Trajectories of Cognitive Decline in Brain Donors With Autopsy-Confirmed Alzheimer Disease and Cerebrovascular Disease

Abstract

Background and Objectives:Cerebrovascular disease (CBVD) is frequently co-morbid with autopsy-confirmed Alzheimer’s disease (AD), but it’s contribution to the clinical presentation of AD remains unclear. We leveraged the National Alzheimer’s Coordinating Center (NACC) uniform and neuropathology data sets 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, CERAD ≥ 2) and complete Uniform Data Set (UDS) evaluations between 2005 and 2019, and most recent UDS evaluation within two years of autopsy. CBVD was defined as moderate to severe arteriosclerosis or atherosclerosis. We employed propensity score weighting to isolate the effects of co-morbid AD and CBVD. This method improved the balance of covariates between AD+/CBVD+ and AD+/CBVD- groups. Longitudinal mixed-effects models were assessed with robust Bayesian estimation. UDS neuropsychological tests and the Clinical Dementia Rating Scale Sum of Boxes (CDR®-SB) 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 x 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 co-morbid CBVD neuropathology in AD.

Trajectory of clinical symptoms in relation to amyloid chronicity

“…These results provide preliminary evidence that in the context of accumulating amyloid, greater WMH volume, suggestive of vascular copathology, was associated with faster decline. This finding has support from the neuropathology literature 22 . Furthermore, in agreement with recent studies, we found that passing the threshold of amyloid positivity at an older age was associated with a shorter period before the emergence of cognitive symtpoms 7,10 .…”

“…This finding has support from the neuropathology literature. 22 Furthermore, in agreement with recent studies, we found that passing the threshold of amyloid positivity at an older age was associated with a shorter period before the emergence of cognitive symtpoms. 7,10 PET tau sample sizes for susceptibility groups were insufficient to detect differences in tau positivity between groups.…”

The Case for a Novel Therapeutic Approach to Dementia: Small Molecule Hepatocyte Growth Factor (HGF/MET) Positive Modulators

“…In addition, a pattern of biomarkers consistent with AD may be found in other brain diseases in which AD pathology presents as a comorbidity. Recently, the incidence of co-morbidity of AD and cerebrovascular disease and its relevance for cognitive outcome was examined in those with autopsy-confirmed AD [ 59 ]. Increased functional and cognitive decline was found in those with AD and co-morbid cerebrovascular disease, and the presence of cerebrovascular disease enhanced the effects on AD neuropathology.…”

A Perspective: Challenges in Dementia Research

“…The same techniques used to study and quantify normal aging can be applied to patients who have diagnoses of different types of dementia: Use the existing data to refine the definitions of the various dementia types [ 103 , 104 , 105 , 106 , 107 , 108 ]. Follow-up longitudinal data over time to find the first difference noted between normal brain aging and pathological aging in patients eventually diagnosed with dementia [ 109 , 110 , 111 , 112 ]. This will form a more effective focus for disease modifying treatment than changes that occur late in the illness.…”

“…Follow-up longitudinal data over time to find the first difference noted between normal brain aging and pathological aging in patients eventually diagnosed with dementia [ 109 , 110 , 111 , 112 ]. This will form a more effective focus for disease modifying treatment than changes that occur late in the illness.…”