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Abstract Background Plasma p ‐tau217 represents a promising alternative to PET‐ and CSF‐based biomarkers of AD in well‐characterized research cohorts. However, the performance of this accessible biomarker in outpatient clinics comprised of patients with multiple causes of cognitive impairment has yet to be established. Method Plasma Aβ42/40 and p ‐tau217 concentrations were measured using Fujirebio Lumipulse assays in patients evaluated within a subspecialty memory clinic at Mayo Clinic in Florida. Syndromic and etiologic diagnoses were established by consensus, integrating clinical data and findings from MRI ( n = 484), FDG‐PET ( n = 117), and CSF AD biomarkers ( n = 440). Plasma biomarker performance was evaluated using established diagnostic cutpoints to identify patients with “positive/elevated”, “intermediate”, or “negligible” levels of cerebral amyloid pathology on amyloid‐PET. Result Plasma AD biomarkers were measured in 509 patients (mean 68.6±9.3 years; 47% female; 91.3% non‐Hispanic White), including patients with typical amnestic AD ( n = 237, 46.6%), non‐amnestic presentations of AD ( n = 48, 9.4%), and non‐AD causes of cognitive concerns ( n = 224, 44.0%). “Intermediate” plasma p ‐tau217 and p ‐tau217/Aβ42 concentrations were reported in <15% of patients (43% of patients with Aβ42/40), implying the need for further testing to inform the likelihood of AD neuropathologic change in these patients. After excluding these patients, plasma p ‐tau217 reliably distinguished patients with symptomatic AD with 95% sensitivity and 82% specificity. Integration of Aβ42 measures (ptau217/Aβ42) incrementally improved specificity (86%). Diagnostic performance was unaffected by age (> vs < 65‐years). Plasma p ‐tau217 (AUC: 0.94; 95%CI: 0.91‐0.96) and p ‐tau217/Aβ42 performance (AUC: 0.96; 95%CI: 0.94‐0.98) were closely aligned with results of established CSF AD biomarkers ( p ‐tau181/Aβ42), outperforming Aβ42/40 (AUC: 0.78; 95%CI: 0.74‐0.83). Reduced kidney function was associated with elevated plasma p ‐tau217 and p ‐tau217/Aβ42 concentrations in patients without AD (referencing CSF AD biomarkers). Conclusion Concentrations of plasma p ‐tau217, but not Aβ42/40, strongly associated with clinical diagnoses of symptomatic AD and CSF AD biomarker results. Integration of Aβ42 measures yielded marginal improvements in performance, with increased complexity and cost. These findings support the use of plasma p ‐tau217 in heterogeneous clinical cohorts, including patients with multiple causes of cognitive impairment. Caution is advised when interpreting p ‐tau217 concentrations in patients with decreased kidney function, due to potential elevations in plasma biomarker concentrations.

Abstract Background Black and Latino Americans experience a disparate dementia burden yet remain underrepresented in dementia research, including clinical trials designed to slow or prevent symptomatic Alzheimer's disease (AD). Accessible and non‐invasive AD blood biomarkers may improve identification and recruitment of underrepresented participants into AD clinical trials. There is a clear need to assess the performance of emergent plasma AD biomarkers for the detection of AD neuropathology in cognitively normal Black and Latino Americans. Method Cognitively normal Black and Latino participants underwent cognitive evaluations and PET (amyloid‐PiB, tau‐flortaucipir) imaging at Mayo Clinic in Florida. Plasma p ‐tau217 was measured using Fujirebio Lumipulse assays. We evaluated the diagnostic performance of a p ‐tau217 threshold (≥0.186 pg/mL) known to identify non‐Hispanic White participants with cognitive impairment and “positive” amyloid PET scans (>25 Centiloids). Next, we derived an optimized threshold to identify participants with “positive” amyloid PET using Youden's method. Result The cohort included 58 Black (55%) and 47 Latino‐White (45%) well‐educated (mean 16.1±2.3 years) individuals, with mean age 64.7±8.8 years, and slight female bias (63%). Plasma p ‐tau217 concentrations increased with age (rho=0.269, p = 0.004) and declined with MoCA scores (rho=‐0.225, p = 0.027). Sixty‐nine participants completed amyloid‐ and tau‐PET imaging. Plasma p ‐tau217 concentrations increased with amyloid‐ (rho=0.254, p = 0.044) but not with tau‐PET standardized uptake value ratio (rho=0.127; p = 0.334). p ‐tau217 concentrations were ≥0.186 pg/mL in 10/69 participants (14%), including 3/3 amyloid‐ and tau‐PET positive (A+T+) participants, 3/8 A+T‐ participants (sensitivity: 55%), and 4/58 A‐T‐ participants (specificity 93%). An optimized p ‐tau217 threshold of ≥0.118 pg/mL identified 10/11 A+T± participants (sensitivity 91%), and 16/58 A‐T‐ participants (specificity 73%). In A‐T‐ participants, estimated glomerular filtration rate was lower in participants with ‘false positive’ elevations in plasma p ‐tau217 (mean difference: 67 vs 81 ml/min/1.73m 2 , p = 0.004), emphasizing the need for caution when interpreting plasma p ‐tau217 concentrations in patients with decreased kidney function. Conclusion Plasma p ‐tau217 thresholds validated in participants with symptomatic AD (≥0.186 pg/mL) failed to identify early AD neuropathology in 5/8 cognitively normal Black and Latino participants. Optimized thresholds are required to improve detection of preclinical AD in Black/Latino individuals.

Abstract Colorectal cancer incidence and mortality have declined over time, due in part to high-quality screening and surveillance colonoscopy. Nevertheless, postcolonoscopy colorectal cancer (PCCRC) occurs in up to 7% of cases and is inversely related to examination quality. Artificial intelligence-assisted colonoscopy aims to improve performance metrics and, ultimately, patient outcomes. Multiple randomized trials show that computer-aided polyp detection (CADe) increases adenoma detection, predominantly for diminutive lesions (≤5 mm). Computer-aided polyp characterization (CADx) enables real-time optical diagnosis, potentially shifting management of diminutive polyps by supporting resect-and-discard and diagnose-and-leave in situ strategies. Computer-aided quality assessment (CAQ) systems monitor key metrics—including cecal intubation rate, withdrawal time, speed, and mucosal exposure. Whether CADe alone leads to a reduction in PCCRC or cancer-related mortality remains to be determined; in the near term, a combined approach using CADe, CADx, and CAQ is most likely to deliver the greatest improvements in patient outcomes.

Abstract Background Plasma phosphorylated‐tau217 (pTau217) is a blood‐based biomarker of Alzheimer's Disease (AD) pathology. Cognitive resilience describes the presence of neurodegenerative pathology and preserved cognition. Cognitive resistance describes avoidance of neurodegeneration. This post hoc analysis of the Post‐Operative Delirium Belfast (PODB) cohort aimed to define cognitive resilience using plasma pTau217 and Mini Mental State Examination (MMSE) measures. Methods PODB was an observational cohort study, investigating people aged 65 and over, without a diagnosis of dementia, undergoing elective hip and knee replacement between 2012‐2014 with subsequent long‐term follow‐up. In this analysis, pre‐operative plasma pTau217 was used as a marker of neuropathology. A cutoff of 0.42 pg/mL was used (Ashton NJ et al. 2024). Pre‐operative and 8‐year follow‐up MMSE scores were used as a marker of cognition. A score of ≥24 was considered preserved. Definitions used were: Cognitive resilience = pTau217 ≥0.42 pg/mL plus MMSE ≥24. Cognitive resistance = pTau217 <0.42pg/mL plus MMSE ≥24. Affected = pTau217 ≥0.42 pg/mL plus MMSE <24. Those with normal markers plus poor cognition were defined as pTau217 <0.42pg/mL plus MMSE <24. These four groups were identified at baseline and follow‐up, respectively. In this analysis, 231 participants were included at baseline, 104 at follow‐up. Results Of the n = 231 participants included at baseline, n = 147/231 (64%) were cognitively resilient, n = 65/231 (28%) resistant, n = 17/231 (7%) affected, and n = 2/231 (<1%) had normal markers and MMSE <24. Of the n = 104 participants with follow‐up information included in this analysis, n = 61/104 (59%) were cognitively resilient, n = 33/104 (32%) were resistant, n = 8/104 (8%) affected, and n = 2/104 (<1%) had normal markers and MMSE <24. Cognitively resilient participants at baseline were younger ( p = 0.011) and tended to be female ( p = 0.977) compared to affected participants. At follow‐up, those who were cognitively resilient tended to be younger ( p = 0.196) and female ( p = 0.212) compared to affected participants (Table 1). Of those cognitively resilient at follow up, n = 59/61 (97%) of these participants were also cognitively resilient at baseline. Conclusions Using pTAu217, at the cut‐off quoted, we found a high incidence of cognitive resilience in an older elective surgical cohort.

Cigarette smoking is associated with numerous adverse pregnancy outcomes, due in part to polycyclic aromatic hydrocarbons and free radicals produced by combustion. Less is known about the impact of smokeless tobacco (ST) use during pregnancy. Alaska Native women report higher rates of cigarette and ST use during pregnancy than non-Native women. We investigated oxidative stress and hypoxia pathways in term placentae from Alaska Native women who did (commercial or iqmik; n = 10) or did not ( n = 18) use ST during pregnancy. Despite substantial maternal exposure to nicotine, placentae of women who used ST had similar mRNA levels of antioxidant enzymes and markers of hypoxia compared to those who did not use tobacco. Although mRNA levels of angiogenesis markers vegf and vegfr2 were similar between groups, vegfr1 mRNA levels are increased in placentae of women using ST compared to women who did not use tobacco. Together these results suggest that, while ST use may not have as significant an effect on oxidative stress pathways in the placenta as cigarette smoking, an effect is present. It is not clear what this limited effect may have on the developing fetus.

Abstract TP53 and PPM1D are key regulators of DNA damage response and repair, and somatic mutations in these genes often co-occur in hematopoietic cells, expanding under genotoxic stress. Unlike TP53 mutations, where mechanisms of progression are defined, pathways underlying clonal fitness and transformation in PPM1D mutant cells remain unclear. In collaboration with 5 academic institutions, we analyzed the clinical and molecular landscape of 337 patients with clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance (CCUS) across 4 genotypes: PPM1Dmt/TP53wt (n = 170 [50%]), PPM1Dmt/TP53mt (n = 25 [7%]), TP53mt/PPM1Dwt (n = 17 [5%]), and TP53wt/PPM1Dwt (n = 125 [38%]). All PPM1D variants were truncating, located in exon 6 of the gene, with a median variant allele frequency (VAF) of 6% (range, 0.3%-64%). The PPM1Dmt/TP53mt genotype was most frequently encountered in therapy-related CH/CCUS (t-CH/t-CCUS; 80%, 66.5%, 76.5%, and 19%; P ≤ .001) and had a shorter time interval to detection from last genotoxic exposure (6.2, 5.9, 11.25, and 24.5 months; P ≤ .001) compared with PPM1Dmt/TP53wt, TP53mt/PPM1Dwt, and TP53wt/PPM1Dwt genotypes, respectively. Acknowledging the short follow-up duration, rates of malignant transformation were lower in the PPM1Dmt/TP53wt (2%) and PPM1Dmt/TP53mt (4%) groups compared with PPM1Dwt/TP53wt (12%) and PPM1Dwt/TP53mt (17%) groups (P ≤ .001), respectively. In summary, PPM1D mutations are frequently observed in t-CH/t-CCUS, with low median VAFs, and are associated with low rates of progression, even when comutated with TP53.

Abstract Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 and CXCR4 mutations, whose prognostic value in patients treated with chemoimmunotherapy remains unclear. Moreover, the typically prolonged progression-free survival (PFS) correlates inconsistently with overall survival (OS), underscoring the importance of examining other surrogates. Progression of disease within 24 months (POD24), an established early end point, delineates functionally high-risk patients in other indolent lymphomas. This international study evaluated 253 patients receiving frontline fixed-duration bendamustine-rituximab (BR), a common chemoimmunotherapy for WM. At a median follow-up of 5.9 years, 5-year PFS and OS were 65% and 87%, respectively; 5-year PFS was similar between MYD88L265P (90%) and MYD88wild-type (WT) subcohorts (64% each; P = .4). Among 89 patients with known CXCR4 status, the subcohort with CXCR4mutation (28%) had shorter PFS (median 3.3 vs 8.8 years; hazard ratio [HR], 2.8; P = .0036) and OS (HR, 2.6; P = .036) compared with CXCR4WT. POD24 occurred in 11.5% of patients who demonstrated inferior subsequent OS (5-year OS, 71% vs 86%; HR, 3.1; P = .005) and higher mortality (standardized mortality ratio [SMR], 3.7), unlike the non-POD24 group, whose mortality was comparable to the matched general population (SMR, 1.1). In conclusion, BR is effective irrespective of the MYD88 status, but CXCR4 mutations and POD24 portend worse outcomes. Patients without POD24 represent a cohort with distinctly favorable outcome.

Abstract Background The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution. In typical (memory‐predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, atypical (non‐amnestic‐predominant) AD variants with heterogeneous tau patterns provide a key opportunity to assess the universality of connectivity as a scaffold for tau progression. Method We included tau‐PET data from 320 subjects with atypical AD, characterized by highly heterogeneous tau patterns ( n = 139 posterior cortical atrophy/PCA‐AD; n = 103 logopenic variant primary progressive aphasia/lvPPA‐AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS‐AD) from 14 sites, with a subset of patients ( n = 78) having longitudinal tau‐PET data. As an independent sample, we further included regional post‐mortem tau stainings from 93 atypical AD patients from two sites ( n = 19 PCA‐AD, n = 32 lvPPA‐AD, n = 23 bvAD, n = 19 CBS‐AD). Gaussian mixture modeling was used to harmonize different tau‐PET tracers by transforming tau‐PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether 1) brain regions with stronger functional connectivity showed greater covariance in cross‐sectional and longitudinal tau‐PET and post‐mortem tau pathology, and 2) functional connectivity of tau‐PET epicenters and tau‐PET accumulation epicenters was associated with cross‐sectional and longitudinal tau patterns. Result Tau‐PET epicenters—defined as the 5% brain regions with the highest tau load—aligned with clinical variants, e.g. a posterior pattern in PCA‐AD (“visual AD”) and left‐hemispheric temporal predominance in lvPPA‐AD (“language AD”) (Figure 1). More strongly functionally connected regions showed correlated concurrent tau‐PET levels, which was confirmed with post‐mortem data (Figure 2). Moreover, the connectivity profile of tau‐PET epicenters and accumulation epicenters corresponded to tau‐PET progression patterns (Figure 3). Conclusion Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a key driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant‐specific endpoints in clinical trials.