journal articles
AUTOPSY FINDINGS IN ALZHEIMER\'S DISEASE CLINICAL TRIAL PARTICIPANTS DEMONSTRATE A HIGH FREQUENCY OF OFF-TARGET COEXISTING PATHOLOGIC FEATURES
E. Pinar Coskun, Justin Barber, Lauren Bojarski, Christopher J. McLouth, Erin L. Abner, Linda J. Van Eldik, Peter T. Nelson, Gregory A. Jicha
BACKGROUND: Having multiple comorbid neuropathologic features may confound the results of interventional trials that were designed to target a specific pathophysiologic mechanism in Alzheimer’s disease (AD) and or related dementias (ADRD). However, it is unknown what percentage of individuals undergoing AD/ADRD interventional studies have mixed pathologies.
OBJECTIVE: To characterize the spectrum of coexisting neuropathologies in brains of AD/ADRD clinical trial participants to inform trial design and therapeutic strategies
METHODS: Autopsied participants from the University of Kentucky Alzheimer Disease Research Center (UK-ADRC) community-based cohort who died between January 2005, and February 2024 were included and queried retrospectively for participation in therapeutic interventional trials. Of a total of 614 autopsied cases, 67had been enrolled in one of the following types of clinical trials: cognitively normal participants in prevention trials for AD/ADRD (designated group P; n = 21); interventions for mild cognitive impairment or early dementia (MCI/D; n = 26); and, interventions for vascular cognitive impairment (V; n = 20). The trial-engaged groups were compared to the trial-naïve group in terms of their demographic, clinical, and genetic characteristics. Pathological features (amyloid-β, tau, α-synuclein, TDP-43, and cerebrovascular disease) were assessed using consensus-based neuropathologic methods.
RESULTS: All interventions were designed to target only a single pathologic feature. The trial-engaged group did not differ significantly from those who were trial-naïve with respect to demographic, genetic (APOE), or clinical characteristics, except for a marginally higher level of education among trial participants (p = 0.04). Pure on-target pathology (i.e., only one isolated pathology was found at autopsy that was the signature pathology targeted by the intervention) was only seen in 10, 23, and 29 % of the engaged participants of V, MCI/D and P trials respectively. Comorbid pathologies were common in all three groups. On average, the trial-engaged groups altogether had a mean of 2.54 pathologic features/person, whereas the MCI/D trial-engaged group had a mean of 3.2 pathologic features/person.
CONCLUSION: Multi-etiology dementia was the norm rather than the exception for AD/ADRD trial participants. Recognizing the heterogeneity of multiple pathologies in clinical trial participants may enable the development of improved inclusion/exclusion criteria, as well as the rational use of antemortem biomarkers to stratify the likelihood of mixed comorbid pathologies that may be undesirable for single-target interventional studies. Further, multitargeted treatment strategies may be required in future trials of disease-modifying agents.
CITATION:
E. Pinar Coskun ; Justin Barber ; Lauren Bojarski ; Christopher J. McLouth ; Erin L. Abner ; Linda J. Van Eldik ; Peter T. Nelson ; Gregory A. Jicha: Autopsy findings in Alzheimer's disease clinical trial participants demonstrate a high frequency of off-target coexisting pathologic features. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1016/j.tjpad.2026.100669