Abstract Details

Title Comorbid Pathology in Clinical Trial Participants: Autopsy Findings and Clinical Features

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P4 - Poster Session 4 (11:45 AM-12:45 PM)

Poster/Presentation
Number 9-014

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.

Authors/Disclosures
Elif P. Coskun, MD (work) PRESENTER	Dr. Coskun has nothing to disclose.
Justin Barber	No disclosure on file
Erin Abner	No disclosure on file
Richard Kryscio	No disclosure on file
Frederick A. Schmitt, PhD (University of Kentucky)	The institution of Dr. Schmitt has received research support from NIH.
Larry B. Goldstein, MD, FAHA, FAAN (University of Kentucky)	The institution of Dr. Goldstein has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Janssen. The institution of Dr. Goldstein has received research support from NIH. The institution of Dr. Goldstein has received research support from NIH. Dr. Goldstein has received intellectual property interests from a discovery or technology relating to health care. Dr. Goldstein has received publishing royalties from a publication relating to health care.
Linda Van Eldik	No disclosure on file
Peter T. Nelson	Peter T. Nelson has nothing to disclose.
Gregory A. Jicha, MD, PhD (University of Kentucky College of Medicine)	Dr. Jicha has nothing to disclose.

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