Ara S. Khachaturian

APOE-ε4 count predicts age when prevalence of AD increases, then declines The Cache County Study

Objective: To examine the prevalence of Alzheimer’s disease (AD) and other dementias in relation to age, education, sex, and genotype at APOE. Recent studies suggest age heterogeneity in the risk of AD associated with the APOE genotype and a possible interaction between APOE-ε4 and female sex as risk factors. We studied these topics in the 5,677 elderly residents of Cache County, Utah, a population known for long life expectancy and high participation rates. Methods: We screened for dementia with a brief cognitive test and structured telephone Dementia Questionnaire, then examined all individuals with apparent cognitive symptoms and a sample of others. We estimated age-specific prevalence of AD and other dementias and used multiple logistic regression models to describe relation of AD prevalence to age, sex, education, and APOE genotype. Results: We found 335 demented individuals, 230 (69%) with definite, probable, or possible AD (positive predictive value versus autopsy confirmation 85%). The adjusted prevalence estimate for AD was 6.5% and for all dementias 9.6%. After age 90, the adjusted prevalence estimate for AD was 28% and for all dementias 38%. Regression models showed strong variation in AD prevalence with age, sex, education, and number of ε4 alleles (effect of ε2 not significant). Models were improved by a term for age-squared (negative coefficient) and by separate terms for interaction of age with presence of one or two ε4 alleles. An association of AD with female sex was ascribable entirely to individuals with ε4. Conclusions: In participants with no ε4 alleles, the age-specific prevalence of AD reached a maximum and then declined after age 95. In ε4 heterozygotes a similar maximum was noted earlier at age 87, in homozygotes at age 73. Female sex was a risk factor for AD only in those with ε4. The ε4 allele accounted for 70% of the population attributable risk for AD.

Neuropsychiatric symptoms in Alzheimer’s disease

Neuropsychiatric symptoms (NPS) are core features of Alzheimers disease and related dementias. Once thought to emerge primarily in people with late‐stage disease, these symptoms are currently known to manifest commonly in very early disease and in prodromal phases, such as mild cognitive impairment. Despite decades of research, reliable treatments for dementia‐associated NPS have not been found, and those that are in widespread use present notable risks for people using these medications. An Alzheimers Association Research Roundtable was convened in the spring of 2010 to review what is known about NPS in Alzheimers disease, to discuss classification and underlying neuropathogenesis and vulnerabilities, and to formulate recommendations for new approaches to tailored therapeutics.

Incidence of AD may decline in the early 90s for men, later for women The Cache County study

Objectives: To characterize the incidence of AD among the elderly population of Cache County, UT, noted for its longevity and high response rates; to explore sex differences; and to examine whether AD incidence plateaus or declines in extreme old age. Methods: Using a multistage screening process in 1998 and 1999, and reexamining 122 individuals who had been identified 3 years earlier as cognitively compromised but not demented, the authors found 185 individuals with incident dementia (123 with AD) among 3,308 participants who contributed 10,541 person-years of observation. Adjusting for nonresponse and screening sensitivity, the authors estimated the incidence of dementia and of AD for men and women in 3-year age intervals. Multivariate discrete time survival analysis was used to examine influences of age, sex, education, and genotype at APOE, as well as interactions of these factors. Results: The incidence of both dementia and AD increased almost exponentially until ages 85 to 90, but appeared to decline after age 93 for men and 97 for women. A statistical interaction between age and the presence of two APOE-ε4 alleles indicated acceleration in onset of AD with this genotype; the interaction of age and one ε4 suggested more modest acceleration. A statistical interaction of sex and age indicated greater incidence of AD in women than in men after age 85. Conclusions: The incidence of AD in the Cache County population increased with advancing age, but then peaked and declined among the extremely old. The presence of APOE-ε4 alleles accelerated onset of AD, but did not appreciably alter lifetime incidence apparent over a span of 100 years.

Vascular Risk Factors for Incident Alzheimer Disease and Vascular Dementia: The Cache County Study

Vascular risk factors for Alzheimer disease (AD) and vascular dementia (VaD) have been evaluated; however, few studies have compared risks by dementia subtypes and sex. We evaluated relationships between cardiovascular risk factors (hypertension, high cholesterol, diabetes mellitus, and obesity), events (stroke, coronary artery bypass graft surgery, and myocardial infarction), and subsequent risk of AD and VaD by sex in a community-based cohort of 3264 Cache County residents aged 65 or older. Cardiovascular history was ascertained by self-report or proxy-report in detailed interviews. AD and VaD were diagnosed using standard criteria. Estimates from discrete-time survival models showed no association between self-reported history of hypertension and high cholesterol and AD after adjustments. Hypertension increased the risk of VaD [adjusted hazard ratio (aHR) 2.42, 95% confidence interval (CI) 0.95-7.44]. Obesity increased the risk of AD in females (aHR 2.23, 95% CI 1.09-4.30) but not males. Diabetes increased the risk of VaD in females after adjustments (aHR 3.33, 95% CI 1.03-9.78) but not males. The risk of VaD after stroke was increased in females (aHR 16.90, 95% CI 5.58-49.03) and males (aHR 10.95, 95% CI 2.48-44.78). The results indicate that vascular factors increase risks for AD and VaD differentially by sex. Future studies should focus on specific causal pathways for each of these factors with regard to sex to determine if sex differences in the prevalence of vascular factors have an influence on sex differences in dementia risk.

Dementia: The leading predictor of death in a defined elderly population The Cache County Study

Objective: To examine the relative risk and population attributable risk (PAR) of death with dementia of varying type and severity and other risk factors in a population of exceptional longevity. Methods: Deaths were monitored over 5 years using vital statistics records and newspaper obituaries in 355 individuals with prevalent dementia and 4,328 without in Cache County, UT. Mean age was 83.3 (SD 7.0) years with dementia and 73.7 (SD 6.8) years without. History of coronary artery disease, hypertension, diabetes, and other life-shortening illness was ascertained from interviews. Results: Death certificates implicated dementia as an important cause of death, but other data suggested a stronger association. Adjusted Cox relative hazard and PAR of death were higher with dementia than with any other illness studied. Relative hazard of death with dementia was highest at ages 65 to 74, but the high prevalence of dementia after age 85 resulted in 27% PAR among the oldest old. Mortality increased substantially with severity of dementia. Alzheimer disease shortened survival time most dramatically in younger participants, but vascular dementia posed a greater mortality risk among the oldest old. Conclusion: In this population, dementia was the strongest predictor of mortality, with a risk two to three times those of other life-shortening illnesses.

Does NSAID use modify cognitive trajectories in the elderly? The Cache County Study

Background: Epidemiologic studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful for the prevention of Alzheimer disease (AD). By contrast, clinical trials have not supported NSAID use to delay or treat AD. Few studies have evaluated cognitive trajectories of NSAID users over time. Methods: Residents of Cache County, UT, aged 65 or older on January 1, 1995, were invited to participate in the study. At baseline, participants provided a detailed inventory of their medications and completed a revised Modified Mini-Mental State Examination (3MS). Participants (n = 3,383) who were cognitively normal at baseline were re-examined after 3 and 8 years. The association between NSAID use and 3MS scores over time was estimated using random effects modeling. Results: Associations depended upon when NSAIDs were started and APOE genotype. In participants who started NSAID use prior to age 65, those with no APOE ε4 alleles performed similarly to nonusers (a difference of 0.10 points per year; p = 0.19), while those with one or more ε4 allele(s) showed more protection (0.40 points per year; p = 0.0005). Among participants who first used NSAIDs at or after age 65, those with one or more ε4 alleles had higher baseline scores (0.95 points; p = 0.03) but did not show subsequent difference in change in score over time (0.06 points per year; p = 0.56). Those without an ε4 allele who started NSAID use after age 65 showed greater decline than nonusers (−0.16 points per year; p = 0.02). Conclusions: Nonsteroidal anti-inflammatory drug use may help to prevent cognitive decline in older adults if started in midlife rather than late life. This effect may be more notable in those who have one or more APOE ε4 alleles.

Can we prevent Alzheimer's disease? Secondary “prevention” trials in Alzheimer's disease

Current research including the basic biology of Alzheimers disease (AD) provides a foundation to explore whether our current state of knowledge is sufficient to initiate prevention studies and allow us to believe prevention of AD is possible. Current research and recently revised criteria for the diagnosis of AD by the National Institutes on Aging and the Alzheimers Association suggest a continuum of disease from preclinical asymptomatic to symptomatic Alzheimers dementia. In light of these revised criteria, the possibility of secondary prevention and even primary prevention is under discussion. The Alzheimers Association Research Roundtable convened a meeting to discuss the rationale and feasibility of conducting secondary prevention trials in AD.

Performance characteristics of a two-stage dementia screen in a population sample.

We analyzed the performance of a two-stage screening protocol [the Modified Mini-Mental State Exam (3MS) or the Informant Questionnaire for Cognitive Decline (IQCODE), and the Dementia Questionnaire (DQ)] in a weighted stratified sample of 839 subjects from a population survey of dementia in Cache County, UT. The subjects were subsequently examined using a standardized diagnostic assessment protocol. Using the method of receiver operating characteristic (ROC) analysis, the main outcome measure was area under the ROC curve (AUC). The overall AUC estimates were 0.956 (95% confidence interval 0.943-0.968) for the 3MS/IQCODE and 0.945 (0.931-0.960) for the DQ. After adjustment for age, the efficiency of the both 3MS/IQCODE and the DQ was better for subjects with genotype epsilon4/epsilon4 at APOE, better among women, and better in those with two or more years duration of dementia. The optimal threshold for this two-stage screen yielded sensitivity and specificity estimates of 91.0% and 92.0%, respectively.

Major depression and cancer: the 13-year follow-up of the Baltimore Epidemiologic Catchment Area sample (United States)

AbstractObjective: The relationship between depression and development of cancer is not well understood, with some studies finding a significant but small increase in risk for cancer among persons with depression. No studies have employed standardized interviews keyed to the diagnostic criteria for Major Depression. Our objective was to evaluate the relationship between Major Depression at baseline and new onset of cancer at follow-up. Method: The study was based on a population-based 13-year follow-up survey of community-dwelling adults living in East Baltimore in 1981. After excluding 372 persons with a history of cancer or those whom reported their health as poor at the baseline interview, 3109 adults remained. Information on baseline depression status and cancer at follow-up was available for 2017 persons. A diagnosis of cancer was ascertained at follow-up through interview of survivors and from death certificates. Results: There were 203 new cases of cancer among 2017 persons at risk. Neither Major Depression (relative risk (RR) = 1.0, 95% confidence interval (CI) 0.5–2.1) nor dysphoric episode (RR = 1.3, 95% CI 0.9–1.9) were significantly associated with increased risk of cancer at follow-up. However, among women with Major Depression, the risk of breast cancer was increased (adjusted RR = 3.8, 95% CI 1.0–14.2). Conclusions: We found no overall association of depression with cancer. However, among women, Major Depression (but not dysphoric episode alone) was associated with the onset of breast cancer.

Assessment of cognition in mild cognitive impairment: A comparative study

The demand for rapidly administered, sensitive, and reliable cognitive assessments that are specifically designed for identifying individuals in the earliest stages of cognitive decline (and to measure subtle change over time) has escalated as the emphasis in Alzheimers disease clinical research has shifted from clinical diagnosis and treatment toward the goal of developing presymptomatic neuroprotective therapies. To meet these changing clinical requirements, cognitive measures or tailored batteries of tests must be validated and determined to be fit‐for‐use for the discrimination between cognitively healthy individuals and persons who are experiencing very subtle cognitive changes that likely signal the emergence of early mild cognitive impairment. We sought to collect and review data systematically from a wide variety of (mostly computer‐administered) cognitive measures, all of which are currently marketed or distributed with the claims that these instruments are sensitive and reliable for the early identification of disease or, if untested for this purpose, are promising tools based on other variables. The survey responses for 16 measures/batteries are presented in brief in this review; full survey responses and summary tables are archived and publicly available on the Campaign to Prevent Alzheimers Disease by 2020 Web site (http://pad2020.org). A decision tree diagram highlighting critical decision points for selecting measures to meet varying clinical trials requirements has also been provided. Ultimately, the survey questionnaire, framework, and decision guidelines provided in this review should remain as useful aids for the evaluation of any new or updated sets of instruments in the years to come.