Ming-Xin Tang

Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease

BACKGROUND Oestrogen use by postmenopausal women has many health benefits, but findings on the effect of oestrogen in Alzheimers disease are conflicting. Oestrogen promotes the growth and survival of cholinergic neurons and could decrease cerebral amyloid deposition, both of which may delay the onset or prevent Alzheimers disease. To investigate whether use of oestrogen during the postmenopausal period affects the risk of Alzheimers disease, we studied 1124 elderly women who were initially free of Alzheimers disease, Parkinsons disease, and stroke, and who were taking part in a longitudinal study of ageing and health in a New York City community. METHODS Relative risks and age-at-onset distributions were calculated from simple and adjusted Cox proportional hazards models. Standard annual clinical assessments and criterion-based diagnoses were used in follow-up (range 1-5 years). FINDINGS Overall, 156 (12.5%) women reported taking oestrogen after onset of menopause. The age at onset of Alzheimers disease was significantly later in women who had taken oestrogen than in those who did not and the relative risk of the disease was significantly reduced (9/156 [5.8%] oestrogen users vs 158/968 [16.3%] nonusers; 0.40 [95% Cl 0.22-0.85], p < 0.01), even after adjustment for differences in education, ethnic origin, and apolipoprotein-E genotype. Women who had used oestrogen for longer than 1 year had a greater reduction in risk; none of 23 women who were taking oestrogen at study enrolment has developed Alzheimers disease. INTERPRETATION Oestrogen use in postmenopausal women may delay the onset and decrease the risk of Alzheimers disease. Prospective studies are needed to establish the dose and duration of oestrogen required to provide this benefit and to assess its safety in elderly postmenopausal women.

Mediterranean Diet and Risk for Alzheimer's Disease

Previous research in Alzheimers disease (AD) has focused on individual dietary components. There is converging evidence that composite dietary patterns such as the Mediterranean diet (MeDi) is related to lower risk for cardiovascular disease, several forms of cancer, and overall mortality. We sought to investigate the association between MeDi and risk for AD.

Aggregation of vascular risk factors and risk of incident Alzheimer disease.

Background: The prevalence of Alzheimer disease (AD) is increasing in the elderly, and vascular risk factors may increase its risk. Objective: To explore the association of the aggregation of vascular risk factors with AD. Methods: The authors followed 1,138 individuals without dementia at baseline (mean age 76.2) for a mean of 5.5 years. The presence of vascular risk factors was related to incident possible and probable AD. Results: Four risk factors (diabetes, hypertension, heart disease, and current smoking) were associated with a higher risk of AD (p < 0.10) when analyzed individually. The risk of AD increased with the number of risk factors (diabetes + hypertension + heart disease + current smoking). The adjusted hazards ratio of probable AD for the presence of three or more risk factors was 3.4 (95% CI: 1.8, 6.3; p for trend < 0.0001) compared with no risk factors. Diabetes and current smoking were the strongest risk factors in isolation or in clusters, but hypertension and heart disease were also related to a higher risk of AD when clustered with diabetes, smoking, or each other. Conclusions: The risk of Alzheimer disease (AD) increased with the number of vascular risk factors. Diabetes and current smoking were the strongest risk factors, but clusters including hypertension and heart disease also increased the risk of AD. These associations are unlikely to be explained by misclassification of the outcome, given strong associations when only probable AD is considered.

Physical Activity, Diet, and Risk of Alzheimer Disease

CONTEXT Both higher adherence to a Mediterranean-type diet and more physical activity have been independently associated with lower Alzheimer disease (AD) risk but their combined association has not been investigated. OBJECTIVE To investigate the combined association of diet and physical activity with AD risk. DESIGN, SETTING, AND PATIENTS Prospective cohort study of 2 cohorts comprising 1880 community-dwelling elders without dementia living in New York, New York, with both diet and physical activity information available. Standardized neurological and neuropsychological measures were administered approximately every 1.5 years from 1992 through 2006. Adherence to a Mediterranean-type diet (scale of 0-9; trichotomized into low, middle, or high; and dichotomized into low or high) and physical activity (sum of weekly participation in various physical activities, weighted by the type of physical activity [light, moderate, vigorous]; trichotomized into no physical activity, some, or much; and dichotomized into low or high), separately and combined, were the main predictors in Cox models. Models were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, body mass index, smoking status, depression, leisure activities, a comorbidity index, and baseline Clinical Dementia Rating score. MAIN OUTCOME MEASURE Time to incident AD. RESULTS A total of 282 incident AD cases occurred during a mean (SD) of 5.4 (3.3) years of follow-up. When considered simultaneously, both Mediterranean-type diet adherence (compared with low diet score, hazard ratio [HR] for middle diet score was 0.98 [95% confidence interval {CI}, 0.72-1.33]; the HR for high diet score was 0.60 [95% CI, 0.42-0.87]; P = .008 for trend) and physical activity (compared with no physical activity, the HR for some physical activity was 0.75 [95% CI, 0.54-1.04]; the HR for much physical activity was 0.67 [95% CI, 0.47-0.95]; P = .03 for trend) were associated with lower AD risk. Compared with individuals neither adhering to the diet nor participating in physical activity (low diet score and no physical activity; absolute AD risk of 19%), those both adhering to the diet and participating in physical activity (high diet score and high physical activity) had a lower risk of AD (absolute risk, 12%; HR, 0.65 [95% CI, 0.44-0.96]; P = .03 for trend). CONCLUSION In this study, both higher Mediterranean-type diet adherence and higher physical activity were independently associated with reduced risk for AD.

Influence of leisure activity on the incidence of Alzheimer’s Disease

Objective: To determine whether leisure activities modify the risk for incident dementia. Background: Although high educational and occupational attainments have been associated with reduced risk of incident dementia, the relation between leisure activities and dementia risk has not been adequately investigated. Methods: A total of 1,772 nondemented individuals aged 65 years or older, living in northern Manhattan, New York, were identified and followed longitudinally in a community-based cohort incidence study. Subjects’ leisure activities at baseline were assessed, annual examinations with the same standardized neurologic and neuropsychological measures were performed for up to 7 years (mean 2.9 years), and incident dementia was assessed as the main outcome measure. Cox proportional hazards models, adjusting for age, ethnic group, education, and occupation, were used to estimate the relative risk (RR) of incident dementia associated with high leisure activities. Results: Of the 1,772 subjects, 207 became demented. The risk of dementia was decreased in subjects with high leisure activities (RR, 0.62; 95% CI 0.46 to 0.83). The association of high leisure with decreased RR of incident dementia was present even when baseline cognitive performance, health limitations interfering with desired leisure activities, cerebrovascular disease, and depression were considered. Conclusions: The data suggest that engagement in leisure activities may reduce the risk of incident dementia, possibly by providing a reserve that delays the onset of clinical manifestations of the disease.

Synergistic Effects of Traumatic Head Injury and Apolipoprotein-epsilon4 in Patients With Alzheimer's Disease

Article abstract-The apolipoprotein-epsilon4 allele increases the risk of Alzheimers disease (AD), but cerebral deposition of beta-amyloid with age, a genetic mutation, or head injury may contribute to the pathogenesis of this disease. We examined the risks of AD associated with traumatic head injury and apolipoprotein-epsilon4 in 236 community-dwelling elderly persons. A 10-fold increase in the risk of AD was associated with both apolipoprotein-epsilon4 and a history of traumatic head injury, compared with a two-fold increase in risk with apolipoprotein-epsilon4 alone. Head injury in the absence of an apolipoprotein-epsilon4 allele did not increase risk. These data imply that the biological effects of head injury may increase the risk of AD, but only through a synergistic relationship with apolipoprotein-epsilon4. NEUROLOGY 1995;45: 555-557

Hyperinsulinemia and risk of Alzheimer disease

Objective: To explore the association between fasting insulin levels and dementia. Methods: Fasting insulin levels were measured from frozen sera using solid-phase chemiluminescent enzyme immunoassay in a sample of elderly subjects chosen at random from a cohort of persons aged 65 years and older from northern Manhattan. Dementia was diagnosed using standard methods. Neuropsychiatric testing was available on all subjects at each follow-up interval. Results: A total of 683 subjects without prevalent dementia were followed for 3,691 person-years and 149 persons developed dementia (137 Alzheimer disease [AD], 6 dementia associated with stroke, 6 other). The risk of AD doubled in the 39% of the sample with hyperinsulinemia (HR = 2.1; 95% CI: 1.5, 2.9) and was highest in people without diabetes. The HR relating presence of hyperinsulinemia or diabetes in 50% of our sample to AD was 2.2 (95% CI: 1.5, 3.1). The risk of AD attributable to the presence of hyperinsulinemia or diabetes was 39%. The HR of AD for the highest quartile of insulin compared to the lowest was 1.7 (95% CI: 1.0, 2.7; p for trend = 0.009). Hyperinsulinemia was also related to a significant decline in memory-related cognitive scores, but not to decline in other cognitive domains. Conclusions: Hyperinsulinemia is associated with a higher risk of AD and decline in memory.

Utility of the Apolipoprotein E Genotype in the Diagnosis of Alzheimer's Disease

BACKGROUND The epsilon4 allele of the gene encoding apolipoprotein E (APOE) is strongly associated with Alzheimers disease, but its value in the diagnosis remains uncertain. METHODS We reviewed clinical diagnoses and diagnoses obtained at autopsy in 2188 patients referred to 1 of 26 Alzheimers disease centers for evaluation of dementia. The sensitivity and specificity of the clinical diagnosis or the presence of an APOE epsilon4 allele were calculated, with pathologically confirmed Alzheimers disease used as the standard. The added value of the APOE genotype was estimated with pretest and post-test probabilities from multivariate analyses to generate receiver-operating-characteristic curves plotting sensitivity against the false positive rate. RESULTS Of the 2188 patients, 1833 were given a clinical diagnosis of Alzheimers disease, and the diagnosis was confirmed pathologically in 1770 patients at autopsy. Sixty-two percent of patients with clinically diagnosed Alzheimers disease, as compared with 65 percent of those with pathologically confirmed Alzheimers disease, had at least one APOE epsilon4 allele. The sensitivity of the clinical diagnosis was 93 percent, and the specificity was 55 percent, whereas the sensitivity and specificity of the APOE epsilon4 allele were 65 and 68 percent, respectively. The addition of information about the APOE genotype increased the overall specificity to 84 percent in patients who met the clinical criteria for Alzheimers disease, although the sensitivity decreased. The improvement in specificity remained statistically significant in the multivariate analysis after adjustment for differences in age, clinical diagnosis, sex, and center. CONCLUSIONS APOE genotyping does not provide sufficient sensitivity or specificity to be used alone as a diagnostic test for Alzheimers disease, but when used in combination with clinical criteria, it improves the specificity of the diagnosis.

Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan

Objective: To compare the incidence rates for AD among elderly African-American, Caribbean Hispanic, and white individuals and to determine whether coincident cerebrovascular disease contributes to the inconsistency in reported differences among ethnic groups. Methods: This was a population-based, longitudinal study over a 7-year period in the Washington Heights and Inwood communities of New York City. Annual incidence rates for AD were calculated and compared by ethnic group, and cumulative incidence adjusted for differences in education, diabetes, cardiovascular risk factors, and stroke was calculated. Results: The age-specific incidence rate for probable and possible AD was 1.3% (95% CI, 0.8 to 1.7) per person-year between the ages of 65 and 74 years, 4.0% (95% CI, 3.2 to 4.8) per person-year between ages 75 and 84 years, and 7.9% (95% CI, 5.5 to 10.5) per person-year for ages 85 and older. Compared to white individuals, the cumulative incidence of AD to age 90 years was increased twofold among African-American and Caribbean Hispanic individuals. Adjustment for differences in number of years of education, illiteracy, or a history of stroke, hypertension, heart disease, or diabetes did not change the disproportionate risks among the three ethnic groups. Conclusion: The incidence rate for AD was significantly higher among African-American and Caribbean Hispanic elderly individuals compared white individuals. The presence of clinically apparent cardiovascular or cerebrovascular disease did not contribute to the increased risk of disease. Because the proportion of African-American and Caribbean Hispanic individuals reaching ages 65 and older in the United States is increasing more rapidly than the proportion of white individuals, it is imperative that this disparity in health among the elderly be understood.

Rate of memory decline in AD is related to education and occupation Cognitive reserve

Objective: To determine whether the rate of decline in performance on a memory test is more rapid in AD patients with higher versus lower educational and occupational attainment. Background: Epidemiologic and imaging studies have suggested that, given comparable clinical severity of dementia, AD pathology is more advanced in patients with higher educational and occupational attainment. Because educational and occupational attainment should not influence the progression of AD pathology, and because severe AD pathology will eventually produce a mortality-causing condition, people with higher attainment might experience clinical AD for a shorter time and have a more rapid clinical progression. Methods: A total of 177 AD patients were tested yearly for up to four study visits with the Selective Reminding Test (a memory test). Analysis of prospective change in the total recall score was performed by applying generalized estimating equations to regression analyses with repeated measures. Results: At the initial visit, scores were comparable in the high- and low-education and the high- and low-occupation groups. Overall, memory scores declined by approximately 1 point yearly (p < 0.01). There was a more rapid decline in memory scores in patients with higher educational (p < 0.057) and higher occupational attainment (p < 0.02). The authors then stratified patients based on their initial memory scores. The more rapid decline in memory scores associated with higher educational and occupational attainment was noted only in the group with low initial scores (p < 0.05 for both). The full group and stratified group analyses were also repeated controlling for other potentially relevant variables including age, gender, race, ethnicity, and the presence of extrapyramidal signs, stroke, or at least one apolipoprotein E-ε4 allele. The results remained unchanged. Conclusions: Memory declined more rapidly in AD patients with higher educational and occupational attainment. This adds support to the idea that the discontinuity between the degree of AD pathology and the observed clinical severity of AD is mediated through some form of reserve.