Maria C. Norton

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.

APOE Genotype Predicts When - not Whether - One is Predisposed to Develop Alzheimer Disease

APOE genotype predicts when — not whether — one is predisposed to develop Alzheimer disease

Vascular factors predict rate of progression in Alzheimer disease.

Background: While there is considerable epidemiologic evidence that cardiovascular risk factors increase risk of incident Alzheimer disease (AD), few studies have examined their effect on progression after an established AD diagnosis. Objective: To examine the effect of vascular factors, and potential age modification, on rate of progression in a longitudinal study of incident dementia. Methods: A total of 135 individuals with incident AD, identified in a population-based sample of elderly persons in Cache County, UT, were followed with in-home visits for a mean of 3.0 years (range: 0.8 to 9.5) and 2.1 follow-up visits (range: 1 to 5). The Clinical Dementia Rating (CDR) Scale and Mini-Mental State Examination (MMSE) were administered at each visit. Baseline vascular factors were determined by interview and physical examination. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) or MMSE as the outcome, and vascular index or individual vascular factors as independent variables. Results: Atrial fibrillation, systolic hypertension, and angina were associated with more rapid decline on both the CDR-Sum and MMSE, while history of coronary artery bypass graft surgery, diabetes, and antihypertensive medications were associated with a slower rate of decline. There was an age interaction such that systolic hypertension, angina, and myocardial infarction were associated with greater decline with increasing baseline age. Conclusion: Atrial fibrillation, hypertension, and angina were associated with a greater rate of decline and may represent modifiable risk factors for secondary prevention in Alzheimer disease. The attenuated decline for diabetes and coronary artery bypass graft surgery may be due to selective survival. Some of these effects appear to vary with age. GLOSSARY: 3MS = revised Modified Mini-Mental State Examination for epidemiologic studies; AF = atrial fibrillation; CABG = coronary artery bypass graft surgery; CCHS = Copenhagen City Heart Study; CCSMHA = Cache County Study on Memory, Health, and Aging; CDR = Clinical Dementia Rating; CVD = cardiovascular disease; DM = diabetes mellitus; DPS = Dementia Progression Study; MI = myocardial infarction; MMSE = Mini-Mental State Examination; SBP = systolic blood pressure.

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.

Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists The Cache County Study

Objective: To test the hypothesis that nonsteroidal anti-inflammatory drugs (NSAIDs) and histamine H2 receptor antagonists (H2RAs) are associated with a decreased risk of AD in late life. Background: Sustained use of non-aspirin NSAIDs has been repeatedly associated with a reduced occurrence of AD. Similar effects with aspirin have been weaker. One prior study showed a strong association between use of H2RAs and reduced AD prevalence. Methods: In a population study of AD in Cache County, UT, we used a sequenced plan of sampling and case ascertainment to identify 201 cases of AD and 4425 participants with no indication of cognitive impairment. Independently, an interview and medicine chest inventory assessed use of several medicines including aspirin, non-aspirin NSAIDs, H2RAs, and three classes of “control” drugs not thought to be associated with AD. Follow-up questioning probed possible indications for use of these drugs. Results: Compared with cognitively intact individuals, the AD cases had significantly less reported current use of NSAIDs, aspirin, and H2RAs. Stronger associations appeared when subjects reported use of both NSAIDs and aspirin (no H2RAs), two different NSAIDs (no H2RAs), or two different H2RAs (with neither aspirin nor NSAIDs). There was little or no such association with use of the control medicines. Adjustment for usage indication did not influence these findings, and there was no appreciable variation with number of APOE ε4 alleles. Conclusions: As predicted, use of NSAIDs and aspirin were specifically associated with reduced occurrence of AD. Notably, a previous observation of an inverse association of AD and use of H2RAs was also affirmed. Definitive evidence for a preventive action of these agents will require randomized prevention trials.

Occupational exposure to pesticides increases the risk of incident AD The Cache County Study

Background: Commonly used organophosphate and organochlorine pesticides inhibit acetylcholinesterase at synapses in the somatic, autonomic, and central nervous systems and may therefore have lasting effects on the nervous system. Few studies have examined the relationship of pesticide exposure and risk of dementia or Alzheimer disease (AD). We sought to examine the association of occupational pesticide exposure and the risk of incident dementia and AD in later life. Methods: Residents of the agricultural community of Cache County, UT, who were aged 65 years and older as of January 1995, were invited to participate in the study. At baseline, participants completed detailed occupational history questionnaires that included information about exposures to various types of pesticides. Cognitive status was assessed at baseline and after 3, 7, and 10 years. Standardized methods were used for detection and diagnosis of dementia and AD. Cox proportional hazards survival analyses were used to evaluate the risk of incident dementia and AD associated with pesticide exposure. Results: Among 3,084 enrollees without dementia, more men than women reported pesticide exposure (p < 0.0001). Exposed individuals (n = 572) had more years of education (p < 0.01) but did not differ from others in age. Some 500 individuals developed incident dementia, 344 with AD. After adjustment for baseline age, sex, education, APOE ε4 status, and baseline Modified Mini-Mental State Examination scores, Cox proportional hazards models showed increased risks among pesticide-exposed individuals for all-cause dementia, with hazard ratio (HR) 1.38 and 95% confidence interval (CI) 1.09–1.76, and for AD (HR 1.42, 95% CI 1.06–1.91). The risk of AD associated with organophosphate exposure (HR 1.53, 95% CI 1.05–2.23) was slightly higher than the risk associated with organochlorines (HR 1.49, 95% CI 0.99–2.24), which was nearly significant. Conclusions: Pesticide exposure may increase the risk of dementia and Alzheimer disease in late life.

Pubertal Development, Parental Communication, and Sexual Values in Relation to Adolescent Sexual Behaviors

There is great interest in understanding adolescent sexual behavior because of its links to unplanned pregnancies and sexually transmitted diseases. This studys purpose was to analyze biological and social antecedents of adolescent sexual intentions and behaviors, including age, pubertal development, quality of parent/adolescent communication, and adolescent sexual values. Analyses were based on longitudinal data collected in 1991, 1992, and 1993 from 473 families. Structural equation modeling was used to test direct and indirect effects among the time-ordered variables separately by gender Both for males and females, parent/adolescent communication quality was related positively to adolescent sexual abstinence values, abstinence values had a strong negative effect on sexual intentions, and sexual intentions had a significant positive effect on sexual behaviors. Parent/adolescent communication quality was related directly to sexual intentions measured 1 year later among females only. Early pubertal development, relative to same-age peers, was related directly to sexual behaviors of both genders.

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.

Progression of Cognitive, Functional, and Neuropsychiatric Symptom Domains in a Population Cohort With Alzheimer Dementia: The Cache County Dementia Progression Study

OBJECTIVESnProgression of Alzheimer dementia (AD) is highly variable. Most estimates derive from convenience samples from dementia clinics or research centers where there is substantial potential for survival bias and other distortions. In a population-based sample of incident AD cases, we examined progression of impairment in cognition, function, and neuropsychiatric symptoms, and the influence of selected variables on these domains.nnnDESIGNnLongitudinal, prospective cohort study.nnnSETTINGnCache County (Utah).nnnPARTICIPANTSnThree hundred twenty-eight persons with a diagnosis of possible/probable AD.nnnMEASUREMENTSnMini-Mental State Exam (MMSE), Clinical Dementia Rating sum-of-boxes (CDR-sb), and Neuropsychiatric Inventory (NPI).nnnRESULTSnOver a mean follow-up of 3.80 (range: 0.07-12.90) years, the mean (SD) annual rates of change were -1.53 (2.69) scale points on the MMSE, 1.44 (1.82) on the CDR-sb, and 2.55 (5.37) on the NPI. Among surviving participants, 30% to 58% progressed less than 1 point per year on these measures, even 5 to 7 years after dementia onset. Rates of change were correlated between MMSE and CDR-sb (r = -0.62, df = 201, p < 0.001) and between the CDR-sb and NPI (r = 0.20, df = 206, p < 0.004). Female subjects (LR χ = 8.7, df = 2, p = 0.013) and those with younger onset (likelihood ratio [LR] χ = 5.7, df = 2, p = 0.058) declined faster on the MMSE. Although one or more apolipoprotein E ε 4 alleles and ever use of FDA-approved antidementia medications were associated with initial MMSE scores, neither was related to the rate of progression in any domain.nnnCONCLUSIONSnA significant proportion of persons with AD progresses slowly. The results underscore differences between population-based versus clinic-based samples and suggest ongoing need to identify factors that may slow the progression of AD.

Hormone therapy and Alzheimer disease dementia: New findings from the Cache County Study

Objectives: Observational studies suggest reduced risk of Alzheimer disease (AD) in users of hormone therapy (HT), but trials show higher risk. We examined whether the association of HT with AD varies with timing or type of HT use. Methods: Between 1995 and 2006, the population-based Cache County Study followed 1,768 women who had provided a detailed history on age at menopause and use of HT. During this interval, 176 women developed incident AD. Cox proportional hazard models evaluated the association of HT use with AD, overall and in relation to timing, duration of use, and type (opposed vs unopposed) of HT. Results: Women who used any type of HT within 5 years of menopause had 30% less risk of AD (95% confidence interval 0.49–0.99), especially if use was for 10 or more years. By contrast, AD risk was not reduced among those who had initiated HT 5 or more years after menopause. Instead, rates were increased among those who began “opposed” estrogen-progestin compounds within the 3 years preceding the Cache County Study baseline (adjusted hazard ratio 1.93; 95% confidence interval 0.94–3.96). This last hazard ratio was similar to the ratio of 2.05 reported in randomized trial participants assigned to opposed HT. Conclusions: Association of HT use and risk of AD may depend on timing of use. Although possibly beneficial if taken during a critical window near menopause, HT (especially opposed compounds) initiated in later life may be associated with increased risk. The relation of AD risk to timing and type of HT deserves further study.