Brandon Frank1, Madeline Ally1, Yorghos Tripodis1, Christian Puzo1, Caroline Labriolo1, Landon Hurley1, Brett Martin1, Joseph Palmisano1, Lawrence Chan1, Eric Steinberg1, Katherine Turk1, Andrew Budson1, Maureen O'Connor1, Rhoda Au1, Wei Qiao Qiu1, Lee Goldstein1, Walter Kukull1, Neil Kowall1, Ronald Killiany1, Robert Stern1, Thor Stein1, Ann McKee1, Jesse Mez1, Michael Alosco2. 1. From the Boston University Alzheimer's Disease Center and CTE Center (B.F., M. Ally, Y.T., C.P., C.L., B.M., J.P., L.C., E.S., K.T., A.B., M.O., R.A., W.Q.Q., L.G., N.K., R.K., R.S., T.S., A.M., J.M., M. Alosco), Boston University School of Medicine; Veteran Affairs Bedford Healthcare System (B.F., M.O., T.S., A.M.), Bedford; Department of Biostatistics (Y.T.), Boston University School of Public Health, MA; Yale School of Public Health (L.H.), New Haven, CT; Biostatistics and Epidemiology Data Analytics Center (B.M., J.P.), Boston University School of Public Health; Department of Neurology (K.T., A.B., R.A., N.K., R.S., A.M., J.M., M. Alosco), Boston University School of Medicine; Veterans Affairs Boston Healthcare System (K.T., A.B., N.K., T.S., A.M); Department of Anatomy & Neurobiology (R.A., R.K., R.S.), Boston University School of Medicine; MA; Framingham Heart Study (R.A.), National Heart, Lung, and Blood Institute, Bethesda, MD; Department of Epidemiology (R.A.), Boston University School of Public Health; Department of Psychiatry (W.Q.Q.), Boston University School of Medicine; Department of Pharmacology & Experimental Therapeutics (W.Q.Q.), Boston University School of Medicine; Department of Pathology and Laboratory Medicine (L.G.), Boston University School of Medicine; Departments of Psychiatry and Ophthalmology (L.G.), Boston University School of Medicine; Departments of Biomedical, Electrical & Computer Engineering (L.G.), Boston University College of Engineering, MA; National Alzheimer's Coordinating Center (W.K.), Department of Epidemiology, University of Washington, Seattle; Center for Biomedical Imaging (R.K.), and Boston University School of Medicine; Department of Neurosurgery (R.S.), Boston University School of Medicine, MA. 2. From the Boston University Alzheimer's Disease Center and CTE Center (B.F., M. Ally, Y.T., C.P., C.L., B.M., J.P., L.C., E.S., K.T., A.B., M.O., R.A., W.Q.Q., L.G., N.K., R.K., R.S., T.S., A.M., J.M., M. Alosco), Boston University School of Medicine; Veteran Affairs Bedford Healthcare System (B.F., M.O., T.S., A.M.), Bedford; Department of Biostatistics (Y.T.), Boston University School of Public Health, MA; Yale School of Public Health (L.H.), New Haven, CT; Biostatistics and Epidemiology Data Analytics Center (B.M., J.P.), Boston University School of Public Health; Department of Neurology (K.T., A.B., R.A., N.K., R.S., A.M., J.M., M. Alosco), Boston University School of Medicine; Veterans Affairs Boston Healthcare System (K.T., A.B., N.K., T.S., A.M); Department of Anatomy & Neurobiology (R.A., R.K., R.S.), Boston University School of Medicine; MA; Framingham Heart Study (R.A.), National Heart, Lung, and Blood Institute, Bethesda, MD; Department of Epidemiology (R.A.), Boston University School of Public Health; Department of Psychiatry (W.Q.Q.), Boston University School of Medicine; Department of Pharmacology & Experimental Therapeutics (W.Q.Q.), Boston University School of Medicine; Department of Pathology and Laboratory Medicine (L.G.), Boston University School of Medicine; Departments of Psychiatry and Ophthalmology (L.G.), Boston University School of Medicine; Departments of Biomedical, Electrical & Computer Engineering (L.G.), Boston University College of Engineering, MA; National Alzheimer's Coordinating Center (W.K.), Department of Epidemiology, University of Washington, Seattle; Center for Biomedical Imaging (R.K.), and Boston University School of Medicine; Department of Neurosurgery (R.S.), Boston University School of Medicine, MA. malosco@bu.edu.
Abstract
BACKGROUND AND OBJECTIVES: Cerebrovascular disease (CBVD) is frequently comorbid with autopsy-confirmed Alzheimer disease (AD), but its contribution to the clinical presentation of AD remains unclear. We leveraged the National Alzheimer's Coordinating Center (NACC) uniform and neuropathology datasets to compare the cognitive and functional trajectories of AD+/CBVD+ and AD+/CBVD- brain donors. METHODS: The sample included NACC brain donors with autopsy-confirmed AD (Braak stage ≥3, Consortium to Establish a Registry for Alzheimer's Disease score ≥2) and complete Uniform Data Set (UDS) evaluations between 2005 and 2019, with the most recent UDS evaluation within 2 years of autopsy. CBVD was defined as moderate to severe arteriosclerosis or atherosclerosis. We used propensity score weighting to isolate the effects of comorbid AD and CBVD. This method improved the balance of covariates between the AD+/CBVD+ and AD+/CBVD- groups. Longitudinal mixed-effects models were assessed with robust bayesian estimation. UDS neuropsychological test and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores were primary outcomes. RESULTS: Of 2,423 brain donors, 1,476 were classified as AD+/CBVD+. Compared with AD+/CVBD- donors, the AD+/CBVD+ group had accelerated decline (i.e., group × time effects) on measures of processing speed (β = -0.93, 95% CI -1.35, -0.51, Bayes factor [BF] 130.75), working memory (β = 0.05, 95% CI 0.02, 0.07, BF 3.59), verbal fluency (β = 0.10, 95% CI 0.04, 0.15, BF 1.28), naming (β = 0.09, 95% CI 0.03, 0.16, BF = 0.69), and CDR-SB (β = -0.08, 95% CI -0.12, -0.05, BF 18.11). Effects ranged from weak (BFs <3.0) to strong (BFs <150). We also found worse performance in the AD+/CBVD+ group across time on naming (β = -1.04, 95% CI -1.83, -0.25, BF 2.52) and verbal fluency (β = -0.73, 95% CI -1.30, -0.15, BF 1.34) and more impaired CDR-SB scores (β = 0.45, 95% CI 0.01, 0.89, BF 0.33). DISCUSSION: In brain donors with autopsy-confirmed AD, comorbid CBVD was associated with an accelerated functional and cognitive decline, particularly on neuropsychological tests of attention, psychomotor speed, and working memory. CBVD magnified effects of AD neuropathology on semantic-related neuropsychological tasks. Findings support a prominent additive and more subtle synergistic effect for comorbid CBVD neuropathology in AD.
BACKGROUND AND OBJECTIVES: Cerebrovascular disease (CBVD) is frequently comorbid with autopsy-confirmed Alzheimer disease (AD), but its contribution to the clinical presentation of AD remains unclear. We leveraged the National Alzheimer's Coordinating Center (NACC) uniform and neuropathology datasets to compare the cognitive and functional trajectories of AD+/CBVD+ and AD+/CBVD- brain donors. METHODS: The sample included NACC brain donors with autopsy-confirmed AD (Braak stage ≥3, Consortium to Establish a Registry for Alzheimer's Disease score ≥2) and complete Uniform Data Set (UDS) evaluations between 2005 and 2019, with the most recent UDS evaluation within 2 years of autopsy. CBVD was defined as moderate to severe arteriosclerosis or atherosclerosis. We used propensity score weighting to isolate the effects of comorbid AD and CBVD. This method improved the balance of covariates between the AD+/CBVD+ and AD+/CBVD- groups. Longitudinal mixed-effects models were assessed with robust bayesian estimation. UDS neuropsychological test and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores were primary outcomes. RESULTS: Of 2,423 brain donors, 1,476 were classified as AD+/CBVD+. Compared with AD+/CVBD- donors, the AD+/CBVD+ group had accelerated decline (i.e., group × time effects) on measures of processing speed (β = -0.93, 95% CI -1.35, -0.51, Bayes factor [BF] 130.75), working memory (β = 0.05, 95% CI 0.02, 0.07, BF 3.59), verbal fluency (β = 0.10, 95% CI 0.04, 0.15, BF 1.28), naming (β = 0.09, 95% CI 0.03, 0.16, BF = 0.69), and CDR-SB (β = -0.08, 95% CI -0.12, -0.05, BF 18.11). Effects ranged from weak (BFs <3.0) to strong (BFs <150). We also found worse performance in the AD+/CBVD+ group across time on naming (β = -1.04, 95% CI -1.83, -0.25, BF 2.52) and verbal fluency (β = -0.73, 95% CI -1.30, -0.15, BF 1.34) and more impaired CDR-SB scores (β = 0.45, 95% CI 0.01, 0.89, BF 0.33). DISCUSSION: In brain donors with autopsy-confirmed AD, comorbid CBVD was associated with an accelerated functional and cognitive decline, particularly on neuropsychological tests of attention, psychomotor speed, and working memory. CBVD magnified effects of AD neuropathology on semantic-related neuropsychological tasks. Findings support a prominent additive and more subtle synergistic effect for comorbid CBVD neuropathology in AD.
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