The Baltimore Longitudinal Study of Aging (BLSA) was established in 1958 and is one the oldest prospective studies of aging in the USA and the world. The mission of the BLSA is to learn what happens to people as they get old and how to sort out changes due to aging from those due to disease or other causes. Over the last year, we have published a number of papers investigating the effects of possible modifiers of cognitive aging, risk for dementia, and the presence of Alzheimer's pathology at autopsy. These potential early markers and modifiers include glucose intolerance and insulin resistance, personality characteristics, changes in regional cerebral blood flow, and evidence of vascular/demyelinating disease on antemortem and postmortem MRI scans. Based on the established link between diabetes and increased risk of dementia and AD, we expected to find an association between glucose intolerance and AD-type neuropathology at autopsy or on in vivo PET amyloid scans. However, in this prospective cohort with multiple assessments of glucose intolerance and insulin resistance over time, measures of glucose and insulin homeostasis were not associated with either amyloid plaques or neurofibrillary tangles. In contrast, we found significant differences in regional cerebral blood flow changes over time between participants with normal glucose tolerance (NGT) and those with impaired glucose tolerance (IGT). This study included 15 participants with IGT and 49 with NGT at mid-life who subsequently received PET studies of regional cerebral blood flow (rCBF) over an 8-year follow-up period. Voxel-based analysis of differences between groups of rCBF changes showed greater rCBF decline over time in the frontal, parietal, and temporal cortices. Some brain regions in the frontal and temporal cortices also showed greater longitudinal increments in rCBF in the IGT group. Our findings suggest that IGT in midlife may be associated with changes in brain function and are consistent with a role of vascular factors in the diabetes-dementia relationship. Although glucose intolerance and insulin resistance were not associated with AD pathology, we did find a relationship between higher amounts of white matter disease on MRI scans and amyloid plaques and neurofibrillary tangles at autopsy. White matter disease was quantified in pre- and postmortem MRI scans for 50 BLSA autopsy study participants using the Cardiovascular Health Study (CHS) criteria in a blinded manner. We also examined amyloid angiopathy and found that amyloid angiopathy was not independently associated with CHS score. Our finding that AD pathology at autopsy is associated with MRI-detected cerebral white matter disease may explain, in part, the association between cerebral white matter disease and cognitive decline in the elderly individuals. In addition to investigation of the associations between metabolic and vascular risk factors and AD pathology at autopsy, we have also investigated associations between behavioral characteristics and later risk for clinical dementia and AD pathology. We found that early personality characteristics were associated with later risk and expression of clinical dementia. Broad factors and specific facets of personality were assessed up to 28 years (mean 11 years) before onset of dementia and up to 30 years (mean 15 years) before death in a cohort (n = 111) evaluated for AD neuropathology at autopsy. Individuals with higher baseline Neuroticism scores (vulnerability to stress, anxiety, and depression) or lower scores on Conscientiousness (order and competence) were less likely to remain asymptomatic in the presence of AD neuropathology. These findings suggest that a resilient personality profile is associated with lower risk or delay of clinical dementia even in persons with AD neuropathology. In a second study, including a meta-analysis of the association between personality domains and risk for AD, we found that high Neuroticism and low Conscientiousness were associated with increased risk for incident diagnosis of clinical AD.
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