The physical and social exposome affects human aging, and brain clocks may track its effects. However, most studies neglect multidomain exposures (physical, social and political) across diverse settings globally and their associations with brain aging. In this study, we characterized the associations between 73 country-level physical and social exposomal factors and multimodal brain age in 18,701 participants from 34 countries (healthy individuals and those with Alzheimer's disease, frontotemporal lobar degeneration or mild cognitive impairment). Exposome effects were assessed using generalized additive models and meta-analytic frameworks. Aggregated exposome models explained up to 15.5-fold more variance than individual exposures (delta Akaike information criterion (ΔAIC): 2,034-3,127). Physical exposome was primarily associated with accelerated structural brain aging (limbic, subcortical and cerebellar regions), whereas social exposome was more strongly associated with functional brain aging (frontotemporal and limbic networks). Exposome burden accounted for 3.3-9.1-fold higher risk of accelerated aging, exceeding effects of clinical diagnoses. Findings were out-of-sample validated in cross-sectional and longitudinal designs, remained consistent across clinical subgroups and persisted after adjustment for demographics, age correction bias, cognition, scanner type and data quality. The exposome accelerates brain aging in health and disease, underscoring the need to address physical, social and political inequities.

Research suggests some individuals with progressive supranuclear palsy (PSP) have socioemotional deficits, typically characterized as reduced emotion recognition, difficulty with perspective taking, and increased apathy. However, the variability of these deficits across individuals and the pattern of impairments across the spectrum of social cognition have not been quantified in larger samples. The present study used multiple face-to-face and informant-based social cognition, neuropsychiatry, and personality measures to identify socioemotional changes occurring as a result of PSP. Data were collected from 287 individuals: 113 with early-stage PSP (Clinical Dementia Rating scale global score < 2) and 174 older healthy controls (HC). Though there was a high degree of individual variability, on average those with PSP had a pervasive pattern of deficits across tests of social cognition compared to HC, including emotion reading, social inferencing, theory of mind, and identifying and applying social behavior rules. Worse neuropsychiatric functioning was reported on both self- and informant-report measures, including increased depression, apathy, and anxiety. Changes in personality, including reduced conscientiousness, openness, and extraversion, from pre-morbid to current presentation were also found. Our analyses revealed that the social withdrawal typical of PSP is not simply a reflection of apathy or emotion reading deficits, but is directly correlated with the degree of the patient’s depression and self-reported sense of hopelessness. These results reveal more clinically significant socioemotional deficits and personality shifts in early-stage PSP than are generally recognized, and suggest face-to-face testing and informant reports of socioemotional functioning may provide critically important information to guide clinical care.

Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick's disease, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.

Prior research identified profound sleep disruption in progressive supranuclear palsy (PSP). The hypothalamus and brainstem, areas that help regulate sleep/wake patterns, are among the earliest affected brain regions in PSP disease progression. Comparing polysomnography and quantitative-neuropathology metrics, we identified relative sparing of wake-promoting nuclei in PSP compared to Alzheimer’s disease, though PSP had more disrupted sleep. It led to the hypothesis that PSP patients have hyperinsomnia (or hyposomnia, little sleep) due to degeneration of sleep nuclei with a preservation of sleep neurons, causing a system unbalance. A higher neuronal count of wake-promoting nuclei was associated with greater nocturnal wake, regardless of disease. Specifically, orexinergic wake-promoting neurons in the lateral hypothalamus, previously described as the sleep-on/off switch, are relatively spared in PSP. Thus, we hypothesized that an orexinergic antagonist may be more effective in treating sleep/wake issues in PSP than other hypnotic medications. This study protocol was established to test the safety and efficacy of an orexinergic antagonist (suvorexant) targeting the wake-promoting system and contrasts it with a GABAergic receptor agonist (zolpidem) targeting sleep-promoting systems and placebo. This is a remote clinical trial, designed as a double-blind, cross-over, within-subject 6-week trial, with 3 one-week-long conditions, separated by 1-week washout periods. The order of the 3 regimens is randomized and counterbalanced: placebo (microcrystalline cellulose), 15 mg/day suvorexant, 5 mg/day zolpidem. Participants are recruited from doctor and study referrals, registries, and support groups. Once onboarded, the trial coordinator maintains communication with the participant/caregiver throughout the 6 weeks. Assessments include neurological interviews, cognitive testing, and subjective questionnaire packets. Sleep and circadian rhythms are assessed through ambulatory EEG and actigraphy monitoring devices worn by the participant throughout the trial. The study design aims to reduce participant and caregiver burden, while improving accessibility to such a study. Administering a remote clinical trial for a rare disease, however, creates unique issues that would otherwise be absent from in-person studies. Particularly, a symptom rather than disease-modifying trial is challenging to recruit for when potential disease-modifying therapeutics are available. Needing to coordinate with non-associated medical offices to attain medical records or prescriptions can cause frustrations for the potential participant, medical office, and study team. In recruitment, onboarding, and trial maintenance, this study design relies on consistent communication to support participant enrollment and satisfaction. Treatment of Disturbed Sleep in Progressive Supranuclear Palsy (PSP); NCT04014389. Registered on June 2, 2019.

Abstract Classifying dementia syndromes is based on phenotypic characterization of clinical symptoms that unfold as the disease spreads across long-range neuro-glial networks of the nervous system. Phenotypes are mapped anatomically onto specific brain networks, and the ultimate distinction across syndromes is based on the initial symptoms that occur related to the nidus of disease. Rate of progression and sequence of symptoms are critically informative, which means that a precise history is critical. The concept of regional vulnerability refers to the predilection of certain brain regions for harboring neurodegenerative disease pathologies. The main biomarkers for neurodegenerative disease are protein deposits in brain cells (neurons and glia), delineating dysfunction of essential molecular and cellular operations, jeopardizing cellular function, and disrupting the brain’s neural networks that control cognitive, behavioral, emotional homeostasis, and sensorimotor functions. The order of impaired functions along with pace of progression provide clues and basis for determining the syndrome. Syndromes can be caused by a variety of pathologies, and ancillary diagnostic studies can help to narrow their molecular etiologic differentials. In the case of inherited disease, especially monogenic diseases, genetics serves as the ultimate biomarker, overriding many aspects of syndromic classifications. Moreover, monogenic forms of disease tend to show less typical patterns of brain atrophy than the more complex nonheritable forms of neurodegenerative diseases. As detailed in this chapter the penetrance of pathogenic variants varies by gene. The chapter focuses on neuropathological substrates, relevant epidemiological data, risk factors, and known distinctive clinical features.

IntroductionCaregiver distress in dementia is multifactorial. The contribution of disease specific factors including anosognosia (poor awareness of cognitive/behavioral deficits) and theory of mind (ToM) deficit (difficulty with understanding other’s perspective) requires further investigation.MethodCross sectional secondary analysis was performed on a dataset of 205 research participants (age = 64.2 ± 9.46): 57 Alzheimer’s disease, 38 behavioral variant frontotemporal dementia, 12 non-fluent primary progressive aphasia (PPA), 24 semantic variant PPA, 18 progressive supranuclear palsy syndrome, 14 corticobasal syndrome, and 42 cognitively normal controls (NC). Anosognosia was measured using the Patient Competency Rating Scale (PCRS-self minus PCRS-caregiver; clinically meaningful anosognosia >20 points difference), ToM deficit was evaluated using The Awareness of Social Inference Test: Social Inference-Enriched (TASIT-SIE), and caregiver distress was measured using the Neuropsychiatric Inventory Questionnaire (NPI-Q) Total Distress score. Differences across syndromes were evaluated controlling for age and sex, and multivariable linear regression was used to determine predictors of caregiver distress.ResultsClinically meaningful anosognosia (patient overestimation of function) and ToM deficit were significantly higher in all dementia syndromes compared to NCs. Anosognosia and ToM deficit each independently predicted caregiver distress and had an additive effect (p < 0.05).DiscussionOur findings are consistent with other research showing that anosognosia in individuals with chronic neurological disorders including dementia can increase caregiver distress; however, our results highlight the additive importance of patients’ theory of mind deficits above and beyond their anosognosia. Evaluation of both patient anosognosia and ToM deficit in clinical contexts may provide meaningful information to predict which caregivers are at particular risk for adverse outcomes.

Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), and other neurodegenerative diseases are characterized by pathological protein misfolding, yet postmortem neuropathological measures collectively explain less than half the variance in antemortem clinical progression. We leveraged large-scale cerebrospinal fluid (CSF) proteomics to identify overlapping and distinct molecular signatures that help explain clinical severity across patients with AD, FTLD-tau, and FTLD-TDP. CSF was assayed via aptamer-based proteomics (SomaScan v4.1 >7k proteins) in 132 symptomatic AD patients (positive CSF p -Tau181/Ab 42 ratios and/or amyloid PET), 64 sporadic FTLD-tau patients, 42 sporadic FTLD-TDP patients, and 72 AD biomarker-negative controls. FTLD cases screened negative for autosomal dominant FTLD mutations and were classified via either autopsy confirmation (65% of cases; FTLD-tau: progressive supranuclear palsy [PSP], corticobasal degeneration, Pick's; FTLD-TDP: types A-C) or clinical diagnosis with high etiologic specificity (35% of cases; FTLD-tau: PSP-RS; FTLD-TDP: semantic variant primary progressive aphasia). Clinical severity was measured via CDR®+NACC FTLD sum of boxes. Differential abundance and co-expression network analyses modeled proteomic differences across groups and in relation to clinical severity. We identified 1,026 differentially abundant proteins (DAPs) across diseases (omnibus ANOVA FDR- p <.05) that mapped onto 21 co-expression modules. Most modules harbored DAPs shared by >1 disease vs. control, suggesting common molecular signatures across diseases. Protein degradation modules exhibited overrepresentation of DAPs that were elevated in AD (module M14 phosphatase binding: 74% DAPs, M2 protein transport: 59% DAPs), neuronal modules had overrepresentation of DAPs that were reduced in FTLD-tau (M3 postsynapse: 73% DAPs, M1 axon guidance: 40% DAPs), and RNA metabolism modules had overrepresentation of DAPs that were reduced in FTLD-TDP (M19 ribonucleoprotein complex: 56% DAPs, M13 RNA splicing: 51% DAPs). Neuronal modules harbored the largest proportion of proteins negatively correlated with clinical severity across the full sample (M3: 79%, M1: 59%; p s<.05), including targets that outperformed CSF neurofilament light in predicting clinical severity across all three disease groups (e.g., NPTX2, IRF1, TMEM132B). Findings highlight overlapping CSF proteomic alterations across AD and sporadic FTLD. Neuron-enriched protein communities robustly tracked with clinical severity across diseases, underscoring their potential as transdiagnostic biomarkers of disease progression and therapeutic targets for all aging brains.

List-learning tasks (LLTs) are important for characterizing memory in Alzheimer’s disease and related dementias. However, as the Uniform Data Set Neuropsychological Battery (UDS-NB) historically did not require a specific LLT, centers have administered different LLTs. The newest UDS version (v4.0) requires one of two LLTs. To support harmonized UDS memory research, we developed a memory composite incorporating UDS memory tests and multiple LLTs. Item-banking confirmatory factor analysis was applied to develop a memory composite in a diagnostically heterogeneous sample (n = 8716) that completed the UDS-NB and one of five LLTs. Construct validity was evaluated through associations with demographics, disease severity, cognitive tasks, brain volume, amyloid/tau PET positivity, and plasma phosphorylated tau. Analyses were replicated in a racially/ethnically diverse cohort (n = 839). Psychometric properties were adequate. Expected associations with demographics and clinical measures within development and validation cohorts supported validity. This composite supports memory research across cohorts that administer the UDS and LLTs. A user-friendly UI is freely available to create the score in other datasets.

Accurately characterizing white matter (WM) microstructure is critical for understanding neurodegenerative diseases such as semantic dementia (SD). Regionally constrained techniques like tract-based spatial statistics (TBSS) rely on diffusion-tensor imaging (DTI) and assume a single fiber population per voxel, limiting their sensitivity to complex architecture. Fixel-based analysis (FBA) overcomes these constraints by resolving multiple fiber populations (fixels) within a single voxel, enabling more anatomically specific assessment of WM organization. Multi-shell diffusion MRI from 16 semantic-variant PPA (svPPA) and 15 semantic-behavioral fronto-temporal dementia (sbvFTD) cases—with imaging-confirmed left- and right-predominant temporal atrophy, respectively—and 44 neurologically healthy controls were analyzed using both TBSS-DTI and whole-brain FBA. Fiber-specific metrics of fiber density and cross-section were evaluated alongside conventional DTI measures. Both methods confirmed damage to the anterior temporal lobe (ATL) connected tracts—the uncinate fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and temporal projections of the arcuate fasciculus. FBA further detected involvement of juxtacortical and other pathways that were not captured by TBSS, including the tapetum and anterior commissure, projections to the parahippocampal gyrus and amygdala, and longer-range parietal connections. By capturing multiple fiber populations within each voxel, FBA provides greater anatomical precision and sensitivity to micro- and macro-structural changes than TBSS. This fiber-specific framework enables a more comprehensive mapping of WM degeneration in SD and helps delineate early alterations in commissural and mesial-temporal pathways that may underlie disease spread and cognitive decline.

Metaphors have long played multiple roles in conceptualizing the mind and brain, guiding the development and refinement of theoretical models and empirical questions. Early analogies (comparing the brain to hydraulic systems, telephone exchanges, factories, or libraries) offered shortcuts to understanding aspects of cognition, memory, and brain dynamics. From theoretical frameworks, metaphors like the mind as a computer evolved into central scientific metaphors, shaping core theoretical frameworks, inspiring predictions, and informing research methodologies. As such, metaphors play a key role in guiding scientific inquiries. Building on that premise, we propose music as a scientific metaphor for understanding multiple brain dynamics and cognitive functions. Unlike metaphors focusing on static components or linear flows, music emphasizes continuous adaptation, context-dependence, and cultural embedding, and presents a model for simultaneous engagement with multiple layers of meaning. Integrating analytical techniques from music theory and experiential insights from performance and listening, we can deepen our understanding of mind and brain dynamics and provide fresh epistemological pathways for interdisciplinary research. Music has a hierarchical structure, temporal complexity, and capacity to integrate multiple processes that parallel key features of the brain's architecture and cognitive functions. Drawing from research on neural oscillations, plasticity, predictive coding, and emotional processing, we illustrate how the musical paradigm can capture the rich entanglement of mind and brain, from large-scale brain dynamics and developmental trajectories to the emergence of consciousness and the interplay of affective states.

INTRODUCTION: Sleep and circadian rest-activity rhythm (RAR) disruption may bidirectionally relate to Alzheimer's disease (AD). Down syndrome (DS), the most common genetic cause of AD, presents sleep disorders, yet RAR patterns across the DS-associated AD continuum remain uncharacterized. METHODS: We analyzed 7-day wrist actigraphy in 140 adults with DS (108 asymptomatic; 32 AD dementia) and 41 unimpaired controls. General linear models, adjusted for age, sex, sleep efficiency, and obstructive sleep apnea (OSA) severity, tested group differences, with interaction terms included to evaluate group-specific associations. RESULTS: DS showed lower relative amplitude and higher nocturnal activity, already in asymptomatic individuals. Rhythm strength declined further with AD progression, while regularity and phase timing remained preserved until dementia. Findings were independent of sleep duration and OSA. DISCUSSION: Adults with DS showed early RAR disturbance that progressed across the AD continuum, paralleling sporadic AD. Circadian RAR features may be scalable biomarkers of AD progression.

INTRODUCTION:Similarities between frontotemporal lobar degeneration with transactive response DNA-binding protein of 43 kDa (TDP-43) (FTLD-TDP) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) raise questions about whether they represent distinct entities or a single disease spectrum. The literature mostly examined series with disproportionate numbers of LATE-NC over FTLD-TDP. METHODS:Leveraging a clinicopathological collection of FTLD-TDP (N = 148) from the University of California, San Francisco, we compared demographic, clinical, genetic, and neuropathological features of FTLD-TDP, particularly FTLD-TDP type A (N = 39), and LATE-NC (N = 42). RESULTS:FTLD-TDP type A cases were younger at onset and death, had shorter disease duration, and frequent genetic causes (GRN, C9ORF72) compared to LATE-NC, which were mostly sporadic and older. Blinded evaluation of middle frontal gyrus (MFG) TDP-43 immunostaining alone proved insufficient to reliably differentiate FTLD-TDP type A from LATE-NC stage 3. However, factoring in all neuropathologic features, FTLD type A and LATE-NC could be differentiated with >95% confidence. DISCUSSION:These overall findings support distinct diagnostic entities for FTLD-TDP and LATE-NC.

The cerebrospinal fluid (CSF) SAA has high specificity for Lewy body disease (LBD) in well-defined research cohorts, but real-world use data are sparse. In persons with Alzheimer's disease markers, SAA positivity correlates with worse cognitive decline and may alter expectations for amyloid-targeting drugs’ effectiveness. The study objective was to characterize current use and potential impact for clinical decision-making of the alpha-synuclein seeding amplification assay (SAA) in a tertiary behavioral neurology clinic. Two retrospective cohorts were derived from all cases who underwent clinical lumbar puncture: 1) those with a commercial SAA test (Amprion) ordered clinically, and 2) those with CSF stored for research and SAA obtained later. Records were reviewed for diagnosis, clinical syndrome/affected cognitive domain(s), cognitive tests, presence of core LBD features and other symptoms, MRI, PET, and SPECT imaging, Alzheimer's disease biofluid markers, tests ordered by the clinician, and subsequent clinical decisions. In the first year, the SAA was performed clinically for 21 patients (cohort 1). Most were men (76%). Patients at time of testing were between 53-86 years old (mean 74). Mild cognitive impairment was the most common severity (71%) followed by dementia (19%) and subjective cognitive impairment or normal (9.5%). The SAA was abnormal in 9 patients (43%). The p(181)-tau/amyloid-beta(42) ratio was abnormal in 44% of SAA-positive cases and 45% of SAA-negative cases. In SAA-positive cases, 5 met the core features from McKeith et al. for probable and 2 for possible LBD syndrome; in SAA-negative cases, none were probable and 7 were possible. Seventeen had questionable or mild motor parkinsonism. Clinical syndromes varied and included amnestic, multidomain (2/6 positive), non-amnestic, dysexecutive and behavioral (0/5), logopenic primary progressive aphasia (1/1), corticobasal syndrome (1/1), behavioral variant frontotemporal dementia (0/1), multiple system atrophy (0/1), and Parkinson's disease (0/1); no purely amnestic patients were tested. Subsequent clinical decisions included additional tests and medication changes (lecanemab included). In cohort 2, SAA was positive in 12 of 50 cases (24%) with similar analyses to be completed soon. Implementation of SAA was successful and used in patients with or without DLB. Meeting possible DLB criteria was poorly predictive, whereas probable DLB was accurate.

INTRODUCTION:Relationships between Alzheimer's disease neuropathology, residential neighborhood, and cognitive impairment remain incompletely understood. METHODS:We examined whether residence within a disadvantaged neighborhood was associated with amyloid positron emission tomography (PET) positivity. We used data from the observational, multisite, Imaging Dementia-Evidence for Amyloid Scanning study that included cognitively impaired Medicare beneficiaries. Our secondary analysis examined multivariable-adjusted associations between neighborhood disadvantage (measured by Area Deprivation Index [ADI] deciles 1-90 vs. 91-100 representing greatest disadvantage) and amyloid PET positivity. RESULTS:Among 15,346 White, 829 Latino, 637 Black/African American, and 321 Asian individuals, 51% were female, mean age was 75.7 years, 535 (3.8%) resided in ADI 91 to 100 decile, and 61.6% were amyloid PET positive. The ADI 91-100 decile was associated with lower odds of PET positivity by visual interpretation (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.67-0.96, p ≤ .001) but not PET Centiloid value ≥ 40 versus ≤ 10 (OR 0.81, 95% CI 0.66-1.01, p = 0.060). CONCLUSION:Residence in the most disadvantaged neighborhoods may be associated with lower amyloid pathology in cognitively impaired individuals.

BACKGROUND/OBJECTIVE:Arterial spin-labeling (ASL) MRI can measure perfusion signal adjacent to CSF spaces and may provide information regarding CSF-adjacent water transport physiology. We developed an automated pipeline to extract cortical-CSF interface (IF) perfusion for comparison between Alzheimer disease (AD) and cognitively normal controls. METHODS:In this retrospective study, participants with AD and cognitively normal controls with ASL and 3D T1-weighted MRI were included. Parenchymal cerebral blood flow (CBF) was evaluated globally (whole brain, gray matter, white matter) and across 12 brain regions. IF-perfusion values were quantified using an automated pipeline with tissue segmentation, registration, partial-volume-aware masking, and arterial-signal exclusion. Multivariable sensitivity analysis was performed, adjusting for age, sex, scanner vendor, and acquisition site. Predictive modeling was performed using LASSO-regularized logistic regression with nested repeated stratified cross-validation, and feature contributions were summarized using SHAP. RESULTS:A total of 51 patients with AD, age (median: 73 years) and 53 cognitively normal subjects (median age: 69) were included. Global CBF did not differ between groups. However, IF-perfusion values were significantly lower in AD (median 4.4, IQR 3.2-4.8) than in controls (median 5.2, IQR 4.5-6.3; p < 0.001). In multivariable analysis, AD remained independently associated with lower IF-perfusion after adjustment for age, sex, scanner vendor, and acquisition site (β = -1.88, 95% CI: -3.52 to -0.25; p = 0.025). In LASSO-regularized logistic regression model, only IF-perfusion and cuneus-CBF remained as significant contributing features for the prediction of AD probability with the highest contribution from IF. The final model showed mean ROC-AUC 0.81 in the training and AUC of 0.78 in the testing dataset. CONCLUSION:ASL-derived IF-perfusion is reduced in AD and may represent a promising imaging marker of altered CSF-adjacent water transport physiology. Further validation against established biomarkers of CSF dynamics and clearance pathways is warranted.

More precise subtyping within dementia syndromes leads to better prediction of pathology, supporting individualized, disease-specific treatments, and measuring emotion recognition abilities is particularly important for disorders like semantic behavioural variant frontotemporal dementia (sbvFTD). To evaluate current tools' effectiveness, we compared two dynamic video-based affect labelling tests-the Dynamic Affect Recognition Test (DART), The Awareness of Social Inference Test-Emotion Evaluation Test (TASIT-EET)-and a static image-based Comprehensive Affect Testing System-Name Affect (CATS-NA) test. A total of 555 persons with dementia (PwD), diagnosed with Alzheimer's disease (n = 154), progressive supranuclear palsy syndrome (n = 88), non-fluent variant primary progressive aphasia (nfvPPA) (n = 77), semantic variant PPA (svPPA) (n = 53), bvFTD (n = 124), sbvFTD (n = 65) and 133 healthy participants underwent emotion testing and MRI. All emotion labelling tests differentiated PwD from healthy controls, and FTD with social cognition deficits (sbvFTD, bvFTD and svPPA) from other PwDs. DART outperformed TASIT-EET and CATS-NA in differentiating sbvFTD from bvFTD and svPPA. Beyond emotion reading, TASIT-EET performance was also mediated by verbal memory and semantics, and CATS-NA was predicted by visuospatial and executive functions, while DART required only semantic knowledge. DART corresponded to expected structural anatomy of emotion, including predominantly right insula, anterior temporal and orbitofrontal lobes. While both TASIT-EET and CATS-NA shared that pattern, TASIT-EET additionally correlated with left temporal structures and CATS-NA associated with more dorsal frontoparietal regions. Careful selection of tests that utilize dynamic stimuli, reflect key neural circuits related to emotion and minimize demands from other cognitive domains may yield more accurate diagnoses.

Chronic psychological stress has been implicated as a risk factor for Alzheimer’s disease (AD), potentially through cortisol-mediated acceleration of disease progression. However, the molecular pathways underlying this relationship remain poorly understood. Epigenetic regulation of the glucocorticoid and mineralocorticoid receptor genes (NR3C1 and NR3C2), which encode receptors for cortisol, may play an important role, but has not been examined in relation to AD progression. Therefore, this study investigated associations between DNA methylation of NR3C1/NR3C2 and AD-related phenotypes, including cognition, brain amyloid-β (Aβ) burden, and regional brain volumes. These associations were examined in two independent cohorts of cognitively unimpaired individuals with accumulating brain Aβ (n = 89–298 across outcomes) using linear regression and meta-analyses. The study also explored whether DNA methylation within NR3C1 and NR3C2 interacted with depression symptoms to influence relationships with AD-related phenotypes. While only nominal associations were observed in direct analyses, stronger associations emerged in interaction with depressive symptoms. Interaction analyses showed that relationships between DNA methylation and AD-related phenotypes (cognition, hippocampal volume and ventricular expansion) differed depending on the presence of depression symptoms. Consistent patterns across cohorts were observed, with associations primarily evident among individuals with clinically relevant depressive symptoms. One site (NR3C1 cg24052866) was associated with cognitive decline, one (NR3C1 cg08845721) with cross-sectional hippocampal volume, and eight (NR3C1 cg21979215, cg16594263; NR3C2 cg27460943, cg17253842, cg04867484, cg10993059, cg25672354, cg27234800) with ventricular expansion. These exploratory findings suggest epigenetic variation within cortisol receptor genes may influence AD-related neurodegeneration in a depression-dependent manner.

Cerebrovascular pathology and neuronal network dysfunction are early features of Alzheimers disease (AD) associated with neuroinflammation and cognitive decline, but the vascular and immune triggers of neuronal hyperactivity remain largely unknown. Here, we show that the blood coagulation protein fibrin disrupts microglia-neuron interactions, promoting neuronal hyperactivity in an AD mouse model. Genetic elimination of the fibrin inflammatory domain reduced neuronal hyperactivity, restored dynamic microglial interactions with active neurons and protected from high-risk decision making in 5XFAD mice. Leveraging the transcriptional signatures of microglia and inhibitory and excitatory neurons, a ligand-receptor atlas revealed fibrin-dependent disruption of innate immune and glutamatergic signaling between microglia and neurons in AD mice. Patients with AD also showed a correlation of cerebrospinal fluid (CSF) fibrinogen levels with biomarkers of inflammation, vascular and synaptic dysfunction. Thus, resilience to neuronal hyperactivity and restoration of the neuroimmune interactome by targeting fibrin may have therapeutic implications for Alzheimers disease and related conditions. There is a companion manuscript cited as Ref #62 submitted to bioRxiv (Lauderdale et al., 2026).

Summary Cerebrovascular pathology and neuronal network dysfunction are early features of Alzheimer’s disease (AD) associated with neuroinflammation and cognitive decline, but the vascular and immune triggers of neuronal hyperactivity remain largely unknown. Here, we show that the blood coagulation protein fibrin disrupts microglia-neuron interactions, promoting neuronal hyperactivity in an AD mouse model. Genetic elimination of the fibrin inflammatory domain reduced neuronal hyperactivity, restored dynamic microglial interactions with active neurons and protected from high-risk decision making in 5XFAD mice. Leveraging the transcriptional signatures of microglia and inhibitory and excitatory neurons, a ligand–receptor atlas revealed fibrin-dependent disruption of innate immune and glutamatergic signaling between microglia and neurons in AD mice. Patients with AD also showed a correlation of cerebrospinal fluid (CSF) fibrinogen levels with biomarkers of inflammation, vascular and synaptic dysfunction. Thus, resilience to neuronal hyperactivity and restoration of the neuroimmune interactome by targeting fibrin may have therapeutic implications for Alzheimer’s disease and related conditions. There is a companion manuscript submitted to bioRxiv (Lauderdale et al., 2026) Highlights Vascular-microglia axis drives neuronal hyperactivity Fibrin inflammatory activity disrupts the microglia-neuron interactome Microglia activation by fibrin impairs decision-making in AD mice Synaptic dysfunction and immune biomarkers correlate with CSF fibrinogen in AD patients

Plasma biomarkers have immense potential to transform dementia diagnosis globally, with phosphorylated tau 217 ( p -tau217) emerging as the most accurate AT(N) biomarker for diagnosis of Alzheimer's Disease (AD). Despite their promise, AT(N) biomarkers remain under-validated in genetically and environmentally diverse populations, including Latin America (LA), where genetic, lifestyle, and social exposomes add layers of complexity. Diagnostic challenges like disease heterogeneity, limited research infrastructure, and restricted access to diagnostic tools further complicate diagnosis. In LA, research on plasma AT(N) biomarkers is scarce, and no studies in the global south have comprehensively integrated p -tau217 with clinical or neuroanatomical correlates, leaving critical gaps in understanding its cognitive and brain-specific associations. Leveraging the ReDLat cohort, comprising participants from six diverse LA countries (Chile, Argentina, Colombia, Peru, Mexico, and Brazil), this study aims to validate plasma p -tau217 as a reliable biomarker for dementia diagnosis in AD and Frontotemporal Lobar Degeneration (FTLD). We hypothesize that p -tau217, combined with cognitive assessments and neuroanatomical correlates, will serve as a robust diagnostic tool for dementia in LA populations. A total of 600 participants (AD, FTLD, and healthy controls-HC) were enrolled from the ReDLat cohort. Plasma samples were collected in EDTA tubes, aliquoted, shipped on dry ice, and stored at -80°C. Plasma p -tau217 levels were quantified using the Lumipulse G600II system. Cognitive and neuroimaging data were used to evaluate associations with p -tau217. Machine learning algorithms integrating plasma biomarker, cognitive, and neuroimaging data were developed to generate classification models. p -tau217 levels were significantly elevated in both AD and FTLD groups compared to HC. Plasma p -tau217 demonstrated strong associations with cognitive domains, and its levels corresponded with structural and functional brain alterations. Machine learning models utilizing p -tau217 achieved high diagnostic accuracy, with performance further improved by integrating neuroimaging and cognitive data. This multimodal study highlights the clinical utility of p -tau217 as a blood-based biomarker for dementia diagnosis in underrepresented LA populations. By addressing the region's genetic, environmental, and socioeconomic diversity, these findings establish a foundation for equitable diagnostic approaches and pave the way for broader implementation of plasma biomarkers in dementia diagnosis across diverse LA populations.