Cache County Memory Study Research Articles

Scheltens ratings, clinical white matter hyperintensities and executive: Functioning in the Cache County Memory Study

ObjectiveExamine 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.MethodWe 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.ResultsHigher 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.ConclusionsThe 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.

Sex differences in risk for Alzheimer’s disease with extended maternal and paternal family history and vascular risk factors. The Cache County Study.

AbstractBackgroundAge, family history (FH), APOE status, and vascular factors are known risk factors for Alzheimer’s disease (AD). Sex differences in AD risk have been reported for some but not all of these factors. We examined sex differences in the association between FH and AD risk, studying the role of maternal/paternal lineage, parental longevity, and vascular factors in a population‐based cohort.Methods3677 participants (59% female) of the Cache County Memory Study [mean(SD) age = 75.75(7.11) years] were studied. FH of AD and health information were obtained from self‐report or Medicare claims and death certificates via data linkage through the Utah Population Database. AD cases were determined via clinical examination and Medicare claims and non‐cases via clinical examination or negative cognitive screenings.ResultsMultivariate logistic regression models (covarying age, education, and APOE) found that individuals with a first‐ degree relative with AD was associated with a 58% and 66% increased risk of AD in males and females, respectively. In males, APOE Ɛ4 carriers with a history of exceptional maternal longevity (survival age 87+) had 3‐times the risk of AD than males with neither risk factor (OR = 3.15, p interaction p = .020). Males with both exceptional maternal and paternal longevity (survival age 87+) had an 11% reduced risk of AD (OR = 0.894, interaction p = .041). A history of both maternal and paternal lineages of AD was associated with a 46% lower risk (OR = 0.544) at trend level significance (interaction p = .054). In females, maternal lineage of AD was associated with a 56% increased risk of AD (OR = 1.56; p = .005). Females with a history of congestive heart failure and paternal lineage of AD had twice the AD‐risk (OR = 2.26, interaction p = .013) compared to females with neither risk factor. Parental exceptional longevity was not associated with AD risk in females.ConclusionRisk for AD associated with family history varies by sex, maternal and paternal lineage of AD and exceptional parental longevity. Elucidating mechanisms and modifiable lifestyle factors underlying sex differences may facilitate developing primary AD prevention strategies.

Clinical Ratings of White Matter Hyperintensities, Hippocampal Ratings, and Neuropsychological Functioning from The Cache County Memory Study.

White matter burden and medial temporal atrophy are associated with cognitive health. A large epidemiological database, such as the Cache County Memory Study (CCMS), can provide additional insight into how visual clinical ratings of brain structural integrity predict cognition in older adults. We used the Scheltens Ratings Scale to quantify white matter lesion burden and medial temporal atrophy in the CCMS sample to determine if these qualitative markers are predictive of memory function. We performed clinical ratings of MRI scans across two ascertainment periods among 187 community-dwelling older adults and correlated these ratings with MMSE, CERAD memory performance, and general cognitive ability. Higher Scheltens ratings measuring white matter and basal ganglia hyperintensities were associated with lower memory performance (r = 0.21). The strongest correlations were observed between medial temporal atrophy and general cognition performance (r = 0.32). The current findings support previous research that the integrity of different regions of the brain correlate to function in a meaningful way.

Sleep disturbance and association with cognitive and functional trajectories in all cause dementia: The Cache County Dementia Progression Study

AbstractBackgroundSleep disturbance is common in older adults, with a prevalence rate of approximately 25%. Sleep disturbance has been associated with increased risk for Alzheimer’s disease (AD), brain Aß deposition, and worse cognition in older adults in general. Few studies have examined the association between sleep disturbance and cognitive or functional decline after the onset of dementia. We examined this issue in a population‐based cohort of persons with dementia.MethodFive hundred eighty‐two participants (aged 65+, 60.3% female) with dementia from the Cache County Memory Study were followed for a mean (sd) of 2.47 (2.72) years, and maximum of 13.28 years. Mean (sd) age of dementia onset was 83.49 (6.29) years. A majority (81.3%) had a high school diploma/GED. Cognition was assessed at baseline and semi‐annual follow‐ups with the Mini‐Mental State Exam (MMSE) and functional status with the Clinical Dementia Rating sum‐of‐boxes (CDR‐sum). Sleep disturbance was based on the sleep domain from the Neuropsychiatric Inventory, or if lacking, a question about the subject being “troubled by sleep problems, insomnia.” Presence of depression was also determined from the NPI. Sleep disturbance (time varying) was examined in separate linear mixed effects models to predict changes in MMSE and CDRsum, controlling for age, gender, education, depression (yes/no) and presence of APOE E4 allele.ResultPrevalence of sleep disturbance was 29.7%. The association between sleep disturbance and cognitive and functional outcomes varied by dementia type (p interactions < .001). Compared to those with Alzheimer’s disease and sleep disturbance, individuals with vascular dementia and sleep disturbance exhibited worse (higher) CDR‐Sum scores across time (M_difference = ‐1.55, SE = .41, p < .001, d = .27) while individuals with “other dementias” and sleep disturbance performed worse on the MMSE (M_difference = 2.14, SE = .55, p < .001, d = .38) as did APOE4 carriers (M_difference = 1.45, SE = .35, p < .001, d = .26).ConclusionIndividuals with various dementia types and those with an APOE E4 allele in combination with sleep disturbance had worse cognitive and functional trajectories. Future work will examine effects of sleep medication use on dementia trajectory.

MRI Clinical Ratings and Cognitive Function in a Cross-Sectional Population Study of Dementia: The Cache County Memory Study.

White matter integrity in aging populations is associated with increased risk of cognitive decline, dementia diagnosis, and mortality. Population-based data can elucidate this association. To examine the association between white matter integrity, as measured by a clinical rating scale of hyperintensities, and mental status in older adults including advanced aging. Scheltens Ratings Scale was used to qualitatively assess white matter (WM) hyperintensities in participants of the Cache County Memory Study (CCMS), an epidemiological study of Alzheimer's disease in an exceptionally long-lived population. Further, the relation between Mini-Mental State Exam (MMSE) and WM hyperintensities were explored. Participants consisted of 415 individuals with dementia and 22 healthy controls. CCMS participants, including healthy controls, had high levels of WM pathology as measured by Scheltens Ratings Scale score. While age did not significantly relate to WM pathology, higher Scheltens Ratings Scale scores were associated with lower MMSE findings (correlation between -0.14 and -0.22; p < .05). WM pathology was common in this county-wide population sample of those ranging in age from 65 to 106. Increased WM burden was found to be significantly associated with decreased overall MMSE performance.

Erratum to: "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.

Family Member Deaths in Childhood Predict Systemic Inflammation in Late Life

ABSTRACTBiological 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.

Depression and antidepressant use moderate association between widowhood and Alzheimer's disease

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. 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. 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). 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.

Population-based Analysis of Alzheimer’s Disease Risk Alleles Implicates Genetic Interactions

Reported odds ratios and population attributable fractions (PAF) for late-onset Alzheimer's disease (LOAD) risk loci (BIN1, ABCA7, CR1, MS4A4E, CD2AP, PICALM, MS4A6A, CD33, and CLU) come from clinically ascertained samples. Little is known about the combined PAF for these LOAD risk alleles and the utility of these combined markers for case-control prediction. Here we evaluate these loci in a large population-based sample to estimate PAF and explore the effects of additive and nonadditive interactions on LOAD status prediction performance. 2419 samples from the Cache County Memory Study were genotyped for APOE and nine LOAD risk loci from AlzGene.org. We used logistic regression and receiver operator characteristic analysis to assess the LOAD status prediction performance of these loci using additive and nonadditive models and compared odds ratios and PAFs between AlzGene.org and Cache County. Odds ratios were comparable between Cache County and AlzGene.org when identical single nucleotide polymorphisms were genotyped. PAFs from AlzGene.org ranged from 2.25% to 37%; those from Cache County ranged from .05% to 20%. Including non-APOE alleles significantly improved LOAD status prediction performance (area under the curve = .80) over APOE alone (area under the curve = .78) when not constrained to an additive relationship (p < .03). We identified potential allelic interactions (p values uncorrected): CD33-MS4A4E (synergy factor = 5.31; p < .003) and CLU-MS4A4E (synergy factor = 3.81; p < .016). Although nonadditive interactions between loci significantly improve diagnostic ability, the improvement does not reach the desired sensitivity or specificity for clinical use. Nevertheless, these results suggest that understanding gene-gene interactions may be important in resolving Alzheimer's disease etiology.

Assessment of TREM2 rs75932628 association with Alzheimer's disease in a population-based sample: the Cache County Study

Recent studies have identified the rs75932628 (R47H) variant in TREM2 as an Alzheimer's disease risk factor with estimated odds ratio ranging from 2.9 to 5.1. The Cache County Memory Study is a large, population-based sample designed for the study of memory and aging. We genotyped R47H in 2974 samples (427 cases and 2540 control subjects) from the Cache County study using a custom TaqMan assay. We observed 7 heterozygous cases and 12 heterozygous control subjects with an odds ratio of 3.5 (95% confidence interval, 1.3–8.8; p = 0.0076). The minor allele frequency and population attributable fraction for R47H were 0.0029 and 0.004, respectively. This study replicates the association between R47H and Alzheimer's disease risk in a large, population-based sample, and estimates the population frequency and attributable risk of this rare variant.

Predictors of progression to severe Alzheimer’s disease in an incidence sample

BackgroundLittle is known about factors influencing time to severe Alzheimer’s disease (AD). MethodsIncident cases of AD in the Cache County Memory Study were identified. Severe AD was defined as Mini-Mental State Examination score of ≤10 or Clinical Dementia Rating Scale score of 3; cases with either Mini-Mental State Examination score of ≥16 or Clinical Dementia Rating <2 were not categorized as severe AD. Kaplan–Meier, log-rank tests, and Cox analyses were used to identify demographic, clinical, and genetic correlates of time to progression to severe AD. ResultsSixty-eight of 335 cases of incident AD developed severe dementia. In bivariate analyses, female gender, less than high school education, at least one clinically significant Neuropsychiatric Inventory domain at baseline, and the youngest and oldest ages exhibited shorter time to severe AD. In competing risk analysis, subjects with mild or at least one clinically significant Neuropsychiatric Inventory domain score, and subjects with worse health were more likely to progress to severe dementia or death. ConclusionsDemographic and clinical variables predict progression to severe AD. Further study should examine whether these relationships are causal or correlational.

Stressful life events and cognitive decline in late life: moderation by education and age. The Cache County Study

Stressful life events (SLE) have been associated with increased dementia risk, but their association with cognitive decline has been inconsistent. In a longitudinal population-based study of older individuals, we examined the association between SLE and cognitive decline, and the role of potential effect modifiers. A total of 2665 non-demented participants of the Cache County Memory Study completed an SLE questionnaire at Wave 2 and were revisited 4 and 7 years later. The events were represented via several scores: total number, subjective rating (negative, positive, and unexpected), and a weighted summary based on their impact. Cognition was assessed at each visit with the modified Mini-Mental State Exam. General linear models were used to examine the association between SLE scores and cognition. Effect modification by age, education, and APOE genotype was tested. Years of formal education (p = 0.006) modified the effect of number of SLE, and age (p = 0.009) modified the effect of negative SLE on the rate of cognitive decline. Faster decline was observed among those with fewer years of education experiencing more SLE and also among younger participants experiencing more negative SLE. There was no association between other indicators of SLE and cognitive decline. APOE genotype did not modify any of the aforementioned associations. The effects of SLE on cognition in late life are complex and vary by individual factors such as age and education. These results may explain some of the contradictory findings in the literature.

Baseline disability in activities of daily living predicts dementia risk even after controlling for baseline global cognitive ability and depressive symptoms

Late-life disability in activities of daily living (ADL) is theorized to be driven by underlying cognitive and/or physical impairment, interacting with psychological and environmental factors. Although we expect that cognitive deficits would explain associations between ADL disability and dementia risk, the current study examined ADL as a predictor of future dementia after controlling for global cognitive status. The population-based Cache County Memory Study (N = 3547) assessed individuals in four triennial waves (average age 74.9 years, years of education 13.36 years; 57.9% were women). Cox proportional hazards regression models assessed whether baseline ADL disability (presence of 2+ Instrumental ADL and/or 1+ Personal ADL) predicted incident dementia after controlling for APOE status, gender, age, baseline cognitive ability (Modified Mini-mental State Exam, 3MS-R; adjusted for education level), and baseline depressive symptoms (Diagnostic Interview Schedule). Over the course of study, 571 cases of incident dementia were identified through in-depth cognitive assessment, ending in expert consensus diagnosis. Results from Cox models suggest that ADL disability is a statistically significant predictor of incident dementia (adjusted hazard ratio = 1.83, p < 0.001), even after controlling for covariates. Findings suggest that ADL disability offers unique contributions in risk for incident dementia, even after controlling for global cognitive status. We discuss how physical impairment and executive function may play important roles in this relationship, and how ADL is useful, not just a diagnostic tool at, or after dementia onset, but also as a risk factor for future dementia, even in individuals not impaired on global cognitive tests.

Latent class-derived subgroups of depressive symptoms in a community sample of older adults: the Cache County Study.

We sought to identify possible subgroups of elders that varied in depressive symptomatology and to examine symptom patterns and health status differences between subgroups. The Cache County memory study is a population-based epidemiological study of dementia with 5092 participants. Depressive symptoms were measured with a modified version of the diagnostic interview schedule-depression. There were 400 nondemented participants who endorsed currently (i.e., in the past 2 weeks) experiencing at least one of the three "gateway" depressive symptoms and then completed a full depression interview. Responses to all nine current depressive symptoms were modeled using the latent class analysis. Three depression subgroups were identified: a significantly depressed subgroup (62%), with the remainder split evenly between a subgroup with low probability of all symptoms (21%), and a subgroup with primarily psychomotor changes, sleep symptoms, and fatigue (17%). Latent class analysis derived subgroups of depressive symptoms and Diagnostic and statistical manual of mental disorders, fourth edition depression diagnostic group were nonredundant. Age, gender, education, marital status, early or late onset, number of episodes, current episode duration, and functional status were not significant predictors of depression subgroup. The first subgroup was more likely to be recently bereaved and had less physical health problems, whereas the third subgroup were less likely to be using antidepressants compared with the second subgroup. There are distinct subgroups of depressed elders, which are not redundant with the Diagnostic and statistical manual of mental disorders, fourth edition classification scheme, offering an alternative diagnostic approach to clinicians and researchers. Future work will examine whether these depressive symptom profiles are predictive of incident dementia and earlier mortality.

Serum IL-15 associated with APOE e4 genotype and Alzheimer's disease in the Cache County Memory Study

Serum IL-15 associated with APOE e4 genotype and Alzheimer's disease in the Cache County Memory Study

A brief metacognition questionnaire for the elderly: comparison with cognitive performance and informant ratings the Cache County Study

To examine the utility of a brief, metacognition questionnaire by examining its association with objective cognitive testing and informant ratings. We hypothesized that the association between self-ratings of change and both outcomes would be greater among individuals without dementia than among those with dementia. Participants were 535 persons without dementia and 152 with dementia from the Cache County Memory Study who had completed a metacognition questionnaire, two administrations of the Modified Mini-Mental State Exam (3 MS) and who had data on the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE). Cronbach's alpha was calculated as a measure of internal consistency of the metacognition questionnaire. Multiple regression was used to examine the relationship between metacognition and 3 MS change. Logistic regression was used to examine the relationship between metacognition and IQCODE ratings (no change vs. worse). Cronbach's alpha was 0.75. Among individuals without dementia, metacognition significantly predicted 3 MS change (p = .027) and IQCODE ratings (OR = 4.0, 95% CI = 1.2-13.8, p = .029), suggesting consistency among measures. For those with dementia, there was a weak, inverse relationship between 3 MS change and metacognition (r = -0.16, p = .056). IQCODE ratings were not significantly associated with metacognition (p = .729). Degree of dementia severity did not modify the relationship between metacognition and either outcome (p > .05). We demonstrated adequate internal consistency and evidence for validity of a brief metacognition questionnaire. The questionnaire may provide a useful adjunct to memory and functional assessments for assessing anosognosia in elderly populations.

Predictors of successful cognitive aging: Findings from the cache county memory study

Predictors of successful cognitive aging: Findings from the cache county memory study

Neuropsychological performance in advanced age: Influences of Demographic factors and Apolipoprotein E: Findings from the Cache County Memory Study

The Cache County Study of Memory in Aging (CCMS) is an epidemiological study of Alzheimer's disease (AD), mild cognitive disorders, and aging in a population of exceptionally long-lived individuals (7th to 11th decade). Observation of population members without dementia provides an opportunity for establishing the range of normal neurocognitive performance in a representative sample of the very old. We examined neurocognitive performance of the normal participants undergoing full clinical evaluations (n = 507) and we tested the potential modifying effects of apolipoprotein E (APOE) genotype, a known genetic risk factor for the later development of AD. The results indicate that advanced age and low education are related to lower test scores across nearly all of the neurocognitive measures. Gender and APOE ϵ 4 both had negligible and inconsistent influences, affecting only isolated measures of memory and expressive speech (in case of gender). The gender and APOE effects disappeared once age and education were controlled. The study of this exceptionally long-lived population provides useful normative information regarding the broad range of “normal” cognition seen in advanced age. Among elderly without dementia or other cognitive impairment, APOE does not appear to exert any major effects on cognition once other demographic influences are controlled.

Modifying dementia risk and trajectories of cognitive decline in aging: The Cache County Memory Study

The Cache County Study of Memory, Health, and Aging, more commonly referred to as the “Cache County Memory Study (CCMS)” is a longitudinal investigation of aging and Alzheimer’s disease (AD) based in an exceptionally long-lived population residing in northern Utah. The study begun in 1994 has followed an initial cohort of 5,092 older individuals (many over age 84) and has examined the development of cognitive impairment and dementia in relation to genetic and environmental antecedents. This article summarizes the major contributions of the CCMS towards the understanding of mild cognitive disorders and AD across the lifespan, underscoring the role of common health exposures in modifying dementia risk and trajectories of cognitive change. The study now in its fourth wave of ascertainment illustrates the role of population-based approaches in informing testable models of cognitive aging and Alzheimer’s disease.

Ten Dimensions of Health and Their Relationships with Overall Self‐Reported Health and Survival in a Predominately Religiously Active Elderly Population: The Cache County Memory Study

To document the extent of healthy aging along 10 different dimensions in a population known for its longevity. A cohort study with baseline measures of overall self-reported health and health along 10 specific dimensions; analyses investigated the 10 dimensions as predictors of self-reported health and 10-year mortality. Cache County, Utah, which is among the areas with the highest conditional life expectancy at age 65 in the United States. Inhabitants of Cache County aged 65 and older (January 1, 1995). Self-reported overall health and 10 specific dimensions of healthy aging: independent living, vision, hearing, activities of daily living, instrumental activities of daily living, absence of physical illness, cognition, healthy mood, social support and participation, and religious participation and spirituality. This elderly population was healthy overall. With few exceptions, 80% to 90% of persons aged 65 to 75 were healthy according to each measure used. Prevalence of excellent and good self-reported health decreased with age, to approximately 60% in those aged 85 and older. Even in the oldest old, the majority of respondents were independent in activities of daily living. Although vision, hearing, and mood were significant predictors of overall self-reported health in the final models, age, sex, and cognition were significant only in the final survival models. This population has a high prevalence of most factors representing healthy aging. The predictors of overall self-reported health are distinct from the predictors of survival in this age group and, being potentially modifiable, are amenable to clinical and public health efforts.