Change in risk of Alzheimer disease over time.

OBJECTIVE: To assess whether the risk of incidence of Alzheimer disease (AD) varies over time. The increase in numbers of people at the oldest ages in the population will bring an increase in the number of people with AD. Projections of the size of the increase assume the risk of AD is constant. METHODS: All persons age 65 or older in a biracial, geographically defined area were invited to participate in a home interview every 3 years. From the approximately 10,000 participants, stratified random samples were selected for detailed clinical evaluation. At each cycle, individuals determined free of AD in a previous cycle, either by examination or by high score on cognitive function tests, were sampled in the subsequent cycle for evaluation for incident AD. The evaluations for disease were structured and uniform across time. These analyses include 1,695 subjects evaluated for incident disease from 1997 through 2008. RESULTS: AD developed in 360 participants. Change over time in risk of incident disease was assessed in logistic regression analyses including evaluation date and controlling for age, gender, education, race, interval from disease-free designation to evaluation for incident disease, and sample design. The time variable (in years) was not significant (odds ratio = 0.970, 95% confidence interval = 0.902 to 1.044). CONCLUSIONS: The null relation of evaluation date to disease incidence suggests no recent change in risk of AD over time, and supports this assumption for projections of AD.

Change in frailty and risk of death in older persons.

The authors developed and validated a continuous composite measure of frailty and examined its rate of change in 832 older persons with annual evaluations for up to 8 years. In generalized estimating equation models adjusted for age, sex, and education, there was a significant increase in frailty during follow-up. In a proportional hazards model controlling for age, sex, education, and baseline frailty, each 1-unit increase in annual change in frailty was associated with an almost 5 times the risk of mortality. Using a continuous measure, the authors document that frailty is progressive in some older persons and that its rate of progression is associated with mortality.

Relation of NSAIDs to incident AD, change in cognitive function, and AD pathology.

OBJECTIVE: To examine the relation of nonsteroidal anti-inflammatory drugs (NSAIDs) to incident Alzheimer disease (AD), change in cognition, and AD pathology. METHODS: Participants were 1,019 older Catholic clergy followed up annually for up to 12 years (mean baseline age = 75.0 years, education = 18.1 years, Mini-Mental State Examination score = 28.5), enrolled in the Religious Orders Study, a longitudinal clinical-pathologic study of aging and AD. Clinical evaluations allowed for AD classification and assessment of global cognition and five cognitive domains. NSAIDs were identified by direct medication inspection at baseline and follow-up evaluations. Neuropathologic data were available on 328 deceased participants. AD pathology was summarized as a global measure and as measures of neuritic plaques, diffuse plaques, and neurofibrillary tangles. We used Cox proportional hazards models and mixed models for incident AD and cognitive decline, respectively, and logistic and linear regression for pathologic outcomes, adjusted for age, sex, and education. RESULTS: Overall, we found no apparent relation of NSAIDs to incident AD (n = 209 cases), change in cognition, or AD pathology. The hazard ratio of incident AD was 1.19 (95% CI 0.87-1.62) comparing those using NSAIDs with those not using NSAIDs at baseline, and 0.84 (95% CI 0.63-1.11) for specific use of aspirin. Findings were similar in analyses in which we considered NSAID use during follow-up. NSAIDs were not related to change in cognition (all p values > 0.14). There was no relation of NSAIDs to global AD pathology or plaques or tangles. CONCLUSION: These data do not support a strong relation between nonsteroidal anti-inflammatory drugs and Alzheimer disease or cognition. Consistent findings across clinical and pathologic outcomes provide additional confidence in these results.

Processing resources reduce the effect of Alzheimer pathology on other cognitive systems.

UNLABELLED: The cognitive abilities of older persons vary greatly, even among those with similar amounts of Alzheimer disease (AD) pathology, suggesting differences in neural reserve. Although its neurobiologic basis is not well understood, reserve may reflect differences in the ability to compensate for the deleterious effects of pathology by recruiting alternative or additional brain networks to perform a specific task. If this is an effective compensatory strategy, then involvement of additional cognitive systems may help maintain function in other cognitive systems despite the accumulation of pathology. OBJECTIVE: We tested the hypothesis that processing resources, specifically perceptual speed and working memory, modify the associations of AD pathology with other cognitive systems. METHOD: A total of 103 older participants of the Rush Memory and Aging Project underwent detailed annual clinical evaluations and brain autopsy. Five cognitive systems including perceptual speed, working memory, semantic memory, visuospatial abilities, and episodic memory were assessed proximate to death, and AD pathology including tau tangles and amyloid load were quantified postmortem. RESULTS: In multiple regression models adjusted for age, sex, and education, processing resources reduced the associations of tangles with other cognitive systems, such that persons with higher levels of perceptual speed and working memory performed better on semantic memory and visuospatial abilities despite the burden of tangles. Perceptual speed also reduced the associations of amyloid with semantic memory, visuospatial abilities, and episodic memory. CONCLUSION: These findings suggest that processing resources may help compensate for the deleterious effects of Alzheimer disease pathology on other cognitive systems in older persons.

Statins, incident Alzheimer disease, change in cognitive function, and neuropathology.

OBJECTIVE: To examine the relation of statins to incident Alzheimer disease (AD) and change in cognition and neuropathology. METHODS: Participants were 929 older Catholic clergy (68.7% women, mean baseline age 74.9 years, education 18.2 years, Mini-Mental State Examination 28.5) free of dementia, enrolled in the Religious Orders Study, a longitudinal clinical-pathologic study of AD. All agreed to brain autopsy at time of death and underwent annual structured clinical evaluations, allowing for classification of AD and assessment of cognition (based on 19 neuropsychological tests). Statins were identified by direct medication inspection. Neuropathologic data were available on 262 participants. All macroscopic chronic cerebral infarctions were recorded. A measure of global AD pathology was derived from silver stain, and separate measures of amyloid and tangles were based on immunohistochemistry. We examined the relation of statins to incident AD using Cox proportional hazards, change in cognition using mixed effects models, and pathologic indices using logistic and linear regression. RESULTS: Statin use at baseline (12.8%) was not associated with incident AD (191 persons, up to 12 follow-up years), change in global cognition, or five separate cognitive domains (all p values > 0.20). Statin use any time prior to death (17.9%) was not related to global AD pathology. Persons taking statins were less likely to have amyloid (p = 0.02). However, among those with amyloid, there was no relation of statins to amyloid load. Statins were not related to tangles or infarction. CONCLUSIONS: Overall, statins were not related to incident Alzheimer disease (AD) or change in cognition, or continuous measures of AD pathology or infarction.

Body mass index and cognitive decline in a biracial community population.

OBJECTIVE: To examine whether a higher body mass index (BMI) in older adults is associated with greater cognitive decline. METHODS: A longitudinal study was conducted from 1993 to 2003 with an average follow-up of 6.4 years of a biracial community population on the south side of Chicago. Participants were 3,885 community-dwelling adults aged 65 and older who participated in at least two assessments. A composite measure of global cognitive function was used which was derived from the average of standardized scores from four cognitive tests. RESULTS: There was a significant curvilinear association between BMI and cognitive function scores at baseline for both black (= -0.0014, p = 0.001) and non-black subjects (= -0.0011, p = 0.002). In a mixed model adjusted for age, sex, race, and education, higher BMI was associated with less cognitive decline in both black (= 0.0013, p = 0.009) and non-black subjects (= 0.0021, p = 0.006). Adjusting for comorbid illnesses did not change these findings substantially. However, the associations were much smaller and no longer significant among participants with no cognitive decline at baseline as measured by a Mini-Mental State Examination score of greater than 24. CONCLUSIONS: The findings suggest that greater body mass index in old age is not predictive of cognitive decline in a cognitively unimpaired community population.

Body mass index in older persons is associated with Alzheimer disease pathology.

OBJECTIVE: We examined the extent to which body mass index (BMI) in older persons is associated with common age-related neuropathologies known to contribute to dementia including Alzheimer disease (AD) pathology, cerebral infarction, and Lewy body disease. METHODS: We studied brain autopsies from 298 deceased Catholic clergy participating in the Religious Orders Study, a longitudinal clinical-pathologic investigation. BMI was assessed at annual clinical evaluations during an average follow-up of 4.9 years (SD = 2.7 years). Each person's average BMI, derived from all evaluations, was used in analyses. Multiple regression analyses were used to examine the relation of common postmortem neuropathologic findings to average BMI prior to death. RESULTS: Mean age at death was 85.7 years (SD = 6.8 years), and average BMI during the course of the study was 26.0 (SD = 5.1). A series of linear regression models was performed with average BMI as the outcome and controlling for age, sex, and education. Level of AD pathology was associated with BMI proximate to death (estimate = -1.15; SE = 0.42; p = 0.007). However, Lewy body pathology (estimate = -0.45; SE = 0.73; p = 0.53) and cerebral infarctions (estimate = -0.10; SE = 0.61; p = 0.88) were not associated with average BMI. The association of AD pathology with BMI was unchanged after controlling for dementia, chronic diseases, and physical activity. CONCLUSION: Body mass in old age is associated with Alzheimer disease pathology in persons with and without dementia.

Memory complaints are related to Alzheimer disease pathology in older persons.

OBJECTIVE: To study the relationship between Alzheimer disease (AD) pathology and memory complaints proximate to death. METHODS: A group of 90 older persons underwent detailed clinical evaluations and brain autopsy at death. The evaluations included administration of questions on subjective memory complaints and clinical classification of dementia and AD. On postmortem examination, neuritic plaques, diffuse plaques, and neurofibrillary tangles in tissue samples from five cortical regions were counted, and a summary measure of overall AD pathology was derived. In addition, amyloid load and tau tangles were quantified in eight regions. RESULTS: In multiple linear regression models adjusted for age, sex, and education, memory complaints were associated with AD pathology, including both amyloid and tau tangles. Subsequent analyses demonstrated that the relationship between memory complaints and AD pathology was present in those with and without dementia, and could not be explained by the potentially confounding effects of depressive symptoms or coexisting common chronic health problems. CONCLUSION: Memory complaints in older persons may indicate self awareness of a degenerative process.

Associations of vegetable and fruit consumption with age-related cognitive change.

OBJECTIVE: To examine the association between rates of cognitive change and dietary consumption of fruits and vegetables among older persons. METHODS: The authors conducted a prospective cohort study of 3,718 participants, aged 65 years and older of the Chicago Health and Aging Project. Participants completed a food frequency questionnaire and were administered at least two of three cognitive assessments at baseline, 3-year, and 6-year follow-ups. Cognitive function was measured using the average z-score of four tests: the East Boston Tests of immediate memory and delayed recall, the Mini-Mental State Examination, and the Symbol Digit Modalities Test. RESULTS: The mean cognitive score at baseline for the analyzed cohort was 0.18 (range: -3.5 to 1.6), and the overall mean change in score per year was a decline of 0.04 standardized units. In mixed effects models adjusted for age, sex, race, and education, compared with the rate of cognitive decline among persons in the lowest quintile of vegetable intake (median of 0.9 servings/day), the rate for persons in the fourth quintile (median, 2.8 servings/day) was slower by 0.019 standardized units per year (p = 0.01), a 40% decrease, and by 0.018 standardized units per year (p = 0.02) for the fifth quintile (median, 4.1 servings/day), or a 38% decrease in rates. The association remained significant (p for linear trend = 0.02) with further control of cardiovascular-related conditions and risk factors. Fruit consumption was not associated with cognitive change. CONCLUSION: High vegetable but not fruit consumption may be associated with slower rate of cognitive decline with older age.

Hallucinations, cognitive decline, and death in Alzheimer's disease.

The relation of psychotic symptoms to cognitive decline and mortality in Alzheimer's disease (AD) was examined during a mean of 2.2 years in 478 persons selected from clinical settings. Psychotic symptoms were ascertained at baseline and cognition was assessed semiannually with nine tests from which a global measure was formed. In analyses that controlled for age, sex, race, and education, hallucinations (29.6%), especially visual ones, were associated with more rapid global cognitive decline and increased mortality, even after controlling for baseline level of cognition and use of antipsychotic medication, and the association with mortality increased with higher level of education. Delusions and misperceptions were not strongly related to cognitive decline or mortality. The results suggest that hallucinations in Alzheimer's disease, particularly visual ones, are associated with more rapid progression.

Parkinsonian signs in subjects with mild cognitive impairment.

BACKGROUND: Parkinsonian signs such as gait disturbance, rigidity, bradykinesia, and tremor are common among individuals with dementia and are associated with negative outcomes, but little is known about parkinsonian signs among individuals with mild cognitive impairment (MCI). OBJECTIVE: To examine the extent to which MCI is associated with parkinsonian signs and the relation between cognitive abilities and parkinsonism among individuals with MCI. METHODS: Participants included 835 individuals from the Rush Memory and Aging Project, a clinical-pathologic study of common chronic conditions of old age. All participants underwent detailed clinical evaluations which included assessments of parkinsonian signs and cognitive function, and linear regression models were used to examine the associations of MCI and parkinsonism. RESULTS: In a series of analyses controlled for age, sex, and education, individuals with MCI exhibited significantly more parkinsonism than individuals without cognitive impairment, particularly gait disturbance, bradykinesia, and rigidity. Among individuals with MCI, lower levels of cognitive function, particularly in perceptual speed, were associated with higher levels of parkinsonism; when classified according to MCI subtype, individuals with amnestic vs non-amnestic MCI differed from each other on only one parkinsonian sign, with non-amnestic MCI showing more gait disturbance. Because vascular factors can contribute to cognitive impairment and parkinsonian signs, the authors repeated the core analyses including terms for vascular risk factors and vascular disease and the associations between MCI and parkinsonism persisted. CONCLUSIONS: Mild cognitive impairment (MCI) is accompanied by parkinsonian signs, which are related to the severity and type of cognitive impairment. The association between MCI and parkinsonism is not explained by vascular risk factors or vascular disease.

Mild cognitive impairment in different functional domains and incident Alzheimer's disease.

BACKGROUND: Little is known about factors that predict transition from mild cognitive impairment to Alzheimer's disease (AD). OBJECTIVE: To examine the relation of impairment in different cognitive systems to risk of developing AD in persons with mild cognitive impairment. METHODS: Participants are 218 older Catholic clergy members from the Religious Orders Study. At baseline, they met criteria for mild cognitive impairment based on a uniform clinical evaluation that included detailed cognitive testing. Evaluations were repeated annually for up to 10 years. Analyses were controlled for age, sex, and education. RESULTS: Eighty two persons (37.6%) developed AD. In separate analyses, episodic memory, semantic memory, working memory, and perceptual speed, but not visuospatial ability, were associated with risk of AD, but when analysed together only episodic memory and perceptual speed were associated with AD incidence, with the effect for episodic memory especially strong. Overall, those with impaired episodic memory were more than twice as likely to develop AD as those with impairment in other cognitive domains (relative risk (RR) = 2.45; 95% confidence interval (CI): 1.53 to 3.92), and they experienced more rapid cognitive decline. Lower episodic memory performance was associated with increased risk of AD throughout the observation period, whereas impairment in other cognitive domains was primarily associated with risk during the following year but not thereafter. CONCLUSION: Among persons with mild cognitive impairment, episodic memory impairment is associated with a substantial and persistent elevation in risk of developing AD compared to impairment in other cognitive systems.

Change in body mass index and risk of incident Alzheimer disease.

OBJECTIVE: To examine the association of change in body mass index (BMI) with risk of Alzheimer disease (AD). METHODS: Nine hundred eighteen older Catholic clergy participating in the Religious Orders Study without dementia at baseline were studied. Outcome measures were the clinical diagnosis of AD and change in cognitive function. RESULTS: During a mean follow-up of 5.5 years, 151 persons developed AD. BMI averaged 27.4 at baseline and declined in about half the participants. In a proportional hazards model adjusted for age, sex, and education, each 1-unit less of BMI at baseline was associated with about a 5% increase in the risk of AD (hazard ratio = 0.944; 95% CI = 0.908 to 0.981), and each 1-unit annual decline in BMI (about the 10th percentile) was associated with about a 35% increase in the risk of AD compared with a person experiencing no change in BMI (about the 50th percentile) (hazard ratio = 0.730; 95% CI = 0.625 to 0.852). The results were similar after controlling for chronic diseases and excluding persons who developed AD during the first 4 years of observation. Random effects models showed that the rate of cognitive decline increased by about 8% for each 1-unit less of BMI at baseline and declined an additional 40%/year in persons losing 1 unit of BMI/year compared with those with no change in BMI. CONCLUSION: Declining body mass index (BMI) is associated with increased risk of incident Alzheimer disease (AD). Loss of BMI may reflect pathologic processes that contribute to the subsequent development of AD.

Socioeconomic characteristics of the community in childhood and cognition in old age.

We examined the relation of early life socioeconomic circumstances to cognition in older residents of a biracial urban community. Participants had brief cognitive testing three times at approximately 3-year intervals. At baseline, information about early life household and county socioeconomic level was collected. In mixed-effects models adjusted for age, sex, race, and education, both early life household and county socioeconomic levels were positively associated with baseline level of cognition but unrelated to cognitive decline. The results suggest that socioeconomic conditions in early life are associated with level of cognitive function in old age but not with rate of cognitive decline.

Education modifies the association of amyloid but not tangles with cognitive function.

The authors quantified amyloid and tau tangles in Religious Orders Study participants. In separate analyses, amyloid and tangles were related to level of cognition. When terms for education's interaction with amyloid and tangles were added, education dampened the association of amyloid with level of cognition (p = 0.02) but not the association of neurofibrillary tangles with level of cognition, suggesting that education is related to factors that reduce the effect of amyloid on cognition.

Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people.

BACKGROUND: The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood. OBJECTIVE: To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death. METHODS: There were 44 subjects with clinically diagnosed Alzheimer's disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education. RESULTS: Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60% and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50% and was no longer significant after controlling for the effect of amyloid load. CONCLUSION: These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to cause cognitive impairment.

The apolipoprotein E epsilon4 allele increases the odds of chronic cerebral infarction [corrected] detected at autopsy in older persons.

BACKGROUND AND PURPOSE: Studies investigating the relation of the apolipoprotein E (apoE) epsilon4 allele to clinical stroke and to vascular changes on magnetic resonance imaging have been conflicting. Little data are available regarding the relation of apoE epsilon4 to cerebral infarctions documented on postmortem examination. METHODS: We studied the apoE epsilon4 allele in 214 deceased members of the Religious Orders Study, a longitudinal clinical-pathologic study of aging and Alzheimer disease. The apoE genotype was determined using DNA from lymphocytes. Brains were removed a median of 5 hours (interquartile range, 5.5) after death. At postmortem examination, age, location, and size of macroscopic chronic cerebral infarctions were recorded from 1-cm coronal slabs after paraformaldehyde fixation. We also examined 20-microm paraffin-embedded sections of midfrontal and calcarine cortex for amyloid angiopathy on a scale of 1 to 4. RESULTS: Subjects included 96 males and 118 females with a mean age at death of 86 years (SD, 7). Sixty-five subjects (30.4%) had at least 1 apoE epsilon4 allele and 76 (35.5%) exhibited cerebral infarctions. More than 74% of the subjects exhibited amyloid angiopathy with a mean score of 1.4+/-1.2. After controlling for age and sex, apoE epsilon4 increased the odds of cerebral infarction by 2.3-fold (95% CI, 1.2 to 4.2). apoE epsilon4 increased the odds of cortical 3.2-fold (95% CI, 1.3 to 7.7) and subcortical infarctions 2.3-fold (95% CI, 1.2 to 4.5). The effect was unchanged after accounting for amyloid angiopathy. CONCLUSIONS: apoE epsilon4 increases the odds of chronic cerebral infarction detected at autopsy in older persons.

Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions.

OBJECTIVES: To examine the extent to which persons with mild cognitive impairment have intermediate levels of Alzheimer disease (AD) pathology, cerebral infarcts, and Lewy body disease. METHODS: A total of 180 Catholic clergy participating in the Religious Orders Study underwent annual detailed evaluation and brain autopsy. Blocks of midfrontal, superior temporal, medial temporal lobe, inferior parietal, entorhinal cortex, hippocampus, and substantia nigra were paraffin embedded, and sectioned at 6 mum. Cortical neuritic plaques, diffuse plaques, and neurofibrillary tangles were visualized with Bielschowsky silver stain, and counted and summarized to yield a Braak stage, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) diagnosis, National Institute on Aging (NIA)-Reagan diagnosis, and composite measure of AD pathology. The authors recorded the number and location of all gross chronic cerebral infarctions. Lewy bodies were identified with antibodies to alpha-synuclein. Multiple regression analyses were used to examine the relation of AD pathology and cerebral infarctions to clinical diagnosis proximate to death, controlling for age, sex, and education. RESULTS: A total of 37 had mild cognitive impairment, 60 did not have cognitive impairment, and 83 had dementia proximate to death. Nearly all persons had at least some AD pathology. Cerebral infarctions were present in 35.2%, and 15.6% had Lewy body disease. Persons with mild cognitive impairment were intermediate in terms of Braak stage and CERAD and NIA-Reagan neuropathologic criteria for AD compared to the other two groups. In multiple regression analyses, persons with mild cognitive impairment had intermediate levels of AD pathology from those without cognitive impairment and those with dementia (test for trend, F = 45.2, p < 0.001). Further, the relation between cognition and AD pathology in persons with mild cognitive impairment did not differ significantly from the relation between cognition and AD pathology in persons with dementia or those without cognitive impairment. Persons with mild cognitive impairment also had intermediate levels of cerebral infarctions (test for trend, p = 0.04). Only 3 (8.1%) persons with mild cognitive impairment had Lewy body disease. CONCLUSION: These data suggest that mild cognitive impairment may be the earliest clinical manifestation of common age-related neurologic diseases.

Proneness to psychological distress and risk of Alzheimer disease in a biracial community.

Persons without dementia residing in a biracial community completed a brief scale of proneness to psychological distress, and 1,064 were subsequently examined for incident Alzheimer disease (AD) 3 to 6 years later. In analyses controlling for selected demographic and clinical variables, persons prone to distress were 2.4 times more likely to develop AD than persons not distress prone. This effect was substantially stronger in white persons compared to African Americans.

Social resources and cognitive decline in a population of older African Americans and whites.

OBJECTIVE: To examine the relation of social resources and cognitive decline in older adults. METHODS: Data are from the Chicago Health and Aging Project, an epidemiologic study of risk factors for Alzheimer disease (AD) and other common conditions in a geographically defined population of older persons. The sample consisted of 6,102 non-Hispanic African Americans (61.2%) and whites, aged > or = 65, who underwent up to three interviews during an average of 5.3 years of follow-up. Each interview included administration of four cognitive function tests from which a composite measure of cognition was formed. Social networks were based on the number of children, relatives, and friends seen at least once a month. Social engagement was measured with four items related to social and productive activity. RESULTS: Higher number of social networks and level of social engagement were positively correlated with initial level of cognitive function (networks estimate = 0.003, engagement estimate = 0.060, both p < 0.001). Both resources were also associated with a reduced rate of cognitive decline. A high (90th percentile) number of networks reduced the rate of decline by 39% compared to a low level (10th percentile), and high social engagement reduced decline by 91%. These relations remained after controlling for socioeconomic status, cognitive activity, physical activity, depressive symptoms, and chronic medical conditions. CONCLUSIONS: Greater social resources, as defined by social networks and social engagement, are associated with reduced cognitive decline in old age.