Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults
Bernard J Hanseeuw1, Heidi I L Jacobs1, Aaron P Schultz1
1From the Department of Radiology (B.J.H., H.I.L.J., N.J.G., J.A.B., J.S.S., J.S., H.-S.Y., M.N., J.C.P., G.E.F., K.A.J.), Massachusetts General Hospital, the Gordon Center for Medical Imaging, Boston; Department of Neurology (B.J.H.), Cliniques Universitaires Saint-Luc, Brussels, Belgium; Faculty of Health, Medicine and Life Sciences (H.I.L.J.), School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, the Netherlands; Department of Neurology (A.P.S., R.F.B., M.E.F., M.P., Y.T.Q., P.V., J.P.C., G.A.M., R.A., K.P., D.M.R., R.A.S., K.A.J.), Massachusetts General Hospital; Center for Alzheimer Research and Treatment (R.F.B., P.V., G.A.M., R.A., K.P., D.M.R., R.A.S., K.A.J.), Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston; Melbourne School of Psychological Sciences (R.F.B.), University of Melbourne, Australia; and Department of Psychiatry (J.G.), and Department of Biostatistics (B.C.H.), Massachusetts General Hospital, Harvard Medical School, Boston.
Background And Objectives:
Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared with β-amyloid (Aβ) 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 Aβ, 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 Aβ and tau.
Methods:
We 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 Aβ 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 Aβ, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline.
Results:
We 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-Aβ burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline (R2 = 0.28, p < 0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aβ 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.
Discussion:
In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aβ 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.
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