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Abstract Background Alzheimer Disease (AD) pathology evolves over decades, and understanding this progression is critical to the understanding of the disease and timing therapeutic interventions. Since individuals with Autosomal Dominant AD (ADAD) develop symptoms around the same age as their parent, it is possible to predict symptom onset and stage individuals by their estimated years to symptom onset (EYO). This approach does not generalize to other forms of AD, thus there is a pressing need for the timecourse of ADAD to be defined in broadly relevant terms. The objective of this project is to validate the Sampled Iterative Local Approximation (SILA) algorithm in a cohort with a known disease timecourse. SILA generates an estimate of time from amyloid positivity (A time ) based on longitudinal PET data. Method We evaluated A time in a longitudinal ADAD sample ( N = 316) with PET PiB data in three ways. First, we compared predicted age at amyloid positive (A+) to observed age at A+ for individuals who became A+ during enrollment. Next, using linear regression, we compared estimated age at A+ to estimated age at symptom onset (EYO=0). Finally, we used generalized additive models to compare the amount of variance in concurrent cognitive performance explained both A time and EYO. Result We observed a mean average error of 1.15 years between actual age at A+ ( N = 26) and the SILA‐predicted A time . Across all participants, SILA‐estimated age at A+ explained 39% of the variance in estimated age at symptom onset ( β = 0.918, p < 0.0001). Finally, we observed a nonlinear association between cognition and both A time and EYO. A time explained 19% of the variance in the general cognitive composite while EYO explained 43% of the variance. Conclusion SILA produces a valid estimate of time‐from‐amyloid positivity in ADAD. This work allows for disease stage in ADAD to be compared to staging for broad forms of AD, which was not previously possible using EYO. However, this work also illustrates that there is a high degree of heterogeneity in preclinical disease duration that is not explained by amyloid alone.

Abstract Background Bedside cognitive screening tools intend to reliably and efficiently detect cognitive impairment in research, clinical, and community settings. Black American (BA) and Hispanic/Latino (H/L) adults obtain lower performance on widely used screeners, largely driven by demographics and structural and social determinants of health (SSDoH). This study characterized the performance of the Montreal Cognitive Assessment (MoCA) performance in a cohort of cognitively normal ethnoracially diverse adults while considering cohort‐specific factors that contributed to misclassification of impairment. Method Cognitively normal BA and H/L participants completed a comprehensive neurological assessment, neuropsychological testing, and MRI and amyloid‐ and tau‐PET imaging as part of a longitudinal study of memory and aging at Mayo Clinic in Florida. Demographically adjusted MoCA cutoffs were applied to BA (MoCA ≤ 22) and WH/L (MoCA ≤ 24) subgroups. Hierarchical binary logistic regression assessed whether amyloid burden (Centiloid value) improved prediction of scoring below demographically adjusted MoCA cutoffs beyond demographic/SSDoH factors, including age, education, and Area Deprivation Index (ADI). Result Participants included 105 (47 WH/L, 58 BA/AA) cognitively normal adults (mean age = 64.71 years, SD = 8.91; 62.9% female) with average of 16.07 years of education (SD=2.35) and mild‐to‐moderate neighborhood disadvantage (mean ADI=47.60, SD=23.77). 40% of H/L participants (MoCA (≤ 24) and 17% of BA participants (MoCa ≤22) scored below demographically adjusted MoCA cut‐offs. For the H/L subgroup, the best fitting model included age, education, ADI, and amyloid burden ( R 2 = 0 .43, χ 2 = 10.98, p = 0.03). Age (OR=1.21, 95% CI: 0.986 – 1.487) and amyloid burden (OR = 0.83, 95% CI: 0.67 – 1.03) approached statistical significance as individual predictors ( p = 0.06, p = 0.09). In the BA/AA subgroup, the best fitting model included age, education and ADI only ( R 2 = 0.47, χ 2 = 9.06, p = 0.02), with education approaching significance as an individual predictor (OR=0.46, 95% CI: 0.21 – 1.01, p = 0.05). Conclusion Sociodemographic factors continued to drive low MoCA performance in cognitively normal individuals despite applying demographically adjusted cut‐off scores by subgroup. These factors differentially impacted performance among BA/AA and WH/L participants. Careful consideration of these factors is warranted to mitigate risk of overdiagnosing impairment based on cognitive screening across clinical and research settings.

Abstract Background African Americans (AA) are twice as likely to develop dementia than non‐Hispanic Whites but remain underrepresented in Alzheimer's Disease (AD) research. Recent studies have identified AA specific risk factors for AD. Therefore, targeted biomarkers and/or therapies may be needed to effectively treat AD in AA. In this study, we aimed to determine if genetic variants that show association with AD‐risk, plasma transcript or protein levels in AA, may serve as accurate and accessible AD biomarkers. Method In 189 clinically diagnosed AA AD cases and 183 AA cognitively unimpaired (CU) controls, we performed targeted DNA sequencing of 10 AD‐associated loci. Genetic variants at these loci were tested for association with corresponding plasma transcripts and total tau protein levels previously measured in this cohort using a custom nanoString panel and Simoa assays, respectively. Utilizing phased haplotypes (SHAPEIT4) from target sequencing, we inferred local ancestry (RFMix v2) using five superpopulations from the 1000 Genomes Project as anchors. Subsequently, we tested the association of each ancestry specific allelic dosages with endophenotypes using Tractor. In receiver operating characteristic (ROC) analyses, the most significant e/pQTLs were added sequentially to a base model that included age and sex to identify e/pQTLs that improved the accuracy to correctly classify AD cases and CU controls. Result Of the 5,112 variants that were tested, 70 were nominally associated with AD‐risk and with plasma transcript or protein levels. Seven of these 70 variants also showed nominally significant associations of AD‐risk and transcript levels with either African or East Asian local ancestry. ROC analysis of age, sex, 33 e/pQTLs in APOE , SORL1 , TLR4 , EPHA1 , ABCA7 , CLU , and CR1 , and plasma levels of APP, ABCA7, AKAP9, CD14, CLU, and APOE ‐ɛ4 dosage achieved 88.2% area under the curve to discriminate AD vs. CU, a 30.4% improvement over the base model that only included age and sex. Conclusion Plasma transcript levels and e/pQTLs are promising diagnostic biomarkers for AD that may improve accessibility and reduce costs for a more accurate diagnosis of AD.

Abstract Background Population aging is expected to increase the burden of Alzheimer's disease (AD) and related dementias (ADRD), yet up to 45% of ADRD risk may be modified. Disparities in ADRD burden among Hispanic/Latino and Black/African Americans suggests that socioeconomic deprivation and medical comorbidities may influence AD risk. The relationship between these factors, symptomatic age of onset, and neuropathologic findings in AD remains unclear. This study aims to investigate these associations in an ethnoracially diverse, neuropathologically diagnosed AD case series. Understanding these risk factors may help develop more effective AD risk reduction strategies. Method We queried the Florida Autopsied Multi‐Ethnic (FLAME) cohort database for neuropathologically‐diagnosed AD cases with available age onset of cognitive symptoms, who self‐identified as Hispanic/Latino ( n = 75) or Black/African American ( n = 22). Cases were matched to non‐Hispanic White decedents ( n = 101) by sex and year of birth. Medical records at the time of brain donation were retrospectively reviewed, assessing completeness for demographics, clinical characteristics, and medical comorbidities (Table 1). Result The table shows a comparative analysis stratified by young‐onset AD (YOAD, onset <65 years) and late‐onset AD (LOAD, onset ≥65 years). YOAD cases had a significantly higher level of education compared to LOAD ( p = 0.003). No differences were observed in sex , APOE ε4 carriership, or Area Deprivation Index between YOAD and LOAD. However, YOAD cases had a longer disease duration and were more likely to present with atypical clinical features compared to LOAD (both p <0.001). YOAD cases also showed a faster rate of decline on MMSE compared to LOAD ( p = 0.002), higher frequency of depression ( p = 0.018), and lower frequency of stroke/TIA ( p = 0.025). YOAD cases also had lower brain weight ( p = 0.041), less cerebrovascular disease burden ( p = 0.003) and higher neurofibrillary tangle density in association cortices ( p <0.001) compared to LOAD cases. Conclusion Socioeconomic deprivation and most medical comorbidities were not associated with AD symptomatic onset. Despite having higher education levels and lower cerebrovascular burden, YOAD decedents experienced faster cognitive decline but a longer disease course, with more frequent atypical clinical presentations and depression compared to LOAD. Further discussion will address the topographic distribution of tangle and plaque pathology.

Abstract Background Disparities in structural and social determinants of health in Latino and Black communities may increase the burden of Alzheimer disease and related dementias (ADRD). Identifying dementia risk factors, which may account for up to 45% of ADRD risk, is crucial to implement effective risk‐reduction strategies. This study aimed to assess ADRD risk factors in community‐dwelling, cognitively normal, Latino and Black Americans by measuring the frequency of modifiable dementia risk factors through subjective and objective measures. Method Community‐dwelling, cognitively normal, Latino and Black adults (≥45‐years‐old) were enrolled in a longitudinal study of memory and aging at Mayo Clinic in Jacksonville, Florida. Baseline assessments conducted between Mach 2022 and November 2024 included demographics, self‐reported race/ethnicity, and history of dementia risk factors. Socioeconomic deprivation [Area Deprivation Index (ADI) State scores] and modifiable dementia risk factors were reported by participants and directly measured, including hypertension (BP >130/80 mmHg), obesity (BMI≥30), hyperlipidemia (LDL>100 mg/dL), hyperglycemia (HbA1C >5.6%), low vitamin B12 (B12<350 pg/mL), hearing loss (bedside assessment), vision loss (bedside assessment), and depression (Geriatric Depression Scale ≥5). Result 105 participants (47 Latino, 55 Black), 64.7 (±8.8) years‐old, female 66 (63%), with 16 (±2.3) years of education were assessed. Black participants experienced higher socioeconomic deprivation than Latino participants (median ADI 7 vs 3; p <0.001). Dementia risk factors were common in Latino and Black participants. These included, hypertension (55.3%, 70.3%; p = 0.291), hyperlipidemia (58.7%, 55.8%; p = 0.908), obesity (29.8%, 45.5%; p = 0.263), hyperglycemia (51.1%, 49.1%; p = 0.834), low vitamin B12 (23.9%, 28.0%; p = 0.270), hearing loss (19.1%, 7.3%; p = 0.111), vision loss (85.1%, 85.2%; p = 0.771), and depression (6.4%, 5.5%; p = 0.168). Objective measures revealed a higher frequency of risk factors compared with participant‐provided history, highlighting a substantial proportion of unrecognized or inadequately treated risk factors: hypertension (62.3%, 45.1%; p = 0.067), hyperlipidemia (57.6%, 47.5%; p = 0.004), hyperglycemia (49%, 20%; p = <0.001), vitamin B12 deficiency (27.8%, 9.3%; p = 0.170), and depression (6.9%, 11.9%; p = 0.009). Conclusion Modifiable dementia risk factors were detected in most cognitively normal Latino and Black adults engaged in a longitudinal study of memory and aging. Objective measures highlighted unrecognized and undertreated risk factors. Active surveillance programs are needed to detect and treat modifiable ADRD risk factors in underrepresented populations.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

The treatment landscape for soft tissue sarcomas (STS) is evolving constantly. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for STS specific to surgical management and systemic therapy recommendations for various subtypes.

Background The hemodynamic profile and remodeling patterns of paradoxical low‐flow, low‐gradient aortic stenosis are well understood. However, some patients with severe aortic stenosis exhibit eccentric remodeling with enlarged left ventricular cavities, enabling a normal flow, low ejection fraction ( NF ‐ LEF ) phenotype. We assessed the prevalence, hemodynamic characteristics, and post‐transcatheter aortic valve implantation outcomes of NF ‐ LEF . Methods In this substudy of the COMPARE‐TAVI 1 trial, 979 patients undergoing transfemoral transcatheter aortic valve implantation were stratified by left ventricular ejection fraction (LVEF) (< or ≥50%) and stroke volume index (< or ≥35 mL/m 2 ) into 4 groups: normal flow, normal LVEF, NF‐LEF, low flow, normal ejection fraction, and low flow, low ejection fraction. Results NF‐LEF was observed in 10.7% of patients. Reduced LVEF was associated with previous myocardial infarction, pacemakers, New York Heart Association class >2, atrial fibrillation, moderate or worse mitral regurgitation, and larger left ventricular cavities ( P <0.001) with eccentric hypertrophy ( P =0.004). Compared with low‐flow, low‐ejection fraction, patients with NF‐LEF more frequently had moderate or worse aortic regurgitation ( P =0.007), whereas low flow, low ejection fraction showed poorer diastolic indices, suggesting diastolic dysfunction with high left ventricular filling pressures. Patients with low flow, normal ejection fraction were the most symptomatic and showed less improvement in 6‐minute walk distance at 1 year compared with normal flow, normal ejection fraction. During follow‐up, both low‐flow groups demonstrated significant increases in stroke volume index ( P <0.001), whereas LVEF also improved among patients with reduced LVEF ( P <0.001). Conclusions NF‐LEF is a prevalent aortic stenosis phenotype characterized by preserved flow despite reduced LVEF, likely driven by eccentric remodeling with moderate or worse aortic regurgitation and more favorable diastolic properties, with similar survival and time‐to‐event outcomes across phenotypes after transcatheter aortic valve implantation at long‐term follow‐up. Despite higher comorbidity burdens, patients with NF‐LEF showed functional and clinical improvements comparable with normal flow, normal ejection fraction, indicating a severe aortic stenosis phenotype.

Background: Carriers of a pathogenic variant (PV) in BRCA1 face a high risk of breast cancer. This study estimated the risk of developing breast cancer according to mutation type and location. Methods: BRCA1 carriers with no personal history of breast cancer or bilateral mastectomy were included. Detailed information on clinical and family history was collected by questionnaire. Survival analysis was used to estimate 15-year cumulative risk according to PV type and location. Results: A total of 3677 BRCA1 carriers were followed for a mean of 7.2 years (range 0.1–15.0 years); 481 incident breast cancers were documented. Overall, the 15-year cumulative incidence was 25%. Risk estimates varied by exon, ranging from 9% (exon 21) to 19% (exon 12) to 36% (exon 15); however, strata were small. Carriers of four founder mutations common in Eastern Europe (c.5263_5264insC, c.181T > G, c.66_67delAG and c.4034delA) experienced a lower-than-expected cancer risk (15.9–24.4%) compared to other PVs (28.8%) (p = 0.02). Conclusions: Although our data suggests some variability in penetrance based on specific BRCA1 PV, this was based on a large number of founder mutations. Breast cancer management strategies should continue to be based on comprehensive risk assessment.

ABSTRACT The concentration of cells is a key component of modern blood tests. Given the biomarker potential of extracellular vesicles (EVs) in blood, we aimed to establish reference ranges for blood cell‐derived EVs using flow cytometry. To address the orders‐of‐magnitude variability in reported EV concentrations between different flow cytometers (FCMs), we first validated a calibration methodology to enable reproducible EV concentration measurements. The methodology was evaluated in an interlaboratory comparison study and shows that calibration reduces the median absolute deviation of EV concentrations measured on 25 different FCMs from 67 % to 25 %–31 %. The calibration methodology was then used to determine reference ranges of erythrocyte‐, leukocyte‐, and platelet‐derived EVs in human blood plasma in a cohort of healthy individuals ( n = 224). This study demonstrates that calibration enables comparable concentration measurements of blood cell‐derived EVs, thereby bringing EVs one step closer to clinical applications.