Petersen, Ronald C.

Background Alzheimer's disease (AD) and related dementias are leading causes of death worldwide. While socioeconomic status (SES) is a critical determinant, its impact on mortality after diagnosis remains understudied. Objective To investigate the roles of neighborhood-level and individual-level SES in predicting mortality risk among older adults with incident dementia. Methods We analyzed data from 924 participants with incident dementia from the Mayo Clinic Study of Aging (N = 6909), a cohort with clinical follow-up visits every 15 months. We assessed mortality risk using Cox's time-varying survival regression, adjusting for time-fixed and time-varying covariates. Primary predictors were neighborhood-level SES (Area Deprivation Index [ADI]) and individual-level SES (housing-based SES index [HOUSES], education, and occupation). We also applied a random survival forest model to assess the predictive contribution of SES indicators and identify influential predictors. Results 857 participants (92.7%) died, with a median time from dementia diagnosis to death of 29 months (IQR: 12–54). Lower SES measured by HOUSES was associated with increased mortality risk (HR 1.28, 95% CI 1.07–1.52). Conversely, ADI, education, and occupation were not associated with mortality. Male sex, older age, congestive heart failure and diabetes were associated with higher mortality risk. In predictive analysis, HOUSES ranked among the top 10 contributors to mortality risk. Conclusions Among older adults with dementia, lower HOUSES was associated with higher mortality risk beyond neighborhood-level deprivation, education, and occupation. Integrating this housing-based individual-level SES measure into dementia care planning may help identify patients with greater socioeconomic vulnerability and inform mortality risk stratification.

Abstract INTRODUCTION Plasma p‐tau217 and p‐tau217/Aβ42 reliably identify non‐Hispanic White individuals with symptomatic and pre‐clinical AD. However, performance across ethnoracially diverse groups remains unknown. METHODS Cognitively normal Black, Hispanic, and non‐Hispanic White participants completed cognitive evaluations, brain magnetic resonance imaging (MRI), amyloid and tau positron emission tomography (PET), and measures of kidney function. Plasma p‐tau217 and Aβ42 were measured using Fujirebio Lumipulse assays. Pre‐clinical AD detection was evaluated using symptomatic and cohort‐derived optimized cutoffs. RESULTS Among 191 participants (57 Black, 46 Hispanic White, 88 non‐Hispanic White), age‐adjusted plasma p‐tau217 and p‐tau217/Aβ42 performed similarly in detecting amyloid‐positive individuals (≥ 25 Centiloids), regardless of race/ethnicity. Both measures independently correlated with amyloid deposition, whereas estimated glomerular filtration rate (eGFR) correlated solely with p‐tau217. Pre‐clinical AD optimized cutoffs (p‐tau217 ≥ 0.132 pg/ml; p‐tau217/Aβ42 ≥ 0.0059) outperformed cutoffs established in symptomatic individuals (sensitivity: 83% vs. 57%; 77% vs. 63%; negative predictive value [NPV] > 93%). DISCUSSION Plasma biomarkers performed similarly across ethnoracially diverse cohorts. Optimized cutoffs may improve early detection and trial enrollment.

Abstract Introduction Alzheimer’s disease (AD) is characterized by pathologies including amyloid, tau, neurodegeneration reflected in established blood biomarkers and track with clinical changes. However, the association between peripheral cell-specific signatures and AD-related phenotypes remain poorly characterized. Methods We analyzed bulk blood transcriptome data from the Mayo Clinic Study of Aging (MCSA) and Emory University Vascular study. We used BayesPrism, CIBERSORTx, and an in-house pipeline CNNreg to deconvolute these data and obtain peripheral cell proportions. Cell type specific transcripts were estimated with BayesPrism. We compared cell proportions between cases (AD/MCI) and controls. Association analysis was performed between cell type specific transcripts and AD-related phenotypes including diagnosis and cognition. Meta-analysis of transcripts associations and gene ontology analysis were conducted to assess the enriched pathways for significant genes. Results In MCSA, B and CD4+ T cells proportions are significantly lower while that of myeloid cells higher in cases. The Emory cohort had similar trends. We identified transcripts associated with AD-related phenotypes in CD4+ T and CD8+ T cells. In CD4+ T cells, transcripts downregulated in case are enriched in response to stimulus pathway, whereas those upregulated in negative regulation of immune response. Downregulation of CD4+ T genes enriched in extracellular matrix disassembly and epigenetic regulation and upregulation of those in protein localization associate with better cognition. In CD8+T cells, genes pertinent to vascular development were downregulated while those to metabolic processes were upregulated in cases. Downregulation of CD8+T genes involved in lipid transportation and upregulation of those in mitochondria associate with better cognition. Conclusion We identified peripheral cellular transcriptional changes associated with AD/MCI phenotypes and involved in important biological pathways, revealing potential disease mechanisms in AD. Funding Source RF1 AG051504 Topic Categories Neuroimmunology (NEUR)

Abstract In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject‐matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence‐synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment‐specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.

BACKGROUND: White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease but reflect late-stage injury. Diffusion magnetic resonance imaging (MRI) biomarkers have been proposed to capture earlier small vessel disease-related microstructural damage but their temporal progression relative to WMH and risk factors associated with progression remain unexplored. METHODS: We identified 2077 participants from the population-based cohort study of the Mayo Clinic Study of Aging in Olmsted County, Minnesota (aged 50–101 years) collected between 05/2005 and 09/2024 with longitudinal neuroimaging. Using multioutput nonlinear mixed-effects models in those with at least 2 fluid-attenuated inversion recovery-MRI and diffusion MRI scans, we characterized the temporal progression of WMH and 4 diffusion MRI biomarkers: fractional anisotropy of the genu of the corpus callosum, peak width of skeletonized mean diffusivity, free water, and Arteriolosclerosis-score, which were automatically estimated. Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education, APOE ε4 status, cardiometabolic conditions). RESULTS: The study population had a mean age of 78 years, 47% were women, 28% were APOE ε4 allele carriers, and 80% were cognitively unimpaired, with an average follow-up of 5.2 years (SD, 4.3 years) for fluid-attenuated inversion recovery-MRI and 4.3 years (SD, 3.9 years) for diffusion MRI. Arteriolosclerosis-score, fractional anisotropy of the genu of the corpus callosum, free water, and peak width of skeletonized mean diffusivity became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH become abnormal (half-width of CI <1 year), respectively. Global markers (Arteriolosclerosis-score, free water, peak width of skeletonized mean diffusivity, and WMH) were correlated, indicating shared substrates of widespread white matter injury. Fractional anisotropy of the genu of the corpus callosum, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Female participants showed earlier WMH, fractional anisotropy of the genu of the corpus callosum, and Arteriolosclerosis-score abnormalities, whereas male participants exhibited earlier peak width of skeletonized mean diffusivity and free water abnormalities. CONCLUSIONS: Diffusion MRI biomarkers were abnormal at least a decade before WMH become abnormal in the population, revealing a prolonged phase of early small vessel disease and highlighting their potential for small vessel disease prevention.

Objective Magnetic resonance imaging (MRI)‐visible enlarged perivascular spaces (PVS) are markers of cerebral small vessel disease (SVD) and aging, processes implicated in both neurodegenerative and cerebrovascular pathologies. However, longitudinal positron emission tomography (PET) studies examining PVS as a mechanism underlying Alzheimer's disease (AD) pathophysiological progression are lacking. Our overall objective was to investigate the associations of baseline PVS burden with white matter hyperintensity (WMH) volume, amyloid‐PET, and tau‐PET, both cross‐sectionally and longitudinally. Methods We examined 2,229 participants across the aging‐AD spectrum from the Mayo Clinic Study of Aging (MCSA) and the Mayo Alzheimer's Disease Research Center (ADRC) (mean age = 68.59 ± 12.70 and 48.94% women). PVS and WMH were quantified using a novel in‐house algorithm. Amyloid on [ 11 C]Pittsburgh Compound B (PiB)‐PET and tau on AV1451‐PET were measured. Cross‐sectional regional and global associations were examined using canonical correlation analysis (CCA). Longitudinal associations were examined using age‐ and sex‐adjusted linear mixed effect (LME) models with natural splines and subject‐wise 10‐fold cross‐validation. Result Three distinct associations were observed: (1) PVS in the basal ganglia (PVS‐BG) was associated with greater WMH volume both cross‐sectionally and longitudinally; (2) PVS‐BG covaried with higher PiB standardized uptake value ratio (SUVR) cross‐sectionally, with longitudinal trajectory associations limited to amyloid‐negative individuals; (3) PVS in the centrum semiovale (PVS‐CSO) was not associated with amyloid or tau, but was associated with occipital WMH, a pattern characteristic of CAA. Interpretation Findings lend support for PVS‐BG as an early indicator of small vessel dysfunction and WMH pathogenesis. Individuals with higher PVS‐BG burden exhibited higher WMH burden and faster WMH progression, suggesting that PVS‐BG may identify individuals at increased risk of progressive SVD. Evidence linking PVS to downstream AD biomarker progression was weaker. Findings support the relevance of PVS‐CSO to CAA, suggesting that they may reflect changes occurring early in the disease process. ANN NEUROL 2026

Abstract Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick’s disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer’s disease and progressive supranuclear palsy, but its role in Pick’s disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick’s disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick’s disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer’s disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick’s disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.

Abstract Background Alzheimer’s disease (AD) is clinicopathologically heterogeneous. A proportion of patients living with AD present clinically at a younger onset of cognitive symptoms before 65 years old and/or non-amnestic clinical syndromes. Neuropathologically, corticolimbic distribution of neurofibrillary tangle pathology occurs on a continuum with some cases having greater cortical tau pathology relative to limbic regions and others with relatively restricted accumulation in limbic structures. These patterns of corticolimbic tangle distribution are associated with clinical presentation and age at onset. This study sought to examine protein expression differences across the spectrum of clinicopathologic heterogeneity using the NULISA targeted proteomics platform. Methods A series of thirteen neuropathologically diagnosed AD cases from Mayo Clinic prospectively followed research studies were selected to reflect heterogeneity of clinical syndromes and corticolimbic distribution of tangle pathology. Frozen postmortem brain tissue samples were isolated from inferior parietal cortex and homogenized in RIPA buffer for analysis using Alamar Biosciences’ NULISA CNS disease 120 panel. Applying a conservative detection threshold of 75% level of detection for the novel application of NULISA in human brain, we evaluated levels of 69 of 129 protein targets across samples. We examined associations between age at onset cognitive symptoms and corticolimbic distribution of tangles (CLix) separately with individual protein targets using linear regression analysis. Results AD cases with a younger age at onset had higher measured levels of ubiquitin, while older age was associated with higher levels of total tau, CRH, and NPTX2. Investigations of corticolimbic heterogeneity revealed AD cases with lower CLix score (i.e., cortical predominant distribution of tau) had higher measured p-tau181, p-tau231, ubiquitin, and p62. AD cases with higher CLix (i.e., relative cortical sparing) had higher levels of total tau, CRH, NPTX2, MDH1, and HBA1. Brain-derived total tau consistently showed a stronger association in both models. Conclusion This work demonstrates the utility of postmortem proteomics for investigating biomarkers associated with AD clinicopathologic heterogeneity. We observed proteomic differences in synapse integrity, tau post-translational modification, and ubiquitination associated with age at symptomatic onset and corticolimbic distribution of tangle pathology.

Abstract INTRODUCTION Face identification algorithms have increased the risk of study participants being identified through different neuroimaging modalities. De‐facing algorithms can de‐identify neuroimages; however, none are validated in individuals with Down syndrome (DS) – a population at high risk of Alzheimer's disease and the focus of numerous Alzheimer's disease cohort studies. METHODS Overall, 37 adults with DS were parcellated using FreeSurfer before and after de‐facing with mri_reface . A group of neurotypically developed individuals balanced on age, sex, and magnetic resonance imaging scanner manufacturer served as controls. RESULTS De‐facing produced no effect on cortical thickness or volumetrics in adults with DS compared to controls or regional discrimination based on an area under the receiver operating characteristic curve analysis after correcting for multiple comparisons. DISCUSSION FreeSurfer‐derived volumetric and cortical thickness measures changed minimally following de‐facing with mri_reface in adults with DS and are unlikely to influence study outcomes. De‐facing should be considered prior to data sharing in studies of adults with DS.