David A. Snowdon

Positive Emotions in Early Life and Longevity: Findings from the Nun Study

Handwritten autobiographies from 180 Catholic nuns, composed when participants were a mean age of 22 years, were scored for emotional content and related to survival during ages 75 to 95. A strong inverse association was found between positive emotional content in these writings and risk of mortality in late life (p < .001). As the quartile ranking of positive emotion in early life increased, there was a stepwise decrease in risk of mortality resulting in a 2.5-fold difference between the lowest and highest quartiles. Positive emotional content in early-life autobiographies was strongly associated with longevity 6 decades later. Underlying mechanisms of balanced emotional states are discussed.

Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: Findings from the Nun Study

The development of interventions designed to delay the onset of dementia highlights the need to determine the neuropathologic characteristics of individuals whose cognitive function ranges from intact to demented, including those with mild cognitive impairments. We used the Braak method of staging Alzheimers disease pathology in 130 women ages 76–102 years who were participants in the Nun Study, a longitudinal study of aging and Alzheimers disease. All participants had complete autopsy data and were free from neuropathologic conditions other than Alzheimers disease lesions that could affect cognitive function. Findings showed a strong relationship between Braak stage and cognitive state. The presence of memory impairment was associated with more severe Alzheimers disease pathology and higher incidence of conversion to dementia in the groups classified as having mild or global cognitive impairments. In addition to Braak stage, atrophy of the neocortex was significantly related to the presence of dementia. Our data indicate that Alzheimers neurofibrillary pathology is one of the neuropathologic substrates of mild cognitive impairments. Additional studies are needed to help explain the variability in neuropathologic findings seen in individuals whose cognitive performance falls between intact function and dementia.

Hippocampal volume as an index of Alzheimer neuropathology Findings from the Nun Study

ObjectiveTo determine whether hippocampal volume is a sensitive and specific indicator of Alzheimer neuropathology, regardless of the presence or absence of cognitive and memory impairment. MethodsPostmortem MRI scans were obtained for the first 56 participants of the Nun Study who were scanned. The area under receiver operating characteristic curves, sensitivity, specificity, and positive and negative predictive values were used to assess the diagnostic accuracy of hippocampal volume in predicting fulfillment of Alzheimer neuropathologic criteria and differences in Braak staging. ResultsHippocampal volume predicted fulfillment of neuropathologic criteria for AD for all 56 participants (p < 0.001): 24 sisters who were demented (p = 0.036); 32 sisters who remained nondemented (p < 0.001), 8 sisters who remained nondemented but had memory impairment (p < 0.001), and 24 sisters who were intact with regard to memory and cognition at the final examination prior to death (p = 0.003). In individuals who remained nondemented, hippocampal volume was a better indicator of AD neuropathology than a delayed memory measure. Among nondemented sisters, Braak stages III and VI were distinguishable from Braak stages II or lower (p = 0.001). Among cognitively intact individuals, those in Braak stage II could be distinguished from those in stage I or less (p = 0.025). ConclusionVolumetric measures of the hippocampus may be useful in identifying nondemented individuals who satisfy neuropathologic criteria for AD as well as pathologic stages of AD that may be present decades before initial clinical expression.

Head Circumference, Education and Risk of Dementia: Findings from the Nun Study

To examine the prevalence of dementia associated with having a smaller brain, lower education or both of these characteristics, 294 Catholic sisters were assessed annually for dementia. Sixty participants died and their brains were evaluated to determine fulfillment of neuropathological criteria for Alzheimer‘s disease (AD). Lower educational attainment and the interaction of smaller head circumference with lower education were associated with the presence of dementia, controlling for age and the presence of one or more apolipoprotein E-e4 alleles. By contrast, neither low educational attainment nor head circumference was significantly associated with fulfillment of neuropathological criteria for AD. Individuals having both low education and small head circumference were four times as likely to be demented as the rest of the sample. The findings suggest that higher education and larger head size, alone or in combination, may reduce the risk of expressing dementia in late life.

Early life linguistic ability, late life cognitive function, and neuropathology: findings from the Nun Study

The relationships between early life variables, cognitive function, and neuropathology were examined in participants in the Nun Study who were between the ages of 75 and 95. Our early life variable was idea density, which is a measure of linguistic ability, derived from autobiographies written at a mean age of 22 years. Six discrete categories of cognitive function, including mild cognitive impairments, were evaluated, using the Consortium to Establish a Registry for Alzheimers Disease (CERAD) battery of cognitive tests. Neuropathologic data included Braak staging, neurofibrillary tangle and senile plaque counts, brain weight, degree of cerebral atrophy, severity of atherosclerosis, and the presence of brain infarcts. Early-life idea density was significantly related to the categories of late-life cognitive function, including mild cognitive impairments: low idea density was associated with greater impairment. Low idea density also was significantly associated with lower brain weight, higher degree of cerebral atrophy, more severe neurofibrillary pathology, and the likelihood of meeting neuropathologic criteria for Alzheimers disease.

Very Early Detection of Alzheimer Neuropathology and the Role of Brain Reserve in Modifying Its Clinical Expression

Numerous studies show that the pathology of Alzheimer’s disease is present decades before a clinical diagnosis of dementia can be made. Given the likelihood that agents will become available that reliably delay onset and/or slow progression of Alzheimer’s disease, it will be important to detect preclinical Alzheimer’s disease as early as possible for maximal treatment effect. Detection of individuals by sensitive cognitive measures provides one way to identify people who are at high risk of developing clinical Alzheimer’s disease. However, it is likely that those with considerable brain or cognitive reserve will be able to mask cognitive deficits until very close to the onset of the dementia, rendering such cognitive measures insensitive. Optimum biomarkers for Alzheimer’s disease therefore need to target the severity of underlying brain pathology independently of brain reserve. Findings are presented showing the importance of higher education and larger brain size in masking the underlying disease pathology.

White matter volumes and periventricular white matter hyperintensities in aging and dementia

Objective: To determine the relationship between MRI periventricular white matter hyperintensities, cerebral white matter volumes, neuropathologic findings, and cognitive status in aged individuals. Background: The significance of periventricular white matter hyperintensities seen on MR images in aged individuals remains controversial. The Nun Study is a longitudinal cohort aging study in which all 678 initially enrolled participants agreed to autopsy neuropathologic examination. Methods: We used MRI to measure white matter volumes of the cerebral hemispheres in 52 formaldehyde-fixed brains for correlation with white matter and neocortical pathology, postmortem MRI observations, and cognitive measures. Results: Reduced white matter volume is associated with dementia, but periventricular white matter hyperintensities were not related to white matter volume, stroke, or dementia. Conclusions: Our results do not support the hypothesis that periventricular hyperintensities seen on MR images have deleterious consequences in these aged individuals.

Age, education, and changes in the Mini-Mental State Exam scores of older women: findings from the Nun Study.

OBJECTIVE: To describe the relationship of Mini‐Mental State Exam (MMSE) scores and changes over time in MMSE scores to age and education in a population of older women.

The loss of independence in activities of daily living: the role of low normal cognitive function in elderly nuns.

OBJECTIVES This study investigated the role of low normal cognitive function in the subsequent loss of independence in activities of daily living. METHODS Of the 678 elderly nuns who-completed cognitive and physical function assessments in 1992/93, 575 were reassessed in 1993/94. Mini-Mental State Examination scores were divided into three categories and related to loss of independence in six activities of daily living. RESULTS Participants with low normal cognitive function at first assessment had twice the risk of losing independence in three activities of daily living by second assessment relative to those with high normal cognitive function. This relationship was largely due to a progression from low normal cognitive function at first assessment to impaired cognitive function at second assessment and was associated with an elevated risk of losing independence in the six activities. CONCLUSIONS Progression from low normal to impaired cognitive function was associated with loss of independence in activities of daily living. Thus low normal cognitive function could be viewed as an early warning of impending cognitive impairment and loss of physical function.

Linguistic Ability in Early Life and the Neuropathology of Alzheimer's Disease and Cerebrovascular Disease: Findings from the Nun Study

Abstract: Findings from the Nun Study indicate that low linguistic ability in early life has a strong association with dementia and premature death in late life. In the present study, we investigated the relationship of linguistic ability in early life to the neuropathology of Alzheimers disease and cerebrovascular disease. The analyses were done on a subset of 74 participants in the Nun Study for whom we had handwritten autobiographies completed some time between the ages of 19 and 37 (mean = 23 years). An average of 62 years after writing the autobiographies, when the participants were 78 to 97 years old, they died and their brains were removed for our neuropathologic studies. Linguistic ability in early life was measured by the idea (proposition) density of the autobiographies, i.e., a standard measure of the content of ideas in text samples. Idea density scores from early life had strong inverse correlations with the severity of Alzheimers disease pathology in the neocortex: Correlations between idea density scores and neurofibrillary tangle counts were −0.59 for the frontal lobe, −0.48 for the temporal lobe, and −0.49 for the parietal lobe (all p values < 0.0001). Idea density scores were unrelated to the severity of atherosclerosis of the major arteries at the base of the brain and to the presence of lacunar and large brain infarcts. Low linguistic ability in early life may reflect suboptimal neurological and cognitive development, which might increase susceptibility to the development of Alzheimers disease pathology in late life.