strategies, facilitated self-reporting of behaviors across 6 behavioral domains, and presented feedback on the user's performance, calculated from reported behaviors against recommended guidelines. RESULTS: This paper explores the rationale for a mobile phone-led intervention and details the app's effect on behavior change and subsequent clinical outcomes. Via the app, the average participant submitted 7.3 (SD 3.2) behavioral logs/day (n=122,719). Analysis of these logs against primary outcome measures revealed that participants who improved their high-density lipoprotein cholesterol levels during the study duration answered a statistically significant higher number of questions per day (mean 8.30, SD 2.29) than those with no improvement (mean 6.52, SD 3.612), t97.74=-3.051, P=.003. Participants who decreased their body mass index (BMI) performed significantly better in attaining their recommended daily goals (mean 56.21 SD 30.4%) than those who increased their BMI (mean 40.12 SD 29.1%), t80 = -2.449, P=.017. In total, 69.2% (n=18) of those who achieved a mean performance percentage of 60% or higher, across all domains, reduced their BMI during the study, whereas 60.7% (n=34) who did not, increased their BMI. One-way analysis of variance of systolic blood pressure category changes showed a significant correlation between reported efforts to reduce stress and category change as a whole, P=.035. An exit survey highlighted that respondents (n=83) reported that the app motivated them to perform physical activity (85.4%) and make healthier food choices (87.5%). CONCLUSIONS: In this study, the ubiquitous nature of the mobile phone excelled as a delivery platform for the intervention, enabling the dissemination of educational intervention material while simultaneously monitoring and encouraging positive behavior change, resulting in desirable clinical effects. Sustained effort to maintain the achieved behaviors is expected to mitigate future AD risk. TRIAL REGISTRATION: ClinicalTrails.gov NCT02290912; https://clinicaltrials.gov/ct2/show/NCT02290912 (Archived by WebCite at http://www.webcitation.org/6ictUEwnm).

Presenilin E318G variant and Alzheimer's disease risk: the Cache County study.

BACKGROUND: Alzheimer's disease is the leading cause of dementia in the elderly and the third most common cause of death in the United States. A vast number of genes regulate Alzheimer's disease, including Presenilin 1 (PSEN1). Multiple studies have attempted to locate novel variants in the PSEN1 gene that affect Alzheimer's disease status. A recent study suggested that one of these variants, PSEN1 E318G (rs17125721), significantly affects Alzheimer's disease status in a large case-control dataset, particularly in connection with the APOEε4 allele. METHODS: Our study looks at the same variant in the Cache County Study on Memory and Aging, a large population-based dataset. We tested for association between E318G genotype and Alzheimer's disease status by running a series of Fisher's exact tests. We also performed logistic regression to test for an additive effect of E318G genotype on Alzheimer's disease status and for the existence of an interaction between E318G and APOEε4. RESULTS: In our Fisher's exact test, it appeared that APOEε4 carriers with an E318G allele have slightly higher risk for AD than those without the allele (3.3 vs. 3.8); however, the 95 % confidence intervals of those estimates overlapped completely, indicating non-significance. Our logistic regression model found a positive but non-significant main effect for E318G (p = 0.895). The interaction term between E318G and APOEε4 was also non-significant (p = 0.689). CONCLUSIONS: Our findings do not provide significant support for E318G as a risk factor for AD in APOEε4 carriers. Our calculations indicated that the overall sample used in the logistic regression models was adequately powered to detect the sort of effect sizes observed previously. However, the power analyses of our Fisher's exact tests indicate that our partitioned data was underpowered, particularly in regards to the low number of E318G carriers, both AD cases and controls, in the Cache county dataset. Thus, the differences in types of datasets used may help to explain the difference in effect magnitudes seen. Analyses in additional case-control datasets will be required to understand fully the effect of E318G on Alzheimer's disease status.

Closer caregiver and care-recipient relationships predict lower informal costs of dementia care: The Cache County Dementia Progression Study.

INTRODUCTION: Identifying factors associated with lower dementia care costs is essential. We examined whether two caregiver factors were associated with lower costs of informal care. METHODS: A total of 271 care dyads of the Cache County Dementia Study were included. Estimates of informal costs were based on caregiver reports of time spent in care-related activities and inflation-adjusted 2012 Utah median hourly wages. Caregiver coping and emotional closeness with the care-recipient were assessed using the Ways of Coping Checklist-Revised and Relationship Closeness Scale, respectively. RESULTS: Higher closeness was associated with 24% lower costs (expß = 0.763 [95% confidence interval: 0.583-0.999]) in linear mixed models controlling for demographics and baseline dementia severity and duration. Problem-focused coping was not associated with informal costs (P = .354). DISCUSSION: Caregiver closeness, a potentially modifiable factor, predicted lower dementia informal care costs over time. Future studies examining the care environment in closer dyads may identify specific care-related behaviors or strategies that are associated with lower costs.

Nutritional Status is Associated with Faster Cognitive Decline and Worse Functional Impairment in the Progression of Dementia: The Cache County Dementia Progression Study1.

Nutritional status may be a modifiable factor in the progression of dementia. We examined the association of nutritional status and rate of cognitive and functional decline in a U.S. population-based sample. Study design was an observational longitudinal study with annual follow-ups up to 6 years of 292 persons with dementia (72% Alzheimer's disease, 56% female) in Cache County, UT using the Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-sb), and modified Mini Nutritional Assessment (mMNA). mMNA scores declined by approximately 0.50 points/year, suggesting increasing risk for malnutrition. Lower mMNA score predicted faster rate of decline on the MMSE at earlier follow-up times, but slower decline at later follow-up times, whereas higher mMNA scores had the opposite pattern (mMNA by time ß= 0.22, p = 0.017; mMNA by time2 ß= -0.04, p = 0.04). Lower mMNA score was associated with greater impairment on the CDR-sb over the course of dementia (ß= 0.35, p <  0.001). Assessment of malnutrition may be useful in predicting rates of progression in dementia and may provide a target for clinical intervention.

Family member deaths across adulthood predict Alzheimer's disease risk: The Cache County Study.

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.