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 distinguish changes due to aging from those due to disease or other causes. The Early Markers of Alzheimer's Disease program continues to perform cognitive assessments and establish research diagnoses of Mild Cognitive Impairment and Alzheimer's Disease for BLSA participants. This information is used in multiple collaborative research projects conducted by intramural and extramural investigators, including our studies of brain aging and neuroimaging biomarkers of cognitive decline and AD. Over the last year, we have continued cognitive assessments of BLSA participants, as well as diagnostic case conferences to establish research diagnoses of cognitive impairment. We have continued to investigate possible modifiers of cognitive aging, risk for dementia, and the presence of Alzheimer's pathology at autopsy. Highlights of our research program over the last year include a study to determine whether plasma ceramides and sphingomyelins were associated with risk of AD, and whether the association varied by sex and APOE genotype (Mielke et al., 2016). We examined plasma sphingolipids in relation to risk of AD in 626 men and 366 women from the BLSA, aged 55 years and older, over a mean (SD) follow-up of 15.0 (7.0) years for men and 13.1 (5.9) years for women. Among men, the highest tertile of most ceramides and sphingomyelins were associated with an increased risk of AD. In contrast, among women there were no associations between any of the ceramides and risk of AD, but women in the highest tertile of most sphingomyelins had a reduced risk of AD, which was most pronounced among APOE 4 carriers. These results highlight the importance of considering sex and APOE genotype in assessing the relationship between sphingolipids and AD risk. In another study, we investigated the relation between the urinary free cortisol, a measure of stress exposure, to creatinine ratio(UFC/Cr) and AD risk (Ennis et al., 2017). UFC/Cr level and UFC/Cr variability, but not UFC/Cr slope over time, were significant predictors of AD risk an average of 2.9 years before AD onset. Elevated UFC/Cr level and elevated UFC/Cr variability were related to a 1.31- and 1.38-times increase in AD risk, respectively. These findings suggest that cortisol dysregulation may modulate the downstream clinical expression of AD pathology or be a preclinical marker of AD. We also collaborated with a 5-study consortium of longitudinal studies focused on preclinical AD to develop and validate an algorithmic classification to predict progression from normal to mild cognitive impairment, using longitudinal cognitive assessments and Clinical Dementia Rating Scale data (Gross et al., 2017). In each of the 5 studies, an algorithmic classification based on both cognitive testing cutoff scores and a CDR 0.5 provided optimal balance of sensitivity and specificity (areas under the curve: 0.85-0.95). Both baseline cognitive scores and longitudinal cognitive change were associated with future diagnostic status using this algorithmic classification, demonstrating the feasibility of combining clinical data across studies. In a study of polymorphisms in cyclic AMP responsive element binding protein 1 gene (CREB1), we examined cross-sectional and longitudinal effects of CREB1 genotypes on individual differences in memory and executive function in cognitively normal individuals (Wolf et al., 2017). We investigated effects of common, independent tag SNPs within CREB1 (rs2253206, rs10932201, rs6785) on age-related longitudinal change and level of executive function and memory performance independent of baseline age, sex, APOE4 status, and education. We found significant effects of all three CREB1 SNPs on performance level and/or longitudinal change in performance based on eight measures assessing semantic memory, episodic memory, or both executive function and semantic memory. SNP rs10932201 showed the most significant and largest effect (Cohen's d = -0.70, p < 0.01) on age-related longitudinal decline of semantic memory. Additionally, there were interactions between all three CREB1 SNPs and APOE4 status on age-related longitudinal declines and levels of memory and executive function. We continue to collaborate extensively with both intramural and extramural investigators, including ongoing studies of motor function, sleep disturbance, hearing loss, and vision changes.
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