Comorbid Pathology in Clinical Trial Participants: Autopsy Findings and Clinical Features
Pinar Coskun1, Justin Barber2, Erin L. Abner3, Richard J. Kryscio4, Frederick A. Schmitt5, Larry Goldstein1, Linda J. Van Eldik2, Peter T. Nelson6, Gregory A. Jicha5
1Department of Neurology, College of Medicine, 2Sanders-Brown Center on Aging, 3Department of Epidemiology, Sanders-Brown Center on Aging, 4Department of Statistics, Sanders-Brown Center on Aging, 5Department of Neurology, College of Medicine; Sanders-Brown Center on Aging, 6Department of Neurology, Department of Pathology and Laboratory Medicine, College of Medicine, University of Kentucky
Objective:
The mixed pathology potentially confounds the results of interventional trials that are designed to target a solitary pathophysiologic mechanism in Alzheimer’s disease(AD) and related dementias(ADRD).
Background:
The presence of multiple comorbid pathologic features in late-onset dementia has been well documented across cohort studies that incorporate autopsy evaluation. It seems that such mixed pathology is common in AD and ADRD.
Design/Methods:
The UK ADRC autopsy database was screened for participants who engaged in therapeutic interventional trials for AD, vascular cognitive impairment, and dementia, and/or ADRD prevention trials from 2005 to the present. Ninety-nine cases (out of a total n=614) had engaged in clinical trials for the prevention or treatment of ADRD. Pathologic features studied included b-amyloid, tau, a-synuclein, TDP-43, and cerebrovascular disease using conventional rating scales.
Results:
Autopsy cases for those who previously engaged in clinical trials did not differ significantly from those that were trial-naïve with respect to demographic, genetic (ApoE), or clinical characteristics except for CDR global scores that were lower for past trial participants (p<0.05). Comorbid pathologies were common across study types with a mean of 3 pathologic features/participant, 15% with quadruple misfolded proteinopathy (QMP; Ab+tau+synuclein+ TDP43), and only 7.5% of MCI/AD trial participants demonstrating a “pure” disease state that was targeted by the study intervention.
Conclusions:
In our study, approximately 9 out of 10 ADRD trial participants had comorbid mixed pathologic features. Understanding the heterogeneity of pathologies seen in clinical trial participants may allow improved inclusion/exclusion criteria based on clinical features and the rational use of antemortem biomarkers to stratify the likelihood of mixed comorbid pathology that may be unwanted or maybe the target for future interventional strategies. Such insights may also enable improved power analyses and statistical designs that may be able to adjust for the confounds of such mixed pathologic disease states that are common in ADRD clinical trials.