Julia L. Bienias

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 μm. 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.

Education modifies the relation of AD pathology to level of cognitive function in older persons

Objective: To test the hypothesis that years of formal education modifies the relation of AD pathology to level of cognitive function. Methods: A total of 130 older Catholic clergy participating in the Religious Orders Study underwent annual cognitive function testing and brain autopsy at the time of death. Individual cognitive function tests were z-scored and averaged to yield a global measure of cognitive function and summary measures of five different cognitive abilities. Neuritic and diffuse plaques and neurofibrillary tangles were counted in separate 1 mm2 areas of maximal density. Counts were converted to standard scores by dividing by their SD, and combined to yield a global AD pathology score and summary scores of each postmortem index. Linear regression was used to examine the relation of education and AD pathology scores to level of cognitive function proximate to death, controlling for age and sex. Subsequent analyses tested the interaction between education and each AD pathology score to determine whether education modified the relation of AD pathology to level of cognitive function. Additional analyses examined these associations on five specific cognitive abilities. Results: Both years of formal education (regression coefficient = 0.073, p = 0.0001) and the global AD pathology score (regression coefficient = −0.689, p < 0.0001) were related to level of cognitive function. When an interaction term between education and AD pathology was added to the model, the association between a unit of AD pathology and level of cognitive function was 0.088 (p = 0.0078) standard unit less for each year of education than the level predicted from the model without the interaction term. Whereas neuritic plaques, diffuse plaques, and neurofibrillary tangles were all strongly related to cognitive function, education only modified the relation of neuritic plaques (p = 0.002) and diffuse plaques (p = 0.03) to cognition, but not neurofibrillary tangles. In analyses examining five different cognitive abilities, the interaction between education and the neuritic plaque score was strongest for perceptual speed and weakest for episodic memory. Conclusions: These data provide strong evidence that the relation between senile plaques and level of cognitive function differs by years of formal education.

Cognitive activity and incident AD in a population-based sample of older persons

Background: Participation in cognitively stimulating activities is hypothesized to be associated with risk of AD, but knowledge about this association is limited. Methods: A biracial community in Chicago was censused, persons aged 65 years and older were asked to participate in an interview, and 6,158 of 7,826 (79%) eligible persons did so. As part of the interview, persons rated current frequency of participation in seven cognitive activities (e.g., reading a newspaper) and nine physical activities (e.g., walking for exercise) from which composite measures of cognitive and physical activity frequency were derived. Four years later, 1,249 of those judged free of AD were sampled for a detailed clinical evaluation of incident disease and 842 (74% of those eligible) participated. Results: The composite measure of cognitive activity ranged from 1.28 to 4.71 (mean 3.30; SD 0.59), with higher scores indicating more frequent activity. A total of 139 persons met National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria for AD on clinical evaluation. In a logistic regression model adjusted for age, education, sex, race, and possession of the APOE ε4 allele, a one-point increase in cognitive activity score was associated with a 64% reduction in risk of incident AD (OR 0.36; 95% CI 0.20 to 0.65). By contrast, weekly hours of physical activity (mean 3.5; SD 5.1) was not related to disease risk (OR 1.04; 95% CI 0.98 to 1.10). Education was associated with risk of AD and a similar trend was present for occupation, but these effects were substantially reduced when cognitive activity was added to the model. Conclusion: Frequency of participation in cognitively stimulating activities appears to be associated with risk of AD and may partially explain the association of educational and occupational attainment with disease risk.

Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology

Background: Alzheimer disease (AD) is the most common cause of dementia. The effect of cerebral infarctions on the likelihood of dementia from AD pathology is not well understood. Methods: The study included 153 deceased Catholic clergy who participated in the Religious Orders Study. Annual evaluations, including 19 tests of cognitive function, were performed to determine a diagnosis of dementia and level of cognitive abilities proximate to death. At autopsy, neuritic and diffuse plaques and neurofibrillary tangles were counted and combined into a standardized summary measure of AD pathology. Number, volume, side, and distribution of old macroscopic infarctions were recorded. Analyses included logistic and linear regression, adjusting for age, sex, and education. Results: The AD pathology score ranged from 0 to 2.93 units, and 54 persons had infarctions. There was no relationship between AD pathology and infarctions (r = 0.04, p = 0.56). Each unit of AD pathology increased the odds of dementia by 4.40-fold (95% CI = 2.33 to 8.32), and this was essentially unchanged after accounting for infarctions. The presence of one or more infarctions independently increased the odds of dementia by 2.80-fold (95% CI = 1.26 to 6.21). There was no interaction between AD pathology and infarctions to further increase the likelihood of dementia (p = 0.39). The number, size, and distribution of infarctions added to the odds of dementia but also did not show an interaction with AD pathology. Similar results were found in analyses with global cognitive function and five different cognitive systems. Conclusion: Cerebral infarctions independently contribute to the likelihood of dementia but do not interact with AD pathology to increase the likelihood of dementia beyond their additive effect.

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 ≥ 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.

Proneness to psychological distress is associated with risk of Alzheimer’s disease

Background: Chronic stress is associated with hippocampal damage and impaired memory in animals and humans. Objective: To examine this relationship with clinical and pathologic data from the Religious Orders Study. Methods: Older Catholic clergy members underwent annual clinical evaluations, which included clinical classification of Alzheimer’s disease (AD) and detailed cognitive function testing from which composite measures of global cognition and specific cognitive functions were derived. At the baseline evaluation, participants completed a measure of the tendency to experience psychological distress, a stable personality trait that served as an indicator of susceptibility to negative emotional states across the life span. More than 90% of participants who died underwent a uniform postmortem examination of the brain from which summary measures of AD pathology were derived. The association of distress proneness with incident AD and cognitive decline and with measures of AD pathology was examined in analyses adjusted for selected demographic and clinical variables. Results: During a mean of 4.9 years of follow-up, 140 persons developed AD. Those high in distress proneness (90th percentile) had twice the risk of developing AD than those low in distress proneness (10th percentile). Distress proneness was related to decline in episodic memory but not in other cognitive domains, with a >10-fold increase in episodic memory decline in those high in distress proneness compared with those low in the trait. Among those who died, however, distress proneness was not related to common measures of AD pathology. Conclusion: Proneness to experience psychological distress is a risk factor for AD, an effect independent of AD pathologic markers such as cortical plaques and tangles.

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.

The Rush Memory and Aging Project: Study Design and Baseline Characteristics of the Study Cohort.

The long-term objective of the Rush Memory and Aging Project is to identify the postmortem indices linking genetic and environmental risk factors to the development of Alzheimer’s disease (AD). The overall study design involves a detailed assessment of risk factors for AD in older persons without known dementia who agree to annual clinical evaluation and organ donation at the time of death. In contrast to other clinical-pathologic studies which are conducted on special populations, the Rush Memory and Aging Project enrolled a cohort with much greater diversity in terms of educational attainment, in addition to gender, race, and ethnicity. From September of 1997 through April of 2005, more than 1,000 older persons without known dementia from more than 30 residential facilities across the Chicago metropolitan area agreed to participate. Their mean age was 81 years, about a third had 12 or fewer years of education, a third were men, and about 10% were members of a racial or ethnic minority group. More than 950 already have completed their baseline clinical evaluation.

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.

Relation of cerebral infarctions to dementia and cognitive function in older persons.

Background: Cerebral infarctions are common in older persons but their relationship with dementia and cognitive function remains controversial. Methods: Participants were 164 older Catholic nuns, priests, and brothers who underwent annual clinical evaluation and brain autopsy at death. The authors quantified number and volume of old cerebral infarctions on postmortem examination and determined the association with dementia and cognitive function proximate to death. Analyses controlled for age, sex, and education. Results: A total of 58 (35.4%) subjects had cerebral infarctions: 29 had one infarction and 29 had multiple infarctions. In logistic regression analyses, infarctions increased the odds of dementia twofold (OR 2.12; 95% CI 1.06 to 4.25). The odds of dementia increased by 2.67-fold for multiple infarctions (95% CI 1.08 to 6.61), whereas the odds of dementia with single infarctions increased by 69% (95% CI 0.70 to 4.09). In linear regression analyses, there was a trend for multiple infarctions to be associated with lower global cognitive scores (−0.44 standard units, p = 0.057). Multiple infarctions were related to perceptual speed, visuospatial skills, and working memory, but not to episodic or semantic memory. The authors found similar results with infarction volume. In secondary analyses, only infarctions that were clinically evident during life were associated with dementia and cognitive function. Conclusion: Cerebral infarctions are associated with a twofold increase in odds of dementia. Odds are higher in persons with multiple, large, or clinically evident infarctions. In addition, cerebral infarctions do not affect all cognitive systems equally, showing the strongest association with perceptual speed and the weakest with episodic memory.