John C. Morris

Simpson’s Paradox, Amyloid Paradox, and Racial Differences

Importance The underlying mechanisms for the paradox of higher prevalence of dementia but lower prevalence of amyloid positivity in self-identified Black US residents than White US residents remain unknown and are important for designing and analyzing prevention and treatment trials of Alzheimer disease. Objective To assess whether the age of mean amyloid onset (AMAO) explains the paradox of the reported racial differences in dementia and amyloid positivity. Design, Setting, and Participants This was a retrospective, multicenter, longitudinal cohort study with harmonized amyloid positron emission tomography (PET) and clinical data from self-identified Black and White individuals who were middle-aged or older across 5 academic institutes in the US conducting studies of memory and aging. The study was conducted from June 2020 to March 2026. Exposures Self-identified race, vascular comorbidities, sex, age, educational attainment, and apolipoprotein E ε4 carrier status. Main Outcomes and Measures Amyloid PET centiloid and cognition measured as a global cognitive composite constructed by averaging z scores across at least 6 cognitive tests in self-identified Black and White participants. Both cross-sectional and longitudinal analyses were conducted to compare racial groups in amyloid burden and cognition. Data were also analyzed using propensity score–matching of 2:1 (White:Black) by main covariates. Results Of 2653 participants (mean [SD] age, 69.0 [8.8] years; 1574 [59.3%] female), 406 (15.3%) were Black and 2247 (84.7%) were White. Black participants had a delayed AMAO compared with White participants in the unmatched (83.86 [95% CI, 76.55-91.35] years vs 71.38 [95% CI, 67.74-73.17] years; difference, 12.48 [95% CI, 5.03-22.28 years) and covariate-matched (85.17 [95% CI, 80.16-91.38] years vs 72.61 [95% CI, 70.79-74.55] years; difference, 12.57 [95% CI, 7.25-19.54] years) analyses. Although Black participants had a lower overall prevalence of amyloid positivity than White participants (24.1% vs 31.7%, P = .002), they had a higher prevalence of amyloid positivity than White participants in almost every interval of expected years to amyloid onset (EYAO, defined as participants’ simple chronological age minus the group-specific AMAO), hence Simpson’s paradox, (eg, −15 to −10 years for Black minus White prevalence in the unmatched cohort, 15.30 percentage points [95% Wilson CI, 0.06-0.26]). No significant racial differences were found in the longitudinal rate of amyloid accumulation after adjusting for the covariates either before the AMAO (eg, unmatched cohort Black minus White difference in slope per year, −0.28 [95% CI, −0.64 to 0.08]; P = .13) or after the AMAO (eg, unmatched cohort Black minus White difference in slope, −1.23 [95% CI, −3.05 to 0.60]; P = .17). Black participants had a higher prevalence of vascular comorbidities than White participants (56.9% vs 39.3%; P < .001), and Black but not White participants showed significant cognitive decline before the AMAO (Black minus White difference in slope per year, −0.016 (95% CI, −0.028 to −0.004)]; P = .009). Conclusions and Relevance This cohort study found that Black participants had delayed AMAO compared with White participants, partially explaining the paradox of the reported racial differences in prevalence of amyloid positivity and dementia. This finding suggests that EYAO may be an important confounder to analyze racial differences and may serve as a better (than age) inclusion or exclusion criterion to improve the representation of Black US residents in clinical trials of Alzheimer disease.

Exploring healthy aging through preclinical Alzheimer disease in the Knight Alzheimer Research Imaging dataset

Alzheimer disease (AD) remains a significant global public health challenge, requiring robust multimodal datasets to elucidate its prolonged preclinical phase, improve early detection, advance understanding of disease trajectories, and guide intervention strategies. Here we present the Knight Alzheimer Research Imaging (KARI) dataset, established by the Washington University Knight ADRC to address this critical need. We detail comprehensive multimodal neuroimaging from 1,645 participants (aged 42-97) across 6,217 acquisitions. Spanning the AD spectrum from healthy aging to symptomatic disease, the cohort undergoes extensive longitudinal imaging using structural and functional magnetic resonance imaging (MRI) alongside positron emission tomography (PET) tracers for amyloid and tau pathology. This is complemented by rich clinical, cognitive, genetic, and biomarker data. In addition to raw imaging, the dataset provides quality-controlled processed outputs, including anatomical segmentations and biomarker quantification. By making this data accessible to researchers, the Knight ADRC aims to accelerate discoveries in pathophysiology, biomarker identification, and therapeutic development. The KARI dataset maps healthy aging through preclinical Alzheimer disease across >6,000 scans from 1,645 adults. Demonstrating its utility, imaging biomarkers scale with clinical severity, providing a resource to accelerate future Alzheimer research.

Mild Amyloid Burden in the Brains of Cognitively Unimpaired Individuals is Associated with Long‐Term Cognitive Impairment

Objective We aimed to identify the minimal amount of amyloid burden measured by positron emission tomography (PET) in amyloid‐negative cognitively unimpaired individuals that predicts the development of cognitive impairment. Methods A total of 1,896 cognitively unimpaired participants underwent longitudinal clinical/cognitive assessments for up to 20.3 years after amyloid PET imaging. Cox proportional hazards models were used to assess how the risk of cognitive impairment was associated with subthresholds of amyloid PET Centiloid. Linear mixed effects models were used to associate the longitudinal cognitive decline and amyloid accumulation with baseline amyloid burden. Results Amyloid‐positive participants (Centiloid >20; n = 421) were 154% (hazard ratio 2.54, p < 0.0001) more likely to develop cognitive impairment than amyloid‐negative participants. Approximately 48.7% of the amyloid‐negative participants had mild amyloid burden (defined by Centiloid from 0.93 to 20) and were 43% more likely to develop cognitive impairment (hazard ratio 1.43, p = 0.008) than the lowest amyloid group (Centiloid <0.93) approximately 10 years post baseline. Longitudinal changes in amyloid PET Centiloid and cognition followed a similar pattern: amyloid‐positive participants were the fastest, followed by the mild amyloid burden group and finally the lowest amyloid group, and the cognitive trajectories for the latter 2 started to separate only approximately 10 years post baseline ( p = 0.003). Interpretation Almost half of amyloid‐negative cognitively unimpaired individuals were at an elevated long‐term risk of cognitive impairment, when compared with those with the lowest amyloid levels. These findings suggest that the current threshold for amyloid positivity may be overly restrictive, potentially excluding a large portion of high‐risk participants from prevention trials.

Gantenerumab reduces brain amyloid-β proteoforms: Biochemical evaluation in dominantly inherited Alzheimer disease

Therapeutic strategies targeting amyloid-β (Aβ) in Alzheimer disease (AD) include antibodies directed against fibrillar amyloid plaques or soluble amyloid-β (Aβ) species, yet how these approaches reshape brain pathology remains poorly understood. Postmortem neuropathological assessment is crucial for evaluating the degree of Aβ removal, providing information and context that fluid biomarkers and positron emission tomography (PET) alone cannot, and guiding development of more effective disease modifying therapies for AD. In this study, using high resolution mass spectrometry we quantitatively measured Aβ and tau proteoforms in postmortem brain tissue homogenates to evaluate the impact of long-term treatment with anti-Aβ monoclonal antibodies gantenerumab or solanezumab in a clinical trial of dominantly inherited Alzheimer disease (DIAD). Symptomatic DIAD participants who had been treated for ∼ 4 years with anti-Aβ monoclonal antibodies (gantenerumab, n=4 or solanezumab, n=4) were compared with untreated, symptomatic DIAD mutation carriers (n=40) and with age-relevant non-DIAD controls with modest or no plaque pathology (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab-treated participant samples showed significantly lower levels of specific Aβ proteoforms (Aβ 42 , Aβ 40 ) in the insoluble plaque associated pool (range: 60-80 % reduction); they also showed lower levels of post-translationally modified Aβ proteoform Aβ 3pGlu in both the insoluble and soluble pool, compared to untreated DIAD participants, but without reaching the levels found in non-DIAD controls. Samples from gantenerumab-treated participants also showed regionally lower amounts of insoluble phosphorylated tau species (pT181, pT205, pT208) and MTBR tau species (354-369, 306-317, 299-317) without apparent differences in insoluble total tau levels. In contrast, brain tissue samples from solanezumab-treated participants did not show significant differences overall in soluble or insoluble levels of Aβ and tau proteoforms in comparison to those from non-treated DIAD individuals. These findings support that amyloid targeting treatment (ATT) with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate “downstream” biochemical and pathophysiological changes associated with AD. Key Summary Question How do amyloid targeting treatments (ATT) affect the Alzheimer disease (AD)-related brain pathologies of soluble and aggregated amyloid-β and tau proteoforms in postmortem tissue? Background Extracellular amyloid plaques and neurofibrillary tangles (NFTs) are the primary pathological hallmarks of AD. For the past three decades, active and passive immunization against cerebral amyloid-β (Aβ) has constituted one of the primary avenues of disease-modifying intervention in AD. Recently, passive immunizations using anti-Aβ targeting antibodies have demonstrated slowing of cognitive decline in sporadic AD and possibly in dominantly inherited AD (DIAD). In these clinical trials, target engagement has been inferred from Aβ-positron emission tomography (PET) and/or biofluid biomarkers during life. However, to confirm evidence of target engagement more directly, identify which pathological proteoforms are affected, quantify the dose dependent treatment effects of these treatments, and begin to evaluate their putative downstream effects on AD pathophysiology, quantitative biochemical comparisons of amyloid plaques and tau pathology (soluble and insoluble Aβ and tau species) in postmortem brain tissue of treated and untreated AD are needed. Findings In this study, using high resolution mass spectrometry we measured the soluble and insoluble Aβ and tau proteoforms in the postmortem brain tissue homogenates from DIAN-TU-001 trial participants who were symptomatic and had been treated for ∼ 4 years with gantenerumab (n=4) or solanezumab (n=4), two antibodies that bind to insoluble and soluble Aβ, respectively. Intervals between treatment discontinuation and death ranged from 5 months to 3 years. Comparisons were made with postmortem brain tissue samples from untreated, symptomatic DIAD participants of the DIAN-Obs study (n=40) and from age-relevant, cognitively normal, non-DIAD controls with or without only modest burdens of diffuse Aβ plaques (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab significantly decreased specific Aβ (Aβ 42 , Aβ 40 ) proteoforms in the insoluble plaque associated pool (range: 60-80% reduction) compared to the untreated DIAD participants, but without reaching the levels found in the non-DIAD controls. Samples from gantenerumab treated participants also showed significantly lower amount of post-translationally modified Aβ (Aβ 3pGlu ) and regionally lower insoluble phosphorylated tau species (pT181, pT205 and pT208), without apparent differences in insoluble total tau levels. In contrast, solanezumab treatment did not show significant effect on the soluble or insoluble levels of Aβ and tau proteoforms in comparison to samples from non-treated DIAD individuals. Significance These findings support that ATT with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate “downstream” biochemical and pathophysiological changes associated with AD.

CSF proteomics and machine learning reveal distinct stages across the Alzheimer’s disease continuum

Cohort study reveals stage-specific cerebrospinal fluid proteomic signatures across the Alzheimer disease continuum, highlighting molecular pathways for targeted interventions.

Sample size determination for a prospective bridging study to harmonize retrospective data from multiple studies—Application to a biofluid biomarker study of Alzheimer’s disease

Methodological study proposes sample size calculations for prospective bridging studies in Alzheimer's disease, demonstrating that testing small sample subsets enables multi-study harmonization.

Network connectivity and amyloid-β align with tau in atypical Alzheimer disease subtypes

Observational study reveals that regional amyloid-β and functional connectivity align with subtype-specific tau spreading, suggesting pre-existing brain network vulnerabilities.

Full-compartmental modeling of [18F]FDG PET suggests divergent brain metabolism trajectories from healthy aging to early Alzheimer disease

Kinetic imaging study reveals paradoxical glucose hyperphosphorylation in preclinical Alzheimer disease, indicating stage-dependent metabolic shifts across disease progression.

Exploring the relationship between methylation of the cortisol receptor genes and brain and cognitive outcomes in individuals with elevated amyloid-β

Explores the link between cortisol gene methylation and cognitive decline in individuals with amyloid-β, suggesting implications for disease progression.

Regional juxtacortical microstructural changes and gene expression provide insights into neurodegeneration in Alzheimer’s disease

Demonstrates insights into cognitive decline in Alzheimer's disease, highlighting potential therapeutic targets.

Blood-based circular RNAs for early diagnosis of Alzheimer’s disease

Analysis of second-generation epigenetic clocks reveals further associations between disproportionate biological ageing and hippocampal volume

A computational model to describe multi-regional brain architecture during neurodegeneration in Alzheimer’s disease

Examines brain changes in Alzheimer’s disease using MRI and machine learning, suggesting improved early detection methods.

Is trait mindfulness associated with pain interference in patients undergoing total knee arthroplasty? A prospective cohort study

A prospective cohort study finds trait mindfulness affects pain and function during recovery after TKA, suggesting further exploration is needed.

What is the psychological and cognitive impact of returning Alzheimer disease dementia research results to healthy research participants? a delayed-start randomised clinical trial protocol for the WeSHARE study (Washington University study of having Alzheimer disease r esearch results explained)

INTRODUCTION: Returning research results that indicate risk of Alzheimer disease (AD) dementia-a disease for which no meaningful treatments or cure exist-to cognitively normal participants is controversial. AD is thought to begin many years before clinical signs and symptoms begin. During this time, individuals are cognitively normal but have biomarkers that indicate pathophysiological changes in the brain. With this study, we aim to evaluate the impact of returning research results on cognitively normal participants recruited from a longitudinal observational cohort on ageing at the Knight Alzheimer Disease Research Centre (Knight ADRC) at Washington University in St. Louis. METHODS AND ANALYSIS: Our study uses a 2-year, delayed-start randomised clinical trial design. Participants are randomised to receive their research results either 2 weeks or 1 year after informed consent. This study was approved to recruit up to 450 participants with existing genetic and biomarker testing results from the Knight ADRC. During the study period, 260 individuals were eligible and approached for entry into the study. The primary cognitive outcomes are 1-year change in subjective cognitive score on the clinical dementia rating sum of box scores and the objective cognitive score on cognitive composite score. The primary psychosocial outcome is change in geriatric depression scale score 1 year after return of research results. The study was powered to answer primary outcomes with 140 participants (70 per study arm). ETHICS AND DISSEMINATION: This study has been approved by the Washington University School of Medicine (WUSM) Institutional Review Board and the Human Research Protection Office. Results from these trials are shared through conferences and publications. TRIAL REGISTRATION NUMBER: NCT04699786.

Standardizing “Rapid”

BACKGROUND AND OBJECTIVES: Rapidly progressive dementia (RPD) accounts for 3%-4% of dementia cases yet presents a disproportionate clinical challenge given the wide differential diagnosis and the need to quickly identify potentially treatment-responsive causes. The lack of a standardized definition of RPD challenges generalization of published findings and precludes multisite studies. We sought to determine whether a standardized definition, based on the Clinical Dementia Rating (CDR), could reliably distinguish individuals with a broad spectrum of causes of RPD early in the symptomatic course. METHODS: tests (binary), respectively. Our definition of RPD was compared against definitions identified through a scoping review conducted using a validated 6-stage approach. Our scoping review identified 22 studies that applied 10 distinct definitions of RPD. Uniquely, our CDR-based definition clearly distinguished individuals with a broad spectrum of causes of RPD, assessed across multiple sites/settings, supporting early diagnosis with minimal resource requirements. DISCUSSION: The CDR-based definition of RPD effectively identified individuals with a broad spectrum of causes of RPD early in the symptomatic course. The need for training and time to reliably administer the CDR may limit application of the proposed definition of RPD. Validation in additional cohorts is required to support generalizability.

Recognizing Structural and Social Determinants of Health in the Diagnosis and Care of Dementia

Structural and social determinants of health are environmental conditions that affect individuals’ health and functioning across the life course. These determinants are salient factors at the apex of individual psychology, community variables, and larger sociological factors, exerting prominent effects on individuals’ wellbeing. The National Institute on Aging seeks to understand their influence on aging and Alzheimer’s disease. We propose that the benefits of doing so may reach beyond knowledge of disease mechanisms – it may also improve clinical outcomes. We describe efforts introducing structural and social determinants of health data into the national network of Alzheimer’s disease research centers. We report results of pilot testing 225 structural and social determinants of health items at the University of Pennsylvania’s center among 135 cognitively unimpaired research participants. We summarize item and instrument completion rates, participant feedback, and survey adjustments. We describe the initiative, potential for its impact, pilot testing results, and future directions.

The Knight Alzheimer Research Imaging (KARI) dataset: a comprehensive multimodal resource for exploring aging, preclinical, and symptomatic Alzheimer disease pathology

The KARI dataset reveals extensive multimodal imaging and clinical data across the Alzheimer disease spectrum, indicating its potential to improve early detection and intervention strategies.

TGF-β1-based restoration of sodium iodide symporter expression in radioiodine-refractory differentiated thyroid cancer via engineered MSCs

Abstract The sodium iodide symporter (NIS) mediates iodine uptake into thyroid follicular cells providing the basis for radioiodine imaging and therapy of differentiated thyroid cancer. Loss of functional NIS expression leads to radioiodine-refractory disease. Restoration of radioiodine uptake via NIS delivery into tumors using mesenchymal stem cells (MSCs) represents a therapeutic strategy for radioiodine-refractory differentiated thyroid cancer. This study exploits transforming growth factor-beta (TGF-β) biology in radioiodine-refractory BRAFV600E-mutant papillary thyroid cancer to selectively drive NIS transgene expression in engineered MSCs using a synthetic TGF-β1-inducible SMAD-responsive promoter (SMAD-NIS-MSCs) to reestablish radioiodine accumulation. ¹²⁵I uptake assay confirmed stimulation of functional NIS expression in SMAD-NIS-MSCs through TGF-β1 released from BRAFV600E-mutant papillary thyroid cancer cell lines (BCPAP, K1) from co-culture or by incubation with tumor-conditioned medium. Chemotaxis assays showed directed chemotaxis of MSCs towards BCPAP- and K1-tumor-conditioned medium. SMAD-NIS-MSCs applied intravenously to mice harboring BCPAP or K1 xenografts followed by ¹²³I-scintigraphy demonstrated tumor-specific MSC recruitment and radioiodine accumulation. Application of SMAD-NIS-MSCs followed by ¹³¹I demonstrated a significant delay in tumor growth with prolonged survival. We demonstrate re-establishment of NIS-mediated radioiodine therapy in radioiodine-refractory BRAFV600E-mutant papillary thyroid cancer tumors using MSC-mediated NIS gene delivery driven by their TGF-β1 biology.

Predicting future cognitive impairment in preclinical Alzheimer’s disease using amyloid PET and MRI: a multisite machine learning study

Predicting the likelihood of developing Alzheimer’s disease (AD) dementia in at-risk individuals is important for the design of and optimal recruitment for clinical trials of disease-modifying therapies. Machine learning (ML) has been shown to excel in this task; however, there remains a lack of models developed specifically for the preclinical AD population, who display early signs of abnormal brain amyloidosis but remain cognitively unimpaired. Here, we trained and evaluated ML classifiers to predict whether individuals with preclinical AD will progress to mild cognitive impairment or dementia within multiple fixed time windows, ranging from one to five years. Models were trained on regional imaging features extracted from amyloid positron emission tomography and magnetic resonance imaging pooled across seven independent sites and from two amyloid radiotracers ([ 18 F]-florbetapir and [ 11 C]-Pittsburgh-compound-B). Out-of-sample generalizability was evaluated via a leave-one-site-out and leave-one-tracer-out cross-validation. Classifiers achieved an out-of-sample receiver operating characteristic area-under-the-curve of 0.66 or greater when applied to all except one hold-out sites and 0.72 or greater when applied to each hold-out radiotracer. Additionally, when applying our models in a retroactive cohort enrichment analysis on A4 clinical trial data, we observed increased statistical power of detecting differences in amyloid accumulation between placebo and treatment arms after enrichment by ML stratifications. As emerging investigations of new disease-modifying therapies for AD increasingly focus on asymptomatic, preclinical populations, our findings underscore the potential applicability of ML-based patient stratification for recruiting more homogeneous cohorts and improving statistical power for detecting treatment effects for future clinical trials. Highlights Machine learning can predict future cognitive impairment in preclinical Alzheimer’s Models achieved high out-of-sample ROC-AUC on external sites and PET tracers Models were able to distinguish cognitively stable from decliners in the A4 cohort ML cohort enrichment enhanced secondary treatment effect detection in the A4 cohort