Recently, quantitative metabolomics identified a panel of 10-plasma lipids that were highly predictive of conversion to Alzheimer’s disease (AD) in cognitively normal older individuals (N=28, area-under-the-curve; AUC=0.92, sensitivity/specificity of 90%/90%). We failed to replicate these findings in a substantially larger study from two independent cohorts - the Baltimore Longitudinal Study of Aging (BLSA, N=93, AUC=0.642, sensitivity/specificity of 51.6%/65.7%) and the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-RS, N=100, AUC=0.395, sensitivity/specificity of 47.0%/36.0%). In analyses applying machine learning methods to all 187 metabolite concentrations assayed, we find a modest signal in the BLSA with distinct metabolites associated with the preclinical and symptomatic stages of AD, whereas the same methods gave poor classification accuracies in the AGES-RS samples. We believe that ours is the largest blood biomarker study of preclinical AD to date. These findings underscore the importance of large-scale independent validation of index findings from biomarker studies with relatively small sample sizes.

Background Hypertensive pregnancy disorders have been associated with subjective cognitive complaints or brain white matter lesions five to ten years after the hypertensive pregnancy. The long-term effects of hypertensive pregnancies on brain structure and cognitive function remain unknown. Methods and Results This study included 1279 women who participated in the Family Blood Pressure Project Genetic Epidemiology Network of Arteriopathy (GENOA) study. As part of the ancillary Genetics of Microangiopathic Brain Injury study, a neurocognitive battery was administered; 1075 also had a brain MRI. A history of a hypertensive pregnancy disorder was obtained by self-report using a validated questionnaire. Linear models fit with generalized estimating equations were used to assess the association between hypertensive pregnancy disorders and cognition, adjusting for age, race, education, body mass index, smoking, current hypertension, hypertension duration, and family history of hypertension. Regression models for the brain MRI outcomes also were adjusted for total intracranial volume. Women with histories of hypertensive pregnancy disorders performed worse on all measures of processing speed: Digital Symbol Substitution Test (mean score 41.2 vs 43.4, P=0.005), Trail Making Test Part A (mean seconds 45.1 vs 42.2, P=0.035), and Stroop (mean score 173.9 vs 181.0, P=0.002) and had smaller brain volumes compared to women with histories of normotensive pregnancies (286 vs 297, P=0.023). Conclusions Hypertensive pregnancy disorders are associated with worse performance on tests of processing speed and smaller brain volumes decades later. Population-based studies are needed to provide critical insight as to the contribution of hypertensive pregnancies to risk of cognitive decline and dementia.