ArticleThe journal of prevention of Alzheimer's disease2026
Autopsy findings in Alzheimer's disease clinical trial participants demonstrate a high frequency of off-target coexisting pathologic features.
Article in The journal of prevention of Alzheimer's disease, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors.
Funding
Abstract
backgroundHaving 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.
objectiveTo characterize the spectrum of coexisting neuropathologies in brains of AD/ADRD clinical trial participants to inform trial design and therapeutic strategies
methodsAutopsied 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.
resultsAll 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.
conclusionMulti-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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.