Disentangling tau, glymphatic dysfunction and astrocytic activation in amyloid-positive Alzheimer's disease.

GLP-1 receptor agonist semaglutide ameliorates motor deficits and tau pathology in the rTg4510s mouse model.

Tauopathies are a group of neurodegenerative diseases characterized by tau accumulation, neuroinflammation, and synaptic dysfunction, yet effective treatments remain elusive. Protein Kinase CK2 has been previously associated with different aspects of tau pathology but genetic evidence for the contribution of CK2 to tauopathy remained lacking. Here, we show CK2α’, one of the two catalytic subunits of CK2, as a novel regulator of tau-mediated neurodegeneration. We found that CK2α’ expression is elevated in postmortem brains of dementia patients and in the hippocampus of PS19 tauopathy mice, especially in neurons and microglia. Using genetic haploinsufficiency in PS19 mice, we demonstrated that reduced CK2α’ levels significantly decrease phosphorylated tau and total tau burden in the hippocampus and cortex. CK2α’ depletion also attenuated microglial activation, pro-inflammatory cytokine production, and microglia synaptic engulfment, enhanced synaptic gene expression, synaptic density, and LTP. Importantly, CK2α’ depletion rescued cognitive deficits assessed in the Barnes maze. These effects appear to be mediated through both neuronal and glial functions and may involve CK2α’-dependent modulation of tau-associated phosphorylation and neuroinflammatory and immune signaling pathways.One Sentence summaryThis study highlights CK2α’ as a key node at the intersection of tau pathology, synaptic dysfunction, and neuroimmune signaling.

There are 14 modifiable factors that are associated with a significantly lower risk of dementia. We tested the interactive effect of modifiable factors, genetic determinants, and initial pathologic burden on the spatial progression and local amplification of tau pathology. Methods: In total, 162 amyloid-positive individuals were included, for whom longitudinal [18F]AV-1451 PET scans, baseline information on global amyloid burden, ApoE4 status, body mass index (BMI), hypertension, education, neuropsychiatric symptom severity, and demographic information were available in the Alzheimer Disease Neuroimaging Initiative. All [18F]AV-1451 scans were intensity-standardized (reference: inferior cerebellum), z-transformed (control sample: 147 amyloid-negative subjects), thresholded (z score, >1.96), and converted to volume maps. Longitudinal tau changes were then assessed in terms of tau spatial extent (i.e., newly affected volume at follow-up) and tau level rise (i.e., tau increase in previously affected volume). These 2 measures were entered as dependent variables in linear mixed-effects models, including baseline modifiable risk factors (BMI, education, hypertension, neuropsychiatric symptom severity), global amyloid, tau volume or tau burden, ApoE4 status, clinical stage, sex, and age as predictors. Next, we tested the interactive effects between baseline amyloid or tau burden with the 4 modifiable factors on tau extent or tau level rise, respectively. Results: Greater tau extent was linked to higher BMI (β = 0.002; 95% CI, 0.0003-0.003), ApoE4 status (β = 0.024; 95% CI, 0.001-0.046), and baseline tau volume (β = 0.207; 95% CI, 0.107-0.308) across groups. In terms of tau level rise, we observed that absence of hypertension (β = 0.295; 95% CI, -0.477 to -0.114), dementia group (β = 0.305; 95% CI, 0.088-0.522), and BMI (β = 0.011; 95% CI, 0.00004-0.022) were linked to increased tau burden. A load-dependent effect of baseline amyloid and tau volume/burden was found for both tau extent (β = -0.005; 95% CI, -0.008 to -0.002) and tau level rise (β = -0.003; 95% CI, -0.005 to -0.001). Higher amyloid and BMI (β = 0.001; 95% CI, 0.0004-0.001) and lower education and higher tau burden (β = -0.035; 95% CI, -0.064 to -0.006) were linked to greater tau level rise. Conclusion: Education, BMI, and hypertension differentially influence tau's spatial extent and increase by its interaction with initial pathologic burden. Timely modification of these factors may overall slow tau progression.

BackgroundGlial responses are involved in neurodegenerative processes, with tau pathology often associated with increased glial inflammatory responses in Alzheimer’s disease (AD). The apolipoprotein E (APOE) ε4 allele, the major genetic susceptibility gene for AD, might contribute to this process by modulating both tau pathology and inflammatory cascades in the brain.MethodsWe used data from the Translational Biomarkers of Alzheimer’s Disease (TRIAD) cohort (n = 137) to investigate the association between YKL-40, a marker of reactive astrogliosis, and tau burden measured with PET imaging, while also exploring the involvement of APOE ε4 carriership. Statistical analyses included correlation and regression models controlling for age and sex.ResultsHere we show that tau pathology is positively associated with YKL-40 levels, reflecting regional patterns of astrocyte activity in the brain. Furthermore, this association is more widespread in individuals carrying the APOE ε4 allele, suggesting a genotype-specific modulation of the glial neuroinflammatory response.ConclusionsOur findings demonstrate a link between tau accumulation and astrocyte-mediated neuroinflammation in AD and highlight the modulatory role of APOE ε4 in this process. Taken together, our findings help inform the multifaceted role of tau-associated neuroinflammation in the progression of AD.

Fibrillar tau is a defining hallmark of Alzheimer's disease, gradually accumulating and spreading throughout the brain. The synapse plays a key role in this process-both by facilitating the spread of tau between neurons and by serving as a direct target of tau-induced neurotoxicity. However, few studies in humans have explored synaptic density both as a facilitating factor and as a target of tau pathology. In this dual PET tracer study, we used 18F-SynVesT-1 synaptic vesicle glycoprotein 2A (SV2A) PET to assess synaptic density and 18F-MK6240 tau-PET to assess fibrillar tau in 59 amyloid-PET-positive patients and 25 amyloid-PET-negative cognitively normal individuals from the Chinese Preclinical Alzheimer's Disease Study (CPAS). Spatial correlation analyses revealed that brain regions with higher SV2A tracer uptake in cognitively normal individuals exhibited higher 18F-MK6240 uptake in Alzheimer's disease. These findings were independently replicated in the Alzheimer's Disease Neuroimaging Initiative (ADNI), where normal SV2A-PET maps from CPAS were correlated with tau-PET data from 372 Aβ+ participants, including longitudinal follow-up in 204 cases. In both cohorts, regions with higher normal synaptic density showed greater tau burden, and in ADNI, higher synaptic density in normal brain also predicted faster tau accumulation over time. Gene-set enrichment analyses of transcriptomic data mapped onto regional tau-PET uptake further showed that areas of high 18F-MK6240 uptake were enriched in genes encoding synapse-related proteins. Together, these findings suggest that synapse-rich regions are especially prone to tau accumulation. We also investigated the downstream impact of tau on synaptic integrity. Notably, regions with higher 18F-MK6240 uptake showed reduced SV2A tracer uptake, indicating synaptic loss, not only in the same regions but also in areas connected to those with high tau. Stronger loss of SV2A tracer uptake was observed in the regions with stronger resting-state functional connectivity to epicenters of high 18F-MK6240 uptake in the Alzheimer's disease group. The connectivity-dependent synaptic loss could not be fully explained by tau levels in the connected target regions but was found to be partially mediated by them. These findings suggest that tau pathology contributes to synaptic loss both locally and in distant, connected brain regions. Overall, our results highlight the central importance of the synapse in Alzheimer's disease: synapses appear to both facilitate fibrillar tau accumulation and become impaired through its toxic effects. Understanding the synapse's role in tau pathology may open new avenues for therapeutic interventions aimed at slowing down tau progression and neurodegeneration.

A 2-min digital clock-drawing test (DCTclock) captures more granular features of the clock-drawing process than the pencil-and-paper clock-drawing test, revealing more subtle deficits at the preclinical stage of Alzheimer's disease (AD). A previous cross-sectional study demonstrated that worse DCTclock performance was associated with higher Aβ and tau burden in older cognitively normal (CN) participants. This study investigates whether longitudinal changes in DCTclock performance are associated with amyloid-β (Aβ) and tau burden in preclinical AD. A total of 219 CN participants completed baseline and follow-up DCTclock assessments, baseline Aβ ([11C]PiB) and tau ([18F]Flortaucipir) PET imaging. Global Aβ and regional tau burden were estimated. Linear mixed models examined associations between longitudinal DCTclock and (1) Aβ, (2) tau, and (3) Aβ and tau burden, adjusted for age, sex, and education. Cognitive domain-specific performance and fine-grained features of DCTclock were analyzed. Elevated baseline Aβ or tau was most strongly associated with accelerated decline in DCTclock performance, particularly in the Information Processing cognitive domain, with stronger associations noted for tau burden. The associations were driven by pen-stroke latency-related features. Participants without elevated Aβ or tau burden demonstrated improved performance in these latency features, suggesting practice effects. Longitudinal declines in DCTclock performance, especially in Information Processing involving speed and executive function, were linked to early Aβ and tau burden in preclinical AD. These findings highlight the potential of digital cognitive assessment tools for tracking disease progression and assessing therapeutic efficacy in clinical trials.

INTRODUCTIONHigher cognitive reserve (CR) is associated with reduced dementia risk. We hypothesized that higher CR is associated with less baseline Alzheimer's disease (AD) pathology in the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort.METHODSA subsample of participants underwent amyloid beta and tau positron emission tomography imaging. Regression analysis was used to model the association between educational attainment (EA) as a CR proxy measure, amyloid positivity, and entorhinal cortex (ERC) and meta‐temporal region of interest (meta‐ROI) tau standardized uptake value ratio (SUVR).RESULTSIn 911 participants with complete imaging data, higher CR was significantly associated with lower ERC tau SUVR. CR was not associated with amyloid status or meta‐ROI tau.DISCUSSIONIn the U.S. POINTER cohort, higher EA predicted lower tau burden in the ERC. Meta‐ROI tau levels may be too low in this cognitively unimpaired sample to reveal associations. CR may have a role in promoting biological resistance to AD pathology.HighlightsHigher cognitive reserve is associated with a lower dementia risk and better cognitive performance after a diagnosis of Alzheimer's disease.The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk trial imaging cohort was cognitively unimpaired at baseline and a subsample received amyloid and tau positron emission tomography scans.Higher educational attainment, a proxy measure of cognitive reserve, was significantly related to tau levels in the entorhinal cortex region of interest.

INTRODUCTIONTau PET informs Alzheimer's disease (AD) staging but is limited by cost and access. Plasma phosphorylated‐to‐nonphosphorylated tau217 ratio (pTau217R) predicts amyloid and tau positron emission tomography (PET), while cerebrospinal fluid (CSF) MTBR‐tau243 (tryptic form) and its endogenous form (eMTBR‐tau243) reflect tau pathology. We evaluated whether combining them improves tau PET prediction in amyloid‐positive early AD.METHODSIn the phase III lecanemab trial, plasma pTau217R was available for 242 participants, CSF markers for 80, and both for 57. Tau PET used [18F]MK6240. Stochastic gradient boosting models included demographics and apolipoprotein E (APOE) ε4, with performance assessed via repeated cross‐validation.RESULTSPlasma pTau217R matched CSF eMTBR‐tau243 and outperformed MTBR‐tau243. Combining pTau217R with either CSF marker improved prediction (R2 to 0.74; AUROC to 0.94) and could reduce PET use by 58%–80% for prescreening at 10% false negatives.DISCUSSIONPlasma pTau217R plus CSF eMTBR‐tau243 predict regional tau burden and may reduce reliance on tau PET in early AD trials.CLINICALTRIALS.GOV IDENTIFIERSNCT03887455 (ClarityAD)HighlightsCombining plasma pTau217R and CSF eMTBR‑tau243 improves tau PET prediction.The model predicts regional tau PET SUVRs with high accuracy across key regions.Single‐marker models show pTau217R and eMTBR‐tau243 outperform MTBR‐tau243.PET‑sparing triage reduces scan burden by up to 80% at 10% false negatives.Stochastic gradient boosting enables region‐specific tau PET prediction in one unified model.

Background/Objectives: Alzheimer’s disease (AD) exhibits clinical and biological variability. This study aimed to identify MRI-defined subtypes reflecting distinct biological pathways of neurodegeneration and cognitive decline. Methods: We applied principal component analysis followed by k-means clustering (k = 3) on volumetric MRI data from 924 participants and validated clusters using cerebrospinal fluid (CSF) biomarkers (Aβ42, total tau, p-tau, CTRED, MAPres, glucose, CTWHITE). Results: Three major phenotypes emerged: (1) a tau/vascular limbic subtype with pronounced hippocampal and amygdala atrophy and elevated tau and CTRED levels; (2) a volume-preserved, low-amyloid subtype consistent with early-stage or cognitively resilient AD; and (3) a diffuse-atrophy subtype with high amyloid and tau burden and ventriculomegaly. Comparative analysis revealed progressive biological shifts from amyloid accumulation to tau aggregation and vascular compromise across these clusters. Conclusions: MRI-based clustering validated by CSF biomarkers delineates biologically meaningful AD endophenotypes. The results suggest a gradual cognitive decline driven by amyloid–tau–vascular interactions, supporting multimodal phenotyping as a practical approach for precision staging and intervention.

BackgroundAntemortem plasma and structural MRI biomarkers of Alzheimer’s disease (AD) are increasingly utilized for diagnosis and prognosis but their ability to predict regional tau burden remains relatively unexplored. We aimed to evaluate predictive models based on antemortem AD plasma and structural MRI for prediction of regional tau pathology in postmortem brain tissue.MethodsAutopsy data from 62 participants in the Mayo Clinic Study of Aging (MCSA) were analyzed (mean age of 84.6 years; 32% female; 1.4 years of mean time of last plasma draw to death). Tau pathology in the hippocampus and parietal cortex was quantified using two immunohistochemical markers: AT8, an early tangle maturity marker, and 2E9, an advanced tangle maturity marker. Three antemortem plasma markers including phosphorylated tau protein at threonine 181 (p-tau181), total amyloid-β (Aβ) 42 relative to Aβ40 ratio (Aβ42/40), and glial fibrillary acidic protein (GFAP) and three regional structural MRI markers including the hippocampus volume adjusted for total intracranial volume (HVA), parietal thickness (PTH) and parietal volume divided by total intracranial volume (PVTIV) were utilized as predictors. Weighted linear regression models using weights based on time from last plasma draw to death were adjusted for age, sex and cardiovascular and metabolic conditions (CMC) score for patients. We report estimated adjusted R2 and partial R2 for predicting postmortem tau pathology in the hippocampus and parietal cortex stained by AT8 and 2E9.ResultsMRI models (adjusted R2 of 0.28–0.66) showed better performance at predicting tau pathology than plasma models (adjusted R2 of 0.19–0.36). The highest adjusted R2 was 0.66 for predicting hippocampal 2E9 using HVA, followed by an adjusted R2 of 0.6 for hippocampal AT8. Predictions for parietal AT8 and 2E9 were lower with an adjusted R2 of 0.28–0.29 based on MRI biomarkers and 0.24–0.36 based on plasma biomarkers. The adjusted R2 values for both regions were higher for AT8 compared to 2E9 prediction for plasma biomarker models.ConclusionsOur study demonstrates the greater sensitivity of regional MRI to tau pathology in comparison to plasma biomarkers. Future studies should explore newer MRI methods and additional plasma biomarkers more specific to tau pathology such as microtubule binding region for prediction of antemortem tau pathology.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13195-025-01852-1.

A significant body of evidence suggests that mitochondrial dysfunction plays a key role in the development and progression of Alzheimer’s disease (AD). However, the absence of peripheral biomarkers for mitochondrial dysfunction limits its clinical applicability. Mitochondrial DNA (mtDNA) copy number, a proxy for mitochondrial function, has shown promise in detecting early stages of AD and predicting AD risk in cerebrospinal fluid (CSF) and blood, respectively. Surprisingly, recent studies have identified mtDNA molecules in human saliva, but their relationship with AD remains unexplored. Here, we investigated potential associations between salivary mtDNA copy number and cortical amyloid-β (Aβ) load measured with PET, and blood AD markers measured with ultrasensitive single molecule array (SIMOA) assays, in cognitively normal older adults. We found that salivary mtDNA copy number was positively correlated with cortical Aβ burden and plasma levels of tau phosphorylated at threonine 181 (pTau-181), and negatively correlated with general cognitive ability. It is worth noting that salivary mtDNA was not significantly associated with other blood-based AD biomarkers, including Aβ1-40, Aβ1-42, neurofilament-light chain (NfL), or glial fibrillary acidic protein (GFAP). Additionally, plasma pTau-181 levels moderated the association between salivary mtDNA and Aβ accumulation in the inferior temporal lobe, while Aβ load in the occipital cortex mediated the association between plasma pTau-181 and salivary mtDNA. Together, these findings represent the first evidence linking salivary mtDNA to well-established AD biomarkers in normal aging, suggesting that salivary mtDNA may serve as a potential non-invasive biomarker for identifying individuals at risk for developing AD in the general population.

Developing human neurons express abundant tau yet show little toxicity, suggesting built-in mechanisms that restrain tau when protein clearance falters. We combined human tissue analyses with cell-based perturbation assays to define this response. In iPSC-derived forebrain neurons, brief proteasome blockade with epoxomicin (0.25 μM, 24 h; n=3/condition) triggered a coordinated transcriptomic program: hierarchical clustering of RNA-seq data resolved two opposing modules—an up-regulated proteostasis module (ubiquitin-proteasome, autophagy-lysosome, chaperone-mediated folding) and a down-regulated MAPT-linked neuronal/energetic module (microtubule/organization/transport, synaptic signaling, oxidative phosphorylation). MAPT transcripts decreased by both PCR and RNA sequencing in proteasome but not-autophagy impaired neurons even though tau protein levels decreased in both. Expressing tau from a constitutive promoter bypassed this transcriptional brake and increased tau during proteasome inhibition. Qualitative confocal imaging of human cortex (fetal, adult control, and Alzheimer’s disease) showed tau locally nested within proteasome-positive regions with partial overlap with lysosomes, consistent with increased quality-control engagement when tau burden is high. To nominate regulators coupling proteostatic stress to MAPT repression, we integrated promoter motif enrichment (HOMER), transcription-factor enrichment from curated libraries (ChEA3; MeanRank on up/downregulated sets), and JASPAR scanning of the MAPT promoter. A consensus highlighted E2F1, EVT1, Lhx1, and TCF3 among top candidates for MAPT regulation. Together, these data support a proteostasis-first adaption in which neurons activate quality-control programs while transcriptionally reducing MAPT and allied neuronal demands, offering transcription-factor targets and a framework for modulating tau homeostasis relevant to Alzheimer’s disease and related tauopathies.

Evaluating the link between hearing loss and Alzheimer's disease neuropathology: A systematic review and meta-analysis.

Relationships between neuronal loss, age of death, disease duration and MRI brain volumes in progressive supranuclear palsy.

Extracellular Tau determines the progression of Alzheimer's disease, yet therapeutic strategies targeting it are hindered by poor brain delivery and limited clearance. Here we developed a Tau-clearing cell therapy based on monocytes functionalized with a high-affinity Tau-specific aptamer. The aptamer was covalently conjugated to the surface of monocytes (derived from bone marrow leucocytes and cultured under monocyte-inducing conditions) via bioorthogonal chemistry without affecting their viability or function. Upon intravenous administration in mice expressing mutant and disease-relevant human Tau, the engineered monocytes actively crossed the blood-brain barrier and accumulated in Tau-rich brain regions such as the hippocampus and striatum. They efficiently phagocytosed extracellular Tau, leading to a significant reduction in Tau burden. As a result, glial activation was suppressed, neuroinflammation was alleviated, and neuronal and mitochondrial integrity was preserved. Long-term treatment improved memory and spatial learning, without inducing toxicity or behavioural side effects. These results demonstrate that aptamer-guided monocytes can achieve targeted delivery, effective clearance and sustained neuroprotection, offering a promising strategy for therapeutic intervention in Alzheimer's disease.

Growing evidence suggests that hippocampal gray matter microstructure, assessed through diffusion-weighted imaging (DWI), is a sensitive marker of neurodegeneration in Alzheimer's disease (AD). While hippocampal atrophy is a characteristic feature of AD, microstructural changes likely precede macrostructural changes such as volumetric loss, offering important insights into the early phases of the disease. This study assessed the relationships between hippocampal microstructure (assessed with mean diffusivity [MD] from DWI) and Braak-staged tau burden (measured by positron emission tomography [PET]) with performance on an episodic memory composite score, among individuals with and without amyloid burden, assessed by PET imaging. The study included 192 participants without dementia (14 with mild cognitive impairment [MCI]) from the BIOCARD cohort (mean age = 68), of which 52 (27%) were amyloid positive. In multiple linear regression analyses, increased hippocampal MD was associated with worse memory and greater tau PET burden in Braak stages II-IV, but only in individuals who were amyloid positive (e.g., significant amyloid × hippocampal MD interactions). Building on prior findings linking early Braak-staged tau to memory, we further assessed whether tau PET burden statistically mediated the relationship between elevated hippocampal MD and poorer memory performance. Tau PET burden in Braak stages II-IV was found to statistically mediate the relationship between elevated hippocampal MD and poorer memory performance, independent of hippocampal volume, but only in amyloid-positive participants. These associations were only significant when MCI participants were included in the analysis. These findings suggest hippocampal microstructure may be sensitive to AD-related pathological burden and associated neurodegeneration, particularly in the early symptomatic phase, and is associated with tau PET and cognitive decline, even after accounting for hippocampal volume.

Background and ObjectivesTau accumulation pattern shows substantial variability in Alzheimer disease (AD), and 4 distinct spatiotemporal trajectories were distinguished using a data-driven approach called the Subtype and Stage Inference (SuStaIn). A visual method to validate and identify these subtypes is a requirement for their clinical translation. Our study aimed to provide a standardized topographic method for identifying tau patterns visually using tau-PET in a clinical setting.MethodsParticipants in this prospective study were included from the memory clinic of Geneva University Hospital. Inclusion criteria required participants to have undergone at least 1 18F-Flortaucipir tau-PET scan and a Mini-Mental State Examination (MMSE) within a 1-year time frame. All scans were classified into different tau subtypes (limbic [S1], medial temporal lobe-sparing [S2], posterior [S3], and lateral temporal [S4]) using both visual rating and SuStain algorithm. A subgroup underwent amyloid-PET and clinical follow-up. Cohen's κ tested the agreement between raters and between visual and automated subtypes. Chi-squared and Kruskal-Wallis tests assessed differences in clinical and biomarker features between subtypes, whereas differences in cognitive trajectories were tested using linear mixed-effects models, controlling for age, sex, and clinical and tau stages.ResultsA total of 245 tau-PET scans of individuals ranging from cognitively unimpaired to mild dementia (mean age: 68.25 years, 52% women) were included and classified into different tau pattern subtypes. A substantial agreement between raters was found in visually interpreting tau subtypes (κ > 0.65, p < 0.001) and a fair agreement between visual and automated subtypes (κ = 0.39, p < 0.001), with the automated approach more likely to classify a scan as tau negative and lower agreement between methods in more severe cases and AD clinical variants. Regarding the visual classification, individuals with S2 subtype were younger than S1 and S3, had lower MMSE and verbal fluency scores than S4 and S1, showed higher global tau burden than other subtypes, and a steeper cognitive decline.DiscussionVisual classification reliably identified 4 tau patterns that differ in global tau load, clinical features, and long-term outcomes, suggesting its clinical usefulness for the detection of higher-risk AD variants. A clinically implementable classification of subtypes with faster decline is paramount for personalized diagnosis, accurate prognosis, and treatment.

Genetic variations in the microtubule-associated protein tau (MAPT) gene play a central role in Alzheimer's disease (AD) pathogenesis. Two major MAPT haplotypes, H1 and H2, show differential associations with tau expression and AD risk. However, data from Middle Eastern populations remain limited, restricting our understanding of population-specific disease susceptibility patterns and therapeutic responses. We conducted a comprehensive literature review using PubMed, Scopus, and Web of Science databases. Search terms included "MAPT haplotype," "Alzheimer's disease," "H1 H2," "tau pathology," and "pharmacogenetics." We analyzed peer-reviewed articles published between 2000 and 2024, focusing on studies reporting haplotype frequencies, MAPT expression levels, APOE interactions, and clinical outcomes. This review synthesizes published data without generating new experimental results. The H1 haplotype consistently associates with increased MAPT expression, tau accumulation, and elevated AD risk, particularly in APOE ε4 noncarriers. Conversely, the H2 haplotype appears protective, correlating with reduced tau burden and slower cognitive decline. Notably, recent reports reveal significant overrepresentation of the H2 haplotype in the Jordanian population compared to European and East Asian cohorts, where H2 frequency is substantially lower or absent. This distinct genetic architecture suggests altered regional AD risk profiles. The elevated H2 frequency in Jordan represents a unique population-specific genetic signature that may influence regional AD susceptibility patterns. These findings challenge current risk models predominantly based on European populations and suggest the need for populationtailored approaches in neurodegenerative disease research. The naturally H2-enriched Jordanian cohort provides an exceptional opportunity to investigate protective mechanisms against tau pathology. MAPT haplotype distributions show significant population variation with important implications for AD risk assessment and therapeutic targeting. The high H2 frequency in Jordan warrants integration into personalized medicine frameworks and population-specific disease models, potentially informing more effective regional prevention and treatment strategies.

Background:Progressive supranuclear palsy (PSP) is typically characterized by vertical supranuclear gaze palsy and early falls, referred to as Richardson’s syndrome (PSP-RS). Other presentations include postural instability (PSP-PI), parkinsonism (PSP-P), speech/language disorder (PSP-SL), frontal presentation (PSP-F), ocular motor dysfunction (PSP-OM), and corticobasal syndrome (PSP-CBS). Differences across the early presentations and in their subsequent progression have yet to be elucidated.Objective:This study aimed to characterize early PSP subtypes and their subsequent progressions using a large postmortem dataset.Methods:An automated pipeline incorporating fine-tuned Chat Generative Pre-trained Transformer (ChatGPT) was developed. The pipeline collected 195 clinical features with onset information from autopsy-confirmed PSP cases without significant neurodegenerative co-pathologies.Results:A structured clinicopathologic dataset from 588 patients was analyzed. After distilling results with unsupervised clustering, a decision tree model was developed. With five clinical manifestations: frontal presentation, postural instability, ocular motor dysfunction, speech/language disorder, and parkinsonism, this mutually exclusive algorithm identified seven subtypes: PSP-PF (postural and frontal dysfunction), PSP-RS, PSP-PI, PSP-P, PSP-SL, PSP-F, and PSP-OM. PSP-PF showed rapid progression, the shortest median disease duration (six years), and high tau burden in cortical and subcortical regions. In PSP-F, frontal presentation preceded other symptoms by four years, with a nine-year disease duration—second longest after PSP-P (10 years). PSP-CBS was not identified as an independent subtype.Conclusions:This data-driven study identified a novel, aggressive PSP phenotype characterized by early postural and frontal dysfunction. Early subtyping utilizing the decision tree model would help clinicians estimate progression and facilitate early patient recruitment for clinical trials.