Suemoto, Cláudia Kimie

Abstract INTRODUCTION Sex differences in dementia‐related neuropathology are understudied in diverse populations. METHODS We analyzed sex differences in neuropathological and cognitive data from the Brazilian Biobank for Aging Studies. Cognitive performance was evaluated with the Clinical Dementia Rating–Sum of Boxes (CDR‐SOB). Linear and logistic regression models were conducted, including interaction terms for age, race, and education. RESULTS In 2229 participants (50.7% female, mean age ± SD 75.4 ± 12.3 years, 62.1% White), female sex was associated with a higher odds of AD pathology (Braak: odds ratio [OR] = 1.42, 95% confidence interval [CI] = 1.17–1.72; Consortium to Establish a Registry for Alzheimer's Disease (CERAD): OR = 1.58, 95% CI = 1.27–1.98), and trans‐activation response (TAR) DNA‐binding protein 43 (TDP‐43) (OR = 1.77, IC 95% = 1.22–2.59), and lower odds of Lewy body disease (OR = 0.69, 95% CI = 0.51–0.95). Female participant had worse cognitive performance ( β = 1.56, 95% CI = 1.03–2.10). Sex modified associations of Braak, CERAD, TDP‐43, and cerebral amyloid angiopathy with cognition. Age also interacted with sex and pathology on CDR‐SOB. DISCUSSION Sex differences in the associations between sex and neuropathology suggest the need for sex‐informed dementia research.

Abstract INTRODUCTION Women are increasingly entering the dementia research workforce, but they frequently fail to attain senior leadership positions in academia. Discrepancies in academic research outputs were investigated to guide equity‐focused policy recommendations. METHODS Bibliometrics was conducted on 400,482 original research articles (2003–2022) followed by surveying the AD/ADRD research community, to quantitatively and qualitatively evaluate discrepancies in publication and authorship trends. In addition, an unsupervised learning algorithm was developed to analyze underlying relationships between author groups. RESULTS Male author gender was consistently predictive of better publication and citation metrics across all bibliometrics outcomes, with senior male authors outperforming all other subgroups and fewer senior female authors in most research areas. Female survey respondents reported more barriers, but comparable productivity and citation strategies as male authors. DISCUSSION Multi‐pronged approaches by stakeholders across institutions, funders, and journals are necessary to provide career support for early‐career scientists working to transition to senior research roles.

A bstract Alzheimer’s disease (AD) presents with substantial clinical and anatomical heterogeneity, including both typical amnestic and atypical variants such as posterior cortical atrophy and logopenic primary progressive aphasia. Although neurofibrillary tangle (NFT) burden is a defining pathological feature of AD, its regional distribution varies across clinical phenotypes, suggesting that selective neuronal vulnerability may shape disease presentation. However, the cellular and molecular determinants underlying this vulnerability remain incompletely understood. Here, we profiled single-nucleus transcriptomes across multiple brain regions, including hippocampal (CA1) and neocortical (superior temporal gyrus and occipital cortex) regions, from individuals with typical and atypical AD and healthy controls. Integrative analysis identified major cell classes and resolved diverse excitatory and inhibitory neuronal subpopulations that were reproducibly observed across regions and individuals. Using quasi-binomial regression models to assess compositional changes, we quantified subtype-specific vulnerability associated with AD pathology. We identified a distinct excitatory neuronal subpopulation characterized by NRGN and BEX1 expression, which showed reproducible depletion across multiple regions, with the strongest evidence in amnestic AD and in neocortical regions in lvPPA. This vulnerable population showed concordance with previously reported AD-associated excitatory neuron signatures, supporting a conserved transcriptional program of susceptibility. Genes enriched in this population were associated with chemical synaptic transmission and regulation of synaptic plasticity and formed interconnected networks in protein-protein interaction analyses. These findings suggest that intrinsic properties related to synaptic function may predispose specific neuronal populations to degeneration in AD. Together, our results define a conserved, transcriptionally distinct excitatory neuron subpopulation that is selectively vulnerable across AD phenotypes and brain regions. This work provides a framework for linking regional pathology to cell-type-specific susceptibility and highlights synaptic regulatory pathways as potential contributors to neuronal degeneration in Alzheimer’s disease.

Abstract Latin America is undergoing rapid population aging alongside a rising burden of dementia. While the region holds substantial potential for dementia risk reduction, challenges remain, such as delayed diagnoses, limited access to specialized care and biomarker testing, persistent stigma, and deep‐rooted structural inequities. To address these gaps and foster regionally informed solutions, the Alzheimer's Association convened the 2025 Alzheimer's Association International Conference (AAIC) Satellite Symposium in Lima, Peru, on May 14–15, in collaboration with the Global Brain Health Institute (GBHI) and the Atlantic Fellows for Equity in Brain Health. The meeting aimed to bring core elements of the global AAIC meeting to regional Latin American settings, recognizing that national and cultural contexts demand tailored approaches to dementia prevention, risk reduction, treatment and care all aimed at promoting brain health in the region. This manuscript synthesizes the symposium's key discussions, scientific advances, and opportunities for collaboration across the region.

Abstract Reported prevalence estimates of Lewy body pathology (LBP) vary widely, often without considering brain regional distributions or demographic influences. Large, population-representative autopsy cohorts are needed to provide estimates and clarify the distribution and clinical implications of LBP. Neuropathological, genetic, and clinical data were pooled from nine community- or population-based brain autopsy cohorts in the USA (n=6), Brazil, Austria, and Finland (n=7309 total; 59% women; mean age of death 84.2 years). Cognitive status was available for 6166 participants: dementia (38.5%), mild cognitive impairment (14.8%), and cognitively unimpaired (47.0%). Frequency of LBP was examined by anatomical distribution (neocortical, limbic, brainstem, amygdala, olfactory) and stratified by covariates. Prevalence was calculated in meta-analysis, and mixed-effect logistic regression examined associations with sex, cognitive status, Alzheimer’s disease neuropathological change (ADNC), and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) co-pathology. Overall, 27.3% of participants had LBP: neocortical 8.4%, limbic 6.8%, brainstem 4.8%, amygdala 3.7%, and olfactory 3.6%. Neocortical LBP was associated with dementia (present in 15%; OR=4.06 [95%CI 3.24-5.10]) and with increased odds of ADNC (OR=2.30 [95%CI 1.88–2.81]) and LATE-NC (OR=2.03 [95%CI 1.69-2.44]). Sex differences were not observed in the frequencies of neocortical or limbic LBP. However, amygdala-predominant LBP was more frequent in women (OR=1.53 [95%CI 1.06-2.21]) whereas brainstem-predominant LBP was more common in men (OR=0.64 [95%CI 0.49-0.84]). Additionally, amygdala-predominant LBP was associated with increased odds of comorbid ADNC (OR=12.7 [95%CI 5.30–30.6]) while brainstem-predominant LBP was not associated with greater odds of ADNC co-pathology (OR=0.88 [95%CI 0.67–1.16]). Pooling data from large, international community-based autopsy cohorts allows for more robust estimates of region-specific LBP prevalence and their associations with cognitive status. The observed sex- and co-pathology–specific differences in brainstem and amygdala-predominant LBP highlight potential biological heterogeneity and suggest that distinct disease pathways may underlie these patterns.

Abstract INTRODUCTION Cognitive impairment in hospitalized older adults without delirium is often undiagnosed. We evaluated the diagnostic accuracy and prognostic value of two brief bedside screening tools—the 10‐point Cognitive Screener (10‐CS) and Short Portable Mental Status Questionnaire (SPMSQ). METHODS Multicenter prospective cohort of 2003 patients ≥65 years of age without delirium, admitted to 43 hospitals in five countries of the Creating a Hospital Assessment Network in Geriatrics (CHANGE) Study. Screening was completed within 48 h of admission. Dementia was defined as informant‐based Clinical Dementia Rating ≥1. RESULTS Dementia prevalence was 22%, with 35% undiagnosed. Both tools showed good accuracy for detecting dementia, with the 10‐CS slightly more accurate than SPMSQ (area under the curve [AUC] = 0.87 vs 0.85; p = 0.02). After adjustment, cognitive impairment detected by either tool was associated with increased risk of incident delirium, hospital‐associated disability in self‐care activities, and 90‐day mortality, but not prolonged stay. DISCUSSION Brief bedside screening identified dementia and predicted adverse outcomes, supporting its integration into routine hospital care.

Importance Sex and racial or ancestral disparities in Alzheimer disease remain incompletely understood; autopsy studies that examine amyloid, tau, and genetic factors are scarce. Objective To test whether neuritic plaque burden and cognitive outcomes differ by sex and whether sex modifies the effects of apolipoprotein E ε4 ( APOEε4 ), informant-reported race, and African ancestry. Design, Setting, and Participants This was a cross-sectional study using postmortem neuropathological data from the Biobank for Aging Studies, University of São Paulo, São Paulo, Brazil. A total of 2268 autopsies from a population-based, diverse clinicopathological sample were collected between April 2004 and March 2025. Exposures Sex, informant-reported race (Black, White), African ancestry proportion, and APOEε4 carrier status. Main Outcomes and Measures Neuritic plaque burden (Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] score), and cognitive function (Clinical Dementia Rating–Sum of Boxes [CDR-SB]). Ordinal logistic regression examined association of sex with CERAD scores and 2- and 3-way interactions among sex, race, ancestry, and APOEε4 ; adjusting for age, education, vascular factors, and Braak stages. Linear models related pathology to CDR-SB, adding copathologies. Results The analysis included 2268 autopsies (median [IQR] age, 74.8 [63.8-83.3] years; 1152 [51% male] and 1116 [49%] female; 802 [35%] Black and 1466 [65%] White; other race groups not included owing to small numbers); female individuals were older than male individuals and more likely to exhibit cognitive impairment (CDR global score ≥0.5). Female individuals had higher plaque burden than male individuals (unadjusted odds ratio [OR], 1.97; 95% CI, 1.67-2.29; P < .001), and this association remained significant in adjusted models for sociodemographic and vascular factors and APOEε4 status (adjusted OR, 1.65; 95% CI, 1.33-2.20; P < .001). APOEε4 carriers of both sexes had an approximately 4-fold greater odds of plaques. Significant 2-way interactions were found between sex, APOEε4 status, race, and ancestry on CERAD scores. Black noncarriers (OR, 0.47; 95% CI, 0.34-0.67) and noncarriers of African ancestry (OR, 0.57; 95% CI, 0.43-0.76) were least likely to have high plaque burden, whereas this protection was weakened in ε4 carriers. No significant 3-way interaction was detected. Among individuals with a CERAD score of 2 or higher, female individuals were more likely than male individuals to reach Braak stage V-VI than male individuals (probability ratio, 1.25; 95% CI, 1.13-1.38; P = .002). Adding Braak stage to multivariable models attenuated the female-male difference in plaques and interaction of sex and plaque on CDR-SB was no longer significant. Conclusions and Relevance The findings indicate that female sex, APOEε4 , and both race and African ancestry were jointly associated with amyloid in this study population. Excess amyloid among women may partly explain their greater tau burden and steeper cognitive decline. These findings highlight the importance of incorporating sex, race, and ancestry into biomarker thresholds, risk stratification, and the design of preventive or disease-modifying trials for Alzheimer disease.

BACKGROUND: Cerebrovascular disease is prevalent in older adults and is associated with cognitive impairment. Although the association between brain infarcts and cognition has been widely investigated, the contribution of vascular disease to cognitive impairment has been less studied, particularly in non-White populations. We investigated the epidemiological and clinical characteristics of vascular disease phenotypes and their association with cognitive abilities in a diverse population. METHODS: In a Brazilian population–based clinicopathological study (recruitment between 2004 and 2024), inclusion criteria were age at death ≥18 years and the availability of an informant. Clinical information and cognitive abilities were assessed through informant interviews. Hyaline arteriolosclerosis (HA) was evaluated in 13 brain areas and categorized as absent, mild, moderate, or severe. Moderate/severe HA defined microvascular disease (Micro[+]). Intracranial atherosclerosis in the circle of Willis was similarly classified, with moderate/severe cases defining macrovascular disease (Macro[+]). Four vascular profiles were compared: Micro[+]/Macro[+], Micro[−]/Macro[+], Micro[+]/Macro[−], and Micro[−]/Macro[−]. Linear regression models adjusted for sociodemographic, clinical, and cerebrovascular/neurodegenerative lesions evaluated the association of cognition with vascular profiles, and microvascular and macrovascular diseases separately. RESULTS: Of 2418 participants, 834 with missing data were excluded, yielding a final sample of 1584 individuals (mean age, 74.3±13.4 years; 776 [49%] women; 982 [62%] White). Microvascular disease was slightly more frequent (31%) than macrovascular (29%). Regarding vascular profiles, 788 (50%) participants were Micro[−]/Macro[−], 334 (21%) Micro[+]/Macro[−], 301 (19%) Micro[−]/Macro[+], and 161 (10%) Micro[+]/Macro[+]. Micro[+] participants were older and more frequently women, and had worse cognitive abilities. Vascular groups were similar regarding most clinical comorbidities. HA (β, 0.81 [95% CI, 0.25–1.36]; P =0.004) and Micro[+]/Macro[+] phenotype (β, 1.25 [95% CI, 0.38–2.12]; P =0.005) were associated with worse cognitive abilities compared with HA-negative and Micro[−]/Macro[−] participants, respectively. CONCLUSIONS: HA was as frequent as intracranial atherosclerosis. HA and the vascular phenotype with both microvascular and macrovascular diseases were associated with worse cognition.

Abstract Background Individuals meeting neuropathological criteria for Alzheimer's disease (AD) can exhibit distinct clinical syndromes, suggesting region‐specific neuronal susceptibilities to tau pathology. Amnestic AD cases show greater tau burden in CA1, logopenic variant primary progressive aphasia (lvPPA) in the superior temporal gyrus (STG), and posterior cortical atrophy (PCA) in the occipital cortex. We hypothesize that by contrasting these AD variants and examining their respective pathological hotspots, we can identify the most vulnerable neuronal subpopulations ‐ those that exhibit the greatest reduction in their specific hotspot area compared to other regions. Using single‐nucleus RNA sequencing (snRNA‐seq), we investigate the molecular mechanisms driving this selective neuronal vulnerability. Methods We performed snRNA‐seq using the Chromium Single Cell 3′ (10X Genomics, USA) platform on nuclei extracted from the CA1 hippocampal sector, posterior STG, and occipital cortex of postmortem brain tissue from 68 individuals. The cohort included 24 amnestic AD cases, 11 lvPPA cases, and 6 PCA cases (all meeting A3B3C3 pathological criteria), along with 27 healthy controls (A≤1B≤1C≤1). Bioinformatics analysis was conducted using the Seurat library in R. Cell subpopulation comparisons were performed using the Wald statistical test, with p ‐values < .05 considered significant. Results Following quality control, we recovered over 1.58 million nuclei, with an average of 2,129 genes detected per nucleus. UMAP clustering identified 17 inhibitory and 16 excitatory neuronal subpopulations across all three regions. Among these, one excitatory subpopulation was highly enriched in CA1. We identified six excitatory subpopulations (Exc‐subs) exhibiting region‐specific vulnerability. Notably, the Ex L2/3 IT RORB GRIN1 subpopulation showed pronounced vulnerability in CA1 among amnestic cases, in STG among amnestic and lvPPA cases, and displayed a vulnerability trend in the occipital cortex among PCA cases, though not statistically significant. Conclusion Our findings suggest that a specific excitatory neuron subpopulation exhibits heightened susceptibility across highly tau‐affected regions in amnestic and atypical AD syndromes, including PCA. Ongoing validation using quantitative pathology aims to confirm these findings, and further case analyses will refine our understanding of the molecular drivers of neuronal vulnerability in AD.

Abstract Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease linked to repetitive traumatic brain injury, but its prevalence and risk factors in the general population remain poorly defined. We investigated CTE neuropathological changes (CTE-NC) in an admixed, population-based clinicopathological cohort. Neuropathological evaluation was conducted on brain samples from 1151 individuals in the University of São Paulo Biobank for Aging Studies collected from 2004 to 2022. CTE-NC and aging-related tau astrogliopathy (ARTAG) were assessed across 14 963 histological slides using p-tau immunostaining. Clinical, cognitive, and neuropsychiatric data were obtained via informant interviews; information on sports exposure and traumatic brain injury history was limited. Seven cases (0.6%) met criteria for CTE-NC, mean age at death 73.4 ± 12.5 years; 1 was female. Dementia was present in 43% of CTE-NC cases; 57% exhibited neuropsychiatric symptoms. Most common co-pathologies were Alzheimer disease-type changes, ARTAG, and argyrophilic grain disease. Comprehensive exposure histories were unavailable for most cases; 2 had documented soccer involvement. These findings indicate that CTE-NC is rare in this population-based Brazilian cohort and predominantly affects males with frequent coexisting neuropathologies. Findings align with reports from high-income countries and support prioritizing primary prevention by reducing exposure to repetitive head impacts in sport and other settings.