Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal AdultsHarvard Aging Brain Study

Background and ObjectivesHippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared with beta-amyloid (A beta) and tau imaging, it is less specific for Alzheimer disease (AD) pathology. This lack of specificity could provide indirect information about potential copathologies that cannot be observed in vivo. In this prospective cohort study, we aimed to assess the associations among A beta, tau, HV, and cognition, measured over a 10-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for A beta and tau.MethodsWe enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI (follow-up duration 1.3-7.0 years), neocortical A beta imaging on Pittsburgh Compound B PET scans (1.9-8.5 years), entorhinal and inferior temporal tau on flortaucipir PET scans (0.8-6.0 years), and the Preclinical Alzheimer Cognitive Composite (3.0-9.8 years) were prospectively collected. We evaluated the longitudinal associations between A beta, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline.ResultsWe analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years (range 63-87). Thirty-four participants (27%) exhibited an initial high-A beta burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline (R-2 = 0.28, p < 0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of A beta and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers.DiscussionIn older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of A beta or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwise in vivo.