Risk Of Incident Alzheimer's Disease Research Articles

Aggregation of vascular risk factors and risk of incident Alzheimer disease

The prevalence of Alzheimer disease (AD) is increasing in the elderly, and vascular risk factors may increase its risk. To explore the association of the aggregation of vascular risk factors with AD. 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. 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. 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.

MRI predictors of risk of incident Alzheimer disease

To determine if baseline entorhinal and hippocampal volumes and their rate of atrophy could predict the risk of incident Alzheimer disease (AD). The authors used proportional odds models to assess the relationship between entorhinal and hippocampal size and risk of incident AD among 58 nondemented elderly people. All participants were followed with annual clinical evaluations and structural MRI scans for up to 5 years (baseline and 5 years of follow-up). At baseline, 23 of 58 participants received a diagnosis of amnestic mild cognitive impairment (MCI) and 35 of 58 were healthy control subjects with no cognitive impairment. Structural MRI scans were acquired with a T1-weighted three-dimensional spoiled gradient-recalled echo pulse sequence in a 1.5 T scanner. Entorhinal and hippocampal volumes were derived from 1.6-mm gapless coronal images reformatted to be perpendicular to the long axis of the hippocampus and were normalized by dividing with intracranial volume. Fourteen of 58 nondemented participants developed AD during the follow-up period. Initial diagnosis of MCI was a significant predictor of incident AD. In addition, both baseline entorhinal volume and its slope of decline were independent predictors of incident AD, but initial hippocampal size and its rate of decline were not, after controlling for entorhinal volume. In nondemented individuals, entorhinal cortex atrophy is associated with risk of Alzheimer disease.

Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease

Extracellular amyloid plaques, intracellular neurofibrillary tangles, and loss of basal forebrain cholinergic neurons in the brains of Alzheimer's disease (AD) patients may be the end result of abnormalities in lipid metabolism and peroxidation that may be caused, or exacerbated, by beta-amyloid peptide (Abeta). Apolipoprotein E (apoE) is a major apolipoprotein in the brain, mediating the transport and clearance of lipids and Abeta. ApoE-dependent dendritic and synaptic regeneration may be less efficient with apoE4, and this may result in, or unmask, age-related neurodegenerative changes. The increased risk of AD associated with apoE4 may be modulated by diet, vascular risk factors, and genetic polymorphisms that affect the function of other transporter proteins and enzymes involved in brain lipid homeostasis. Diet and apoE lipoproteins influence membrane lipid raft composition and the properties of enzymes, transporter proteins, and receptors mediating Abeta production and degradation, tau phosphorylation, glutamate and glucose uptake, and neuronal signal transduction. The level and isoform of apoE may influence whether Abeta is likely to be metabolized or deposited. This review examines the current evidence for diet, lipid homeostasis, and apoE in the pathogenesis of AD. Effects on the cholinergic system and response to cholinesterase inhibitors by APOE allele carrier status are discussed briefly.

Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease.

Dietary n-3 polyunsaturated fatty acids improve brain functioning in animal studies, but there is limited study of whether this type of fat protects against Alzheimer disease. To examine whether fish consumption and intake of different types of n-3 fatty acids protect against Alzheimer disease. Prospective study conducted from 1993 through 2000, of a stratified random sample from a geographically defined community. Participants were followed up for an average of 3.9 years for the development of Alzheimer disease. A total of 815 residents, aged 65 to 94 years, who were initially unaffected by Alzheimer disease and completed a dietary questionnaire on average 2.3 years before clinical evaluation of incident disease. Incident Alzheimer disease diagnosed in a structured neurologic examination by means of standardized criteria. A total of 131 sample participants developed Alzheimer disease. Participants who consumed fish once per week or more had 60% less risk of Alzheimer disease compared with those who rarely or never ate fish (relative risk, 0.4; 95% confidence interval, 0.2-0.9) in a model adjusted for age and other risk factors. Total intake of n-3 polyunsaturated fatty acids was associated with reduced risk of Alzheimer disease, as was intake of docosahexaenoic acid (22:6n-3). Eicosapentaenoic acid (20:5n-3) was not associated with Alzheimer disease. The associations remained unchanged with additional adjustment for intakes of other dietary fats and of vitamin E and for cardiovascular conditions. Dietary intake of n-3 fatty acids and weekly consumption of fish may reduce the risk of incident Alzheimer disease.

Plasma total cholesterol level as a risk factor for Alzheimer disease: the Framingham Study.

Previous studies examining the association of plasma cholesterol levels with the risk for development of Alzheimer disease (AD) have been inconclusive. We examined the impact of baseline and lifetime plasma total cholesterol levels averaged across many years on the risk for AD in a large, population-based cohort. Five thousand two hundred nine subjects from the Framingham Study original cohort underwent biennial evaluation for cardiovascular risk factors since 1950, with estimations of serum total cholesterol levels at 19 of these 25 biennial examinations. The study sample consisted of 1026 subjects from this cohort who were alive and free of stroke and dementia at examination cycle 20 (1988-1989) and had undergone apolipoprotein E (APOE) genotyping. The main outcome measure was incident AD diagnosed using standard criteria, according to average total cholesterol levels across biennial examination cycles 1 to 15 and baseline total cholesterol level measured at the 20th biennial examination cycle. Alzheimer disease developed in 77 subjects from 1992 to 2000. After adjustment for age, sex, APOE genotype, smoking, body mass index (calculated as weight in kilograms divided by the square of height in meters), coronary heart disease, and diabetes, we found no significant association between the risk for incident AD and average cholesterol level at biennial examination cycles 1 to 15 (hazard ratio per 10-mg/dL [0.3-mmol/L] rise, 0.95; 95% confidence interval, 0.87-1.04) or baseline total cholesterol level at examination 20 (hazard ratio, 0.97; 95% confidence interval, 0.90-1.05). In this large, population-based cohort, baseline and long-term average serum total cholesterol levels were not associated with the risk for incident AD.

Parkinsonianlike signs and risk of incident Alzheimer disease in older persons.

Parkinsonianlike signs are common in older persons, but little is known about how their severity or rate of progression is related to the development of Alzheimer disease (AD) or decline in cognition. To examine the association of progression of parkinsonianlike signs with incident AD and cognitive decline. Longitudinal cohort study. For up to 8 years, 824 older Catholic clergy members without clinical evidence of AD or Parkinson disease at baseline underwent annual clinical evaluations that included a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS), detailed cognitive function testing, and clinical classification of AD. Clinically diagnosed AD and change in global and specific measures of cognitive function. During an average of 4.6 years of observation, 114 persons developed AD. The global UPDRS score increased in 79% of participants, who were divided into tertiles with the least, moderate, or most rapid progression. We examined the relationship of progression to disease risk in a proportional hazards model that controlled for baseline global UPDRS and demographic variables. Compared with the 21% without progression, risk of AD more than doubled in the subgroup with the least progression (P =.08), more than tripled in the moderate subgroup (P =.02), and increased more than 8-fold in the subgroup with the most rapid progression (P<.001). This effect was mainly due to worsening gait and rigidity. Rate of change on the global UPDRS measure was inversely correlated with rate of change on a global measure of cognitive function (r = -0.64). Progression of parkinsonianlike signs in old age is associated with decline in cognitive function and the development of AD.

Dietary fats and the risk of incident Alzheimer disease.

Few studies have investigated the effects of dietary fats on the development of Alzheimer disease. We examined the associations between intake of specific types of fat and incident Alzheimer disease in a biracial community study. We performed clinical evaluations on a stratified random sample of 815 community residents aged 65 years and older who were unaffected by Alzheimer disease at baseline and who completed a food-frequency questionnaire a mean of 2.3 years before clinical evaluation. After a mean follow-up of 3.9 years, 131 persons developed Alzheimer disease. Intakes of saturated fat and trans-unsaturated fat were positively associated with risk of Alzheimer disease, whereas intakes of omega-6 polyunsaturated fat and monounsaturated fat were inversely associated. Persons in the upper fifth of saturated-fat intake had 2.2 times the risk of incident Alzheimer disease compared with persons in the lowest fifth in a multivariable model adjusted for age, sex, race, education, and apolipoprotein E epsilon4 allele status (95% confidence interval, 1.1-4.7). Risk also increased with consumption of trans-unsaturated fats, beginning with the second fifth of intake (relative risk, 2.4 compared with the lowest fifth; 95% confidence interval, 1.1-5.3). We observed linear inverse associations between Alzheimer disease and vegetable fat (P =.002), and, after further adjustment for other types of fat, marginally significant associations with intake of omega-6 polyunsaturated fat (P =.10 for trend) and monounsaturated fat (P =.10 for trend). Intakes of total fat, animal fat, and dietary cholesterol were not associated with Alzheimer disease. High intake of unsaturated, unhydrogenated fats may be protective against Alzheimer disease, whereas intake of saturated or trans-unsaturated (hydrogenated) fats may increase risk.

Dementia and Alzheimer disease incidence rates do not vary by sex in Rochester, Minn.

Incidence rates of Alzheimer disease (AD) were higher in women than in men in several recent European and Asian studies. Cohort studies in the United States, on the other hand, have consistently reported no difference in incidence across sex. To measure age- and sex-specific incidence rates of dementia and AD for persons aged 50 years and older residing in Rochester, Minn, during 1985 to 1989. Cases were ascertained through the medical records linkage system of the Rochester Epidemiology Project, which encompasses the records of all medical care providers (including outpatient clinics, hospitals, general practitioners, and nursing homes) in Rochester. Computer indices of clinical diagnoses, histologic diagnoses, and medical procedures were screened for indications of dementia. All medical records of potential cases were reviewed and abstracted by a trained nurse abstractor. A neurologist (E.K.) confirmed the presence of dementia and established a differential diagnosis of AD using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and estimated the year of onset. A total of 482 incident cases of dementia were identified; 356 of them (73.9%) had AD. For both dementia and AD, incidence rates increased steeply with age, and there were no consistent differences between men and women. The sex pattern for AD did not change after removing cases with silent bilateral infarcts on imaging. Contrary to observations from European and Asian populations, women were not at increased risk of incident AD in Rochester. Our findings, based on a medical records linkage system, corroborate findings from several other US studies that involved the direct contact of cohort members. The consistency of findings across study designs suggests that sex or sex-related exposures do not consistently play a major role in AD causation in American populations.

Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study.

Oxidative processes have been suggested as elements in the development of Alzheimer disease (AD), but whether dietary intake of vitamin E and other antioxidant nutrients prevents its development is unknown. To examine whether intake of antioxidant nutrients, vitamin E, vitamin C, and beta carotene is associated with incident AD. Prospective study, conducted from 1993 to 2000, of individuals selected in a stratified random sample of community-dwelling residents. The 815 residents 65 years and older were free of AD at baseline and were followed up for a mean of 3.9 years. They completed food frequency questionnaires an average of 1.7 years after baseline. Incident AD diagnosed in clinical evaluations with standardized criteria. Increasing vitamin E intake from foods was associated with decreased risk of developing AD after adjustment for age, education, sex, race, APOE epsilon 4, and length of follow-up. Relative risks (95% confidence intervals [CIs]) from lowest to highest quintiles of intake were 1.00, 0.71 (0.24-2.07), 0.62 (0.26-1.45), 0.71 (0.27-1.88), and 0.30 (0.10-0.92) (P for trend =.05). The protective association of vitamin E was observed only among persons who were APOE epsilon 4 negative. Adjustment for other dietary factors reduced the protective association. After adjustment for baseline memory score, the risk was 0.36 (95% CI, 0.11-1.17). Intake of vitamin C, beta carotene, and vitamin E from supplements was not significantly associated with risk of AD. This study suggests that vitamin E from food, but not other antioxidants, may be associated with a reduced risk of AD. Unexpectedly, this association was observed only among individuals without the APOE epsilon 4 allele.

Participation in cognitively stimulating activities and risk of incident Alzheimer disease.

Frequent participation in cognitively stimulating activities has been hypothesized to reduce risk of Alzheimer disease (AD), but prospective data regarding an association are lacking. To test the hypothesis that frequent participation in cognitive activities is associated with a reduced risk of AD. Longitudinal cohort study with baseline evaluations performed between January 1994 and July 2001 and mean follow-up of 4.5 years. A total of 801 older Catholic nuns, priests, and brothers without dementia at enrollment, recruited from 40 groups across the United States. At baseline, they rated frequency of participation in common cognitive activities (eg, reading a newspaper), from which a previously validated composite measure of cognitive activity frequency was derived. Clinical diagnosis of AD by a board-certified neurologist using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria and change in global and specific measures of cognitive function, compared by cognitive activity score at baseline. Baseline scores on the composite measure of cognitive activity ranged from 1.57 to 4.71 (mean, 3.57; SD, 0.55), with higher scores indicating more frequent activity. During an average of 4.5 years of follow-up, 111 persons developed AD. In a proportional hazards model that controlled for age, sex, and education, a 1-point increase in cognitive activity score was associated with a 33% reduction in risk of AD (hazard ratio, 0.67; 95% confidence interval, 0.49-0.92). Results were comparable when persons with memory impairment at baseline were excluded and when terms for the apolipoprotein E epsilon4 allele and other medical conditions were added. In random-effects models that controlled for age, sex, education, and baseline level of cognitive function, a 1-point increase in cognitive activity was associated with reduced decline in global cognition (by 47%), working memory (by 60%), and perceptual speed (by 30%). These results suggest that frequent participation in cognitively stimulating activities is associated with reduced risk of AD.

Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease.

Oxidative stress may play a role in neurologic disease. The present study examined the relation between use of vitamin E and vitamin C and incident Alzheimer disease in a prospective study of 633 persons 65 years and older. A stratified random sample was selected from a disease-free population. At baseline, all vitamin supplements taken in the previous 2 weeks were identified by direct inspection. After an average follow-up period of 4.3 years, 91 of the sample participants with vitamin information met accepted criteria for the clinical diagnosis of Alzheimer disease. None of the 27 vitamin E supplement users had Alzheimer disease compared with 3.9 predicted based on the crude observed incidence among nonusers (p = 0.04) and 2.5 predicted based on age, sex, years of education, and length of follow-up interval (p = 0.23). None of the 23 vitamin C supplement users had Alzheimer disease compared with 3.3 predicted based on the crude observed incidence among nonusers (p = 0.10) and 3.2 predicted adjusted for age, sex, education, and follow-up interval (p = 0.04). There was no relation between Alzheimer disease and use of multivitamins. These data suggest that use of the higher-dose vitamin E and vitamin C supplements may lower the risk of Alzheimer disease.

Education and other measures of socioeconomic status and risk of incident Alzheimer disease in a defined population of older persons.

To assess the relations of 3 measures of socioeconomic status (education, occupational prestige, and income) to risk of incident clinically diagnosed Alzheimer disease (AD). Cohort study with an average observation of 4.3 years. East Boston, Mass. a geographically defined community. A stratified random sample of 642 community residents 65 years of age and older who were free of AD at baseline. Clinical diagnosis of probable AD according to standard criteria, using structured uniform evaluation. The relations of the 3 measures of socioeconomic status to risk of disease were assessed using logistic regression analyses. In individual analyses, fewer years of formal schooling, lower income, and lower occupational status each predicted risk of incident AD; risk of disease decreased by approximately 17% for each year of education. In an analysis including all 3 measures, the effect of education on risk for disease remained approximately the same, but the effects of the other 2 measures were somewhat less and did not attain formal statistical significance, compared with separate analysis of each measure. Markers of lower socioeconomic status predict risk of developing incident AD. The mechanism of this relation is uncertain, but the possibility that it reflects unidentified and potentially reversible risk factors for the disease deserves careful investigation.

Influence of Education and Occupation on the Incidence of Alzheimer's Disease

Several cross-sectional studies have found an association between Alzheimer's disease (AD) and limited educational experience. It has been difficult to establish whether educational experience is a risk factor for AD because educational attainment can influence performance on diagnostic tests. This study was designed to determine whether limited educational level and occupational attainment are risk factors for incident dementia. Cohort incidence study. General community. A total of 593 nondemented individuals aged 60 years or older who were listed in a registry of individuals at risk for dementia in North Manhattan, NY, were identified and followed up. We reexamined subjects 1 to 4 years later with the identical standardized neurological and neuropsychological measures. Incident dementia. We used Cox proportional hazards models, adjusting for age and gender, to estimate the relative risk (RR) of incident dementia associated with low educational and occupational attainment. Of the 593 subjects, 106 became demented; all but five of these met research criteria for AD. The risk of dementia was increased in subjects with either low education (RR, 2.02; 95% confidence interval [Cl], 1.33 to 3.06) or low lifetime occupational attainment (RR, 2.25; 95% Cl, 1.32 to 3.84). Risk was greatest for subjects with both low education and low life-time occupational attainment (RR, 2.87; 95% Cl, 1.32 to 3.84). The data suggest that increased educational and occupational attainment may reduce the risk of incident AD, either by decreasing ease of clinical detection of AD or by imparting a reserve that delays the onset of clinical manifestations.