Antihypertensive medication use and incident Alzheimer disease: the Cache County Study

BACKGROUND: Recent reports suggest that antihypertensive (AH) medications may reduce the risk of dementing illnesses. OBJECTIVES: To examine the relationship of AH medication use with incidence of Alzheimer disease (AD) among the elderly population (aged 65 years and older) of Cache County, Utah, and to examine whether the relationship varies with different classes of AH medications. METHODS: After an initial (wave 1) multistage assessment (1995 through 1997) to identify prevalent cases of dementia, we used similar methods 3 years later (wave 2) to identify 104 incident cases of AD among the 3308 survivors. At the baseline assessment, we obtained a detailed drug inventory from the study participants. We carried out discrete time survival analyses to examine the association between the use of AH medications (including angiotensin converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics) at baseline with subsequent risk of AD. RESULTS: Use of any AH medication at baseline was associated with lower incidence of AD (adjusted hazard ratio, 0.64; 95% confidence interval, 0.41-0.98). Examination of medication subclasses showed that use of diuretics (adjusted hazard ratio, 0.57; 95% confidence interval, 0.33-0.94), and specifically potassium-sparing diuretics (adjusted hazard ratio, 0.26; 95% confidence interval, 0.08-0.64), was associated with the greatest reduction in risk of AD. Corresponding analysis with a fully examined subsample controlling for blood pressure measurements did not substantially change our findings. CONCLUSIONS: These data suggest that AH medications, and specifically potassium-sparing diuretics, are associated with reduced incidence of AD. Because the latter association is a new finding, it requires confirmation in further study.     

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 epsilon4 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.     

Vascular factors and risk for neuropsychiatric symptoms in Alzheimer's disease: the Cache County Study

OBJECTIVE: To examine, in an exploratory analysis, the association between vascular conditions and the occurrence of neuropsychiatric symptoms (NPS) in a population-based sample of incident Alzheimer's disease (AD). METHODS: The sample consisted of 254 participants, identified through two waves of assessment. NPS were assessed using the Neuropsychiatric Inventory. Prior to the onset of AD, data regarding a history of stroke, hypertension, hyperlipidemia, heart attack or coronary artery bypass graft (CABG), and diabetes were recorded. Logistic regression procedures were used to examine the relationship of each vascular condition to individual neuropsychiatric symptoms. Covariates considered were age, gender, education, APOE genotype, dementia severity, and overall health status. RESULTS: One or more NPS were observed in 51% of participants. Depression was most common (25.8%), followed by apathy (18.6%), and irritability (17.7%). Least common were elation (0.8%), hallucinations (5.6%), and disinhibition (6.0%). Stroke prior to the onset of AD was associated with increased risk of delusions (OR = 4.76, p = 0.02), depression (OR = 3.87, p = 0.03), and apathy (OR = 4.48, p = 0.02). Hypertension was associated with increased risk of delusions (OR = 2.34, p = 0.02), anxiety (OR = 4.10, p = 0.002), and agitation/aggression (OR = 2.82, p = 0.01). No associations were observed between NPS and diabetes, hyperlipidemia, heart attack or CABG, or overall health. CONCLUSIONS: Results suggest that a history of stroke and hypertension increase the risk of specific NPS in patients with AD. These conditions may disrupt neural circuitry in brain areas involved in NPS. Findings may provide an avenue for reduction in occurrence of NPS through the treatment or prevention of vascular risk conditions.     

Antioxidant vitamin intake and risk of Alzheimer disease

BACKGROUND: The generation of oxygen free radicals is involved in the pathogenesis of Alzheimer disease (AD). OBJECTIVE: To determine whether the intake of antioxidant vitamins decreases the risk of AD. METHODS: We investigated the relationship between AD and the intake of carotenes, vitamin C, and vitamin E in 980 elderly subjects in the Washington Heights-Inwood Columbia Aging Project who were free of dementia at baseline and were followed for a mean time of 4 years. Semiquantitative food frequency questionnaires were administered between baseline and the first follow-up visit. Cox proportional hazards regression models were conducted with quartiles of each vitamin intake as the exposure of interest and incident AD as the outcome, adjusted for age, level of education, sex, APOE epsilon4 status, ethnicity, and smoking. RESULTS: There were 242 incident cases of AD in 4,023 person-years of follow-up (6 per 100 person-years). Intake of carotenes and vitamin C, or vitamin E in supplemental or dietary (nonsupplemental) form or in both forms, was not related to a decreased risk of AD. Trend tests for the association between quartiles of total intake of vitamins C and E also were not significant. CONCLUSION: Neither dietary, supplemental, nor total intake of carotenes and vitamins C and E was associated with a decreased risk of AD in this study.     

Better cognitive performance in elderly taking antioxidant vitamins E and C supplements in combination with nonsteroidal anti-inflammatory drugs: The Cache County Study

Studies have shown less cognitive decline and lower risk of Alzheimer's disease in elderly individuals consuming either antioxidant vitamins or nonsteroidal anti-inflammatory drugs (NSAIDs). The potential of added benefit from their combined use has not been studied. We therefore analyzed data from 3,376 elderly participants of the Cache County Study who were given the Modified Mini-Mental State examination up to three times during a period of 8 years. Those who used a combination of vitamins E and C supplements and NSAIDs at baseline declined by an average 0.96 fewer points every 3 years than nonusers (P < .05). This apparent effect was attributable entirely to participants with the APOE ε4 allele, whose users declined by 2.25 fewer points than nonusers every 3 years (P < .05). These results suggest that among elderly individuals with an APOE ε4 allele, there is an association between using antioxidant supplements in combination with NSAIDs and less cognitive decline over time.     

Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study

BACKGROUND: Previous analyses from the Cache County (UT) Study showed inverse associations between the prevalence of AD and the use of nonsteroidal anti-inflammatory drugs (NSAID), aspirin compounds, or histamine H(2) receptor antagonists (H(2)RA). The authors re-examined these associations using data on incident AD. METHODS: In 1995 to 1996, elderly (aged 65+) county residents were assessed for dementia, with current and former use of NSAID, aspirin, and H(2)RA as well as three other "control" medication classes also noted. Three years later, interval medication histories were obtained and 104 participants with incident AD were identified among 3,227 living participants. Discrete time survival analyses estimated the risk of incident AD in relation to medication use. RESULTS: AD incidence was marginally reduced in those reporting NSAID use at any time. Increased duration of use was associated with greater risk reduction, and the estimated hazard ratio was 0.45 with >/=2 years of exposure. Users of NSAID at baseline showed little reduction in AD incidence, regardless of use thereafter. By contrast, former NSAID users showed substantially reduced incidence (estimated hazard ratio = 0.42), with a trend toward greatest risk reduction among those with extended exposure. Similar patterns appeared with aspirin but not with any other medicines examined. CONCLUSIONS: Long-term NSAID use may reduce the risk of AD, provided such use occurs well before the onset of dementia. More recent exposure seems to offer little protection. Recently initiated randomized trials of NSAID for primary prevention of AD are therefore unlikely to show effects with treatment until participants have been followed for several years.     

Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study

BACKGROUND: The incidence of Alzheimer disease (AD) increases strongly with age, but little is known about the cumulative incidence of AD over a lifetime of 100 years, or its relationship to the polymorphic APOE locus that encodes apolipoprotein E. APOE is a strong genetic risk factor for AD. OBJECTIVES: To estimate the occurrence of AD as a function of age and number of APOE epsilon4 alleles; and to explore evidence for heterogeneity of AD risk related to APOE genotype and to other sources. DESIGN: Nonparametric and parametric survival analyses of AD incidence in prospective longitudinal study. SETTING AND PARTICIPANTS: A total of 3308 elderly residents of Cache County, Utah. MAIN OUTCOME MEASURES: Cumulative incidence of AD; in mixture models assuming susceptible and nonsusceptible individuals, the proportion of individuals not susceptible to AD at any age. RESULTS: Models that assumed a proportion of invulnerable individuals provided strongly improved fit to the data. These models estimated the 100-year lifetime incidence of AD at 72%, implying that 28% of individuals would not develop AD over any reasonable life expectancy. We confirmed the acceleration of AD onset in individuals with 1 or, especially, 2 APOE, epsilon4 alleles but observed no meaningful difference in 100-year lifetime incidence related to number of epsilon4 alleles. CONCLUSIONS: The APOE epsilon4 allele acts as a potent risk factor for AD by accelerating onset. However, the risk of AD appears heterogeneous in ways independent of APOE.Some individuals seem destined to escape AD, even over an extended lifespan. Their relative invulnerability may reflect other genes or environmental factors that can be investigated.     

Reduced hippocampal functional connectivity in Alzheimer disease

OBJECTIVE: To determine if functional connectivity of the hippocampus is reduced in patients with Alzheimer disease. DESIGN: Functional connectivity magnetic resonance imaging was used to investigate coherence in the magnetic resonance signal between the hippocampus and all other regions of the brain. PARTICIPANTS: Eight patients with probable Alzheimer disease and 8 healthy volunteers. RESULTS: Control subjects showed hippocampal functional connectivity with diffuse cortical, subcortical, and cerebellar sites, while patients demonstrated markedly reduced functional connectivity, including an absence of connectivity with the frontal lobes. CONCLUSION: These findings suggest a functional disconnection between the hippocampus and other brain regions in patients with Alzheimer disease.     

The Cache County Study on Memory in Aging: Factors affecting risk of Alzheimer's disease and its progression after onset

Abstract

The Cache County Study on Memory in Aging is a longitudinal, population-based study of Alzheimer's disease (AD) and other dementias. Initiated in 1995 and extending to 2013, the study has followed over 5,000 elderly residents of Cache County, Utah (USA) for over twelve years. Achieving a 90% participation rate at enrolment, and spawning two ancillary projects, the study has contributed to the literature on genetic, psychosocial and environmental risk factors for AD, late-life cognitive decline, and the clinical progression of dementia after its onset. This paper describes the major study contributions to the literature on AD and dementia.     

Conjugal Alzheimer disease: risk in children when both parents have Alzheimer disease

BACKGROUND: There is limited information regarding children's risk of Alzheimer disease (AD) if both parents are affected. OBJECTIVE: To determine the risk of AD in families in which both parents have AD. DESIGN: Retrospective study. SETTING: University research center. PARTICIPANTS: A total of 111 families in which both parents had a clinical diagnosis of AD. Main Outcome Measure Frequency of AD in the children of spouses with AD. RESULTS: The 111 couples with AD had 297 children surviving to adulthood; 22.6% of these adult children have developed AD. The risk of AD in these children increases with age, being 31.0% (58 of 187) in those older than 60 years and 41.8% (41 of 98) in those older than 70 years. Many children (79.0%) at risk in these families are still younger than 70 years, meaning that the occurrence of AD will increase in the coming years. A family history of AD beyond the parents did not change the risk of AD in the children but did reduce the median age at onset in affected children. The apolipoprotein E epsilon4 allele played an important part in this phenomenon but did not explain all cases of AD in the children. CONCLUSIONS: When both parents have AD, there is an increased risk of AD in their children beyond that of the general population. The role of family history and the specific genes involved in this phenomenon require a better definition.     

Depression as a risk factor for Alzheimer disease: the MIRAGE Study

BACKGROUND: Depression symptoms may be associated with the development of Alzheimer disease (AD). OBJECTIVES: To evaluate the association between depression symptoms and risk of AD, and to explore the temporal aspects of this association. SETTING: Academic institutions with specialized memory clinics. DESIGN: Cross-sectional, family-based, case-control study with standardized self- and proxy questionnaires to collect information on depression symptoms and other risk factors. PARTICIPANTS: A total of 1953 subjects with AD and 2093 of their unaffected relatives enrolled in the Multi-institutional Research in Alzheimer's Genetic Epidemiology Study. MAIN OUTCOME MEASURES: Odds ratios (ORs) of AD were estimated with and without depression symptoms, adjusted for age, sex, education, history of head trauma, and apolipoprotein E status. RESULTS: There was a significant association between depression symptoms and AD (adjusted OR, 2.13; 95% confidence interval [CI], 1.71-2.67). In families where depression symptoms first occurred within 1 year before the onset of AD, the association was higher (OR, 4.57; 95% CI, 2.87-7.31), while in the families where the depression symptoms first occurred more than 1 year before the onset of AD, the association was lower (OR, 1.38; 95% CI, 1.03-1.85). In families where depression symptoms first occurred more than 25 years before the onset of AD, there was still a modest association (OR, 1.71; 95% CI, 1.03-2.82). CONCLUSIONS: Depression symptoms before the onset of AD are associated with the development of AD, even in families where first depression symptoms occurred more than 25 years before the onset of AD. These data suggest that depression symptoms are a risk factor for later development of AD.     

Reduced levels of amyloid beta-peptide antibody in Alzheimer disease

OBJECTIVE: To investigate whether it was possible to detect the presence and different levels of naturally occurring anti-beta-amyloid (Abeta) antibodies in the CSF of patients with AD and age-matched controls by employing a sensitive ELISA. BACKGROUND: Immunization with preaggregated amyloid beta-peptide (Abeta(1-42)) and administration of antibodies against Abeta into amyloid precursor protein APP(V717F)- transgenic mice (an animal model of AD) have recently been reported to dramatically reduce amyloid plaque deposition, neuritic dystrophy, and astrogliosis, most likely by enhancing Abeta clearance from brain. METHODS: A sensitive ELISA was performed to detect levels of naturally occurring anti-Abeta antibodies in the CSF of patients with AD and age-matched controls. Additionally, an immunoprecipitation assay was performed to confirm that naturally occurring anti-Abeta antibodies also exist in the human blood. RESULT: - Naturally occurring antibodies directed against Abeta were found in the CSF and plasma of patients with AD and healthy control subjects. Moreover, CSF anti-Abeta antibody titers are significantly lower in patients with AD compared with healthy control subjects. CONCLUSION: Naturally occurring antibodies directed against Abeta exist in human CSF and plasma. The CSF anti-Abeta antibody titers may be helpful in better understanding the effects of future immunologic therapies for AD.