OBJECTIVE:Recent studies suggest that combining plasma phosphorylated tau (p-tau) with β-amyloid (Aβ) may improve diagnosis accuracy for Alzheimer's disease (AD). However, the cross-sectional and longitudinal concordance of these markers with Aβ positron emission tomography (PET) positivity remains incompletely understood. This study aimed to evaluate the diagnostic performance of plasma p-tau, alone and in combination with plasma Aβ, in AD. METHODS:We included 326 participants from the Alzheimer's Disease Neuroimaging Initiative and 357 Chinese older adults from the Greater-Bay-Area Healthy Aging Brain Study who underwent Aβ-PET imaging. Longitudinal data were available for 285 Alzheimer's Disease Neuroimaging Initiative participants. Plasma p-tau181, p-tau217, Aβ42, and Aβ40 were measured on different analytical platforms. Diagnostic performance for Aβ-PET positivity was assessed using a two-cutoff approach. RESULTS:Combining plasma p-tau with Aβ42 or the Aβ42/40 ratio reduced the intermediate zone. Notably, p-tau217/Aβ42 showed stronger agreement with Aβ-PET positivity than p-tau217 alone. Among individuals classified as p-tau217/Aβ42 positive but p-tau217 intermediate, 57.1 to 83.3% were Aβ-PET positive. Longitudinally, most Stable Positive (88.0-96.1%) and Stable Negative (89.4-90.9%) cases defined by p-tau217 or p-tau217/Aβ42 were Aβ-PET positive and Aβ-PET negative, respectively. Critically, 69.7 to 75.8% of Non-positive to Positive cases defined by p-tau217/Aβ42 were Aβ-PET positive. INTERPRETATION:These findings provide novel insights into the cross-sectional and longitudinal diagnostic performance of plasma p-tau217/Aβ42 in AD. To be specific, plasma p-tau217/Aβ42 can reduce the intermediate zone and improve agreement with Aβ-PET positivity, and longitudinal p-tau217/Aβ42 monitoring is particularly informative for identifying Aβ-PET-positive patients who were p-tau217/Aβ42 negative or intermediate at baseline and were misclassified as low risk of AD. ANN NEUROL 2026.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory loss, and behavioral disturbances, eventually leading to dementia and severely diminishing quality of life. With the global population aging, AD has become an unprecedented challenge for society and families. Recent advances in the development of amyloid-beta (Aβ)-targeting monoclonal anti-bodies, like lecanemab and donanemab, provided hope for slowing or even halting disease progression. However, these treatments have not yet achieved the ultimate goal of reversing cognitive deterioration and restoring normal function. The complexity of AD stems from multiple contributing factors, with Aβ deposition and tau protein tangles being central to its pathology, while genetic predispositions, aging, and systemic factors further drive disease progression. Addressing AD by targeting a single factor has proven insufficient, highlighting the need for a comprehensive understanding of its multifaceted mechanisms. This review explores the latest advances in AD mechanistic research and therapeutic development, focusing on key areas such as amyloid precursor protein (APP) metabolism, Aβ dynamics, Aβ antibody immunotherapy, tau protein dysfunction, genetic influences, aging mechanisms, and systemic factors. By critically examining these aspects, we aim to provide insights that support more holistic approaches to AD diagnosis and treatment, ultimately laying the groundwork for innovative strategies to combat this debilitating disease.

The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD) and exacerbates AD-related pathologies. Identifying strategies to mitigate the pathogenic effects of APOE4 remains a critical challenge in the field of AD research. The rare APOE3 Christchurch (APOE3Ch) variant has been suggested to be potentially protective against AD. Our study investigated whether hepatic expression of APOE3Ch could mitigate APOE4-associated AD pathologies. We successfully delivered APOE3Ch or APOE3 into the liver by adeno-associated virus in APP/PS1 mice expressing human APOE4. We observed that hepatic APOE3Ch delivery reduced amyloid-β (Aβ) burden in the brain. Hepatic APOE3Ch expression attenuated neuroinflammation, neurodegeneration, and cognitive impairments. Mechanistically, APOE3Ch expression increased the capacity of Aβ clearance by monocytes and hepatocytes. Our findings demonstrate that hepatic APOE3Ch expression attenuates AD-type pathologies in APOE4-expressing APP/PS1 mice, highlighting liver-directed APOE3Ch gene transfer as a promising therapeutic strategy for APOE4-associated AD.

Alzheimer’s disease (AD) is characterized histologically by amyloid-β (Aβ) deposition in the brain. Immunotherapies targeting Aβ clearance have become a leading treatment strategy. Although these therapies effectively reduce cerebral Aβ burden, their cognitive benefits remain modest during the trial period. This review systematically assesses the extent of Aβ clearance by immunotherapies and its related cognitive outcomes, focusing on whether cognitive benefits increase over time. We refine a model of the “lag effect” between plaque clearance and cognitive benefit, which is potentially influenced by clearance rate, treatment duration, disease stage, genetic factors, and aging. We also discuss the underlying biological mechanisms and potential neuroprotective targets. Future research should prioritize long-term studies, early intervention, personalized therapies, and combination approaches addressing multiple pathological pathways. Given limited short-term cognitive gains, optimizing outcomes will require tailoring treatments to individual patient factors—including genetics, disease progression, and aging—to minimize side effects and enhance long-term cognitive function.

Circulating brain-derived extracellular vesicles (BDEVs) have emerged as promising biomarkers for neurodegenerative diseases, including Alzheimer’s disease (AD). However, it remains unclear to what extent extracellular vesicles (EVs) proteomes reflect the molecular states and disease-associated alterations of their parent brain cell types. Here, using a multi-line human induced pluripotent stem cell (hiPSC) platform derived from three AD and three cognitively normal (CN) donors, we generated neurons, astrocytes, microglia, and oligodendrocytes, and performed paired proteomic profiling of each cell type and its secreted EVs. We systematically compared protein profiles to evaluate cell-EV similarity, disease-associated features, and concordance with proteomic datasets from human AD brain tissue. Across all four lineages, EV proteomes showed extensive overlap with parent cells (>97

REM sleep constitutes a critical window for memory consolidation, yet the brain circuits orchestrating this process remain incompletely defined. Here, we identify a lateral supramammillary nucleus (SuM)-medial septum (MS) projection as a REM sleep-specialized pathway essential for hippocampal memory consolidation. Fiber photometry and optrode recordings revealed that lateral SuM-MS projecting neurons were selectively active during REM sleep. REM-specific optogenetic silencing of this projection impaired consolidation of both social and contextual fear memories. Crucially, silencing of its downstream target, the MS-CA2 pathway, during REM sleep selectively disrupted social memory while sparing contextual fear memory. This functional dissection establishes a hypothalamo-septo-hippocampal circuit (lateral SuM-MS-CA2) dedicated to social memory processing, in parallel to the recently-described direct SuM-CA2 pathway. These results also position the SuM as a REM sleep-hub that routes information via parallel septal pathways to consolidate distinct memory modalities.

INTRODUCTION:Longitudinal diagnostic and prognostic validity of plasma phosphorylated tau217 (p-tau217) in Alzheimer's disease (AD) remains uncertain. METHODS:In this multi-cohort study of 2117 individuals, we established baseline plasma p-tau217 thresholds for amyloid-β-positron emission tomography (Aβ-PET) and assessed their longitudinal classification stability and prognostic relevance for AD-related outcomes. RESULTS:Baseline-defined cutoffs achieved high and sustained accuracy (86%-95%) for Aβ-PET positivity over up to 5 years of follow-up. Longitudinally, most p-tau217-positive individuals remained stable (93%-98%), whereas the intermediate zone group progressed more to positive (44%-78%) than p-tau217-negative individuals (4%-21%). Participants with stable-positive and progress-to-positive p-tau217 profiles more frequently exhibited Aβ abnormalities (90%-100% and 64%-96%, respectively) and experienced accelerated tau accumulation, hippocampal atrophy, and incident dementia compared to those with a stable-negative p-tau217 profile. DISCUSSION:These findings support the high stability and Aβ-PET classification performance of longitudinal plasma p-tau217 monitoring in AD, providing a scalable tool for risk stratification and disease monitoring.

Background Immunological dysregulation is a hallmark of Alzheimer's disease (AD), a neurodegenerative disorder characterized by amyloid-β (Aβ) plaque accumulation and hyperphosphorylated Tau protein pathology. AD is associated with altered humoral immunity, which may play a role in its pathogenesis. Objective This study aimed to investigate alterations in plasma levels of B lymphocyte-associated cytokines and their clinical relevance in AD. Methods We performed quantitative detections of 13 cytokines associated with B lymphocytes (TNF-β, IL-13, IFN-γ, TNF-α, IL-2, BAFF, IL-6, CD40L, IL-10, IL-12p70, IL-4, IL-17A, and IL-7) in plasma and analyzed their associations with cognitive functions and biomarkers of AD. Results We found that plasma levels of CD40L, BAFF, TNF-β, IL-6 and IL-17A were increased in AD patients. However, the plasma IL-10 concentrations were decreased in Aβ-PET + subjects. Plasma levels of CD40L, BAFF, TNF-β, IL-6, IL-17A were negatively associated with the plasma Aβ 42/40 ratio. Plasma levels of IL-10 were negatively associated with pTau181. Plasma levels of BAFF were negatively associated with MMSE scores. Conclusions These findings demonstrate an altered B lymphocyte-associated cytokine secretion profile in AD patients, which correlates with the clinical severity and biomarkers of the disease.

Both Apolipoprotein E-ε4 (APOE-ε4) and astrocytic activation, as measured by glial fibrillary acidic protein (GFAP), play critical roles in Alzheimer's disease (AD). However, the influence of astrocytic activation on the relationship between APOE-ε4 and AD pathologies remains unclear. This study investigates the interrelationships among astrocytic activation, APOE-ε4, and AD pathophysiology in 529 participants who underwent plasma biomarker measurements, APOE genotyping, and cognitive testing. Additionally, 277, 284, and 104 underwent structural magnetic resonance imaging (MRI), amyloid-β (Aβ) positron emission tomography (PET), and tau PET, respectively. The associations of plasma GFAP, APOE-ε4, and AD-related biomarkers, as well as whether plasma GFAP mediates APOE-ε4-related effects on AD, were investigated. Higher plasma GFAP and APOE-ε4 were independently associated with more severe Aβ and tau aggregation, as well as cognitive decline. Mediation analyses showed a significant indirect effect of APOE-ε4 on plasma p-tau biomarkers (21.1%-24.9%), Aβ PET (16.4%), and cognition (19.6%), while the indirect effect on tau PET was trend-level (29.1%, pFDR = 0.051). These findings highlight the central role of astrocytic activation in AD pathogenesis and underscore plasma GFAP as a promising biomarker for risk stratification and therapeutic targeting.

BACKGROUND:Secondary platelet activation peaks ≈2 hours after intravenous thrombolysis with alteplase. This study evaluated the safety and efficacy of ultra-early tirofiban administration and compared different tirofiban regimens following intravenous thrombolysis in patients with noncardioembolic acute ischemic stroke. METHODS:This observational study enrolled patients with acute ischemic stroke who received tirofiban within 24 hours following intravenous thrombolysis. Patients were divided into ultra-early (within 2 hours) and early (2-24 hours) groups based on tirofiban initiation time. A secondary analysis was performed based on whether the tirofiban regimen included a bolus dose. The primary outcome was 90-day excellent functional outcome (modified Rankin Scale score 0-1). The safety outcomes included symptomatic intracranial hemorrhage, intracranial hemorrhage, and 3-month all-cause mortality. RESULTS:A total of 472 patients were enrolled, with 214 in the ultra-early tirofiban group and 258 in the early tirofiban group. The ultra-early tirofiban group was associated with 3-month excellent functional outcomes (67.5% versus 53.3%; adjusted odds ratio [aOR], 1.56 [95% CI, 1.01-2.42]). There were no significant differences in intracranial hemorrhage (3.7% versus 1.6%; P=0.18), symptomatic intracranial hemorrhage (0.5% versus 0.4%; P=0.99), or 3-month mortality (1.5% versus 2.5%; P=0.94). Propensity score matching analyses showed consistent outcomes. No significant differences in excellent functional outcomes (61.4% versus 71.0%; aOR, 0.68 [95% CI, 0.36-1.30]) or symptomatic intracranial hemorrhage (0.4% versus 0%; P=0.99) were observed between bolus and maintained groups for prophylactic tirofiban after intravenous thrombolysis. CONCLUSIONS:Ultra-early tirofiban administration following recombinant tissue plasminogen activator was associated with excellent functional outcomes without increasing the risk of symptomatic intracranial hemorrhage, intracranial hemorrhage, or mortality. The extra bolus dose did not show superiority over only maintained dose administration.

The meningeal lymphatic system has recently emerged as a critical regulator of brain homeostasis, facilitating cerebrospinal fluid drainage, metabolic waste clearance, and immune cell trafficking. Accumulating evidence now implicates meningeal lymphatic dysfunction as a pivotal contributor to the pathogenesis of Alzheimer’s disease (AD). This review critically evaluates current neuroimaging techniques for assessing meningeal lymphatic function in humans, highlighting their technical limitations in capturing dynamic pathological changes specific to AD. We summarize recent advances demonstrating that meningeal lymphatic impairment exacerbates key AD hallmarks—including amyloid-β (Aβ) and tau deposition, neuroimmune dysregulation, and myelin degradation—collectively accelerating disease progression. Building on these insights, we systematically analyse emerging therapeutic strategies aimed at enhancing meningeal lymphatic function, such as pharmacological approaches (e.g., vascular endothelial growth factor C (VEGF-C)-mediated lymphangiogenesis), physical interventions (e.g., transcranial photobiomodulation), and surgical techniques (e.g., cervical lymphaticovenous anastomosis). However, significant challenges remain, including the scarcity of direct human evidence linking meningeal lymphatic dysfunction to AD and the lack of standardized, noninvasive assessment tools. To address these gaps, we propose future fundamental and clinical research directions for meningeal lymphatic vessels and AD. By bridging mechanistic insights with translational applications, this review highlights the role of the meningeal lymphatic system as a promising yet underexplored target for AD modification.

The ε4 allele of the apolipoprotein E gene (APOE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). However, its impact on monocyte-mediated amyloid-β (Aβ) clearance and associated immune dysfunction remains poorly understood. Through Aβ uptake assays in humans and mice coupled with transcriptomic profiling, we identified a significant and persistent monocytic Aβ uptake deficiency in APOE4 carriers. This deficit was quantitatively associated with poor cognitive function and elevated plasma Aβ levels. Mechanistically, RNA sequencing revealed that this impairment is driven by a stage-specific molecular transition: in cognitively normal individuals, APOE4 induces a functional mismatch characterized by proinflammatory priming and lipid metabolic dysregulation, whereas in AD patients, this evolves into profound immune exhaustion or transcriptional collapse of core immune and endocytosis pathways. These findings establish APOE4 as a systemic modulator of innate immune competence, suggesting that monocyte-targeted functional rejuvenation may be a potential therapeutic strategy for AD.

Coordinated cell-to-cell communications is crucial for the proper functioning and maintenance of brain activities, and its disruption contributes to neurological disorders, including Alzheimer’s disease (AD). Altered astrocyte-neuron communications have been implicated in AD progression, yet the underlying regulatory networks remain poorly understood. Given that secretory proteins mediate both local and long-range intercellular signaling, we constructed a spatiotemporal profile of the astrocyte-derived secretome using in vivo TurboID proximity labeling in mice of amyloid pathology. Early alterations in the entorhinal cortex secretome were identified and enriched in metabolic pathways, whereas changes in the hippocampus were observed later, correlating with neuronal and synaptic maintenance. These findings suggest that early remodeling of the astrocyte secretome in the entorhinal cortex may be involved in AD pathogenesis, while later changes in the hippocampus contribute to neurodegeneration and cognitive decline. This work provides a systematic map of the dynamic, region-specific remodeling of the astrocyte secretome in AD, identifying novel spatiotemporal vulnerabilities and potential therapeutic targets.

Outer nuclear layer (ONL) thinning has been identified in frontotemporal lobar degeneration (FTLD); however, its utility for distinguishing the subtypes of FTLD-tauopathy (FTLD-tau) and TDP-43 proteinopathy (FTLD-TDP) remains unknown. We investigated whether ONL thickness provides a subtype-informative retinal signal for differentiating PET-supported probable FTLD-tau (pFTLD-tau) from probable FTLD-TDP (pFTLD-TDP) in vivo. Patients clinically diagnosed with FTLD were subtyped into pFTLD-tau and pFTLD-TDP groups based on multimodal PET and clinical criteria. Normal controls (NCs) were cognitively unimpaired on standardized testing and clinical evaluation. Macular images were acquired using swept-source OCT. A custom deep learning algorithm segmented the retina into eight sublayers. The thickness of each retinal sublayer was assessed across the eight sectors of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid. Retinal thickness differences were analyzed using generalized estimating equations, and exploratory discrimination models were evaluated using age- and sex-adjusted stepwise logistic regression with apparent and bootstrap optimism-corrected AUCs reported. Exploratory partial correlation analysis was conducted to examine the associations between ONL thickness and cognitive scores. A total of 86 participants were included (21 pFTLD-tau, 27 pFTLD-TDP and 38 NCs). Widespread ONL thinning was observed in pFTLD-tau (Cohen’s d= -0.753 to -1.268 vs. controls; -0.666 to -1.069 vs. pFTLD-TDP; all FDR-adjusted P < 0.05), while ONL in pFTLD-TDP remained preserved. A model combining retinal nerve fiber layer (RNFL), ONL, and myoid–ellipsoid zone (MEZ) thickness showed exploratory discrimination for differentiating pFTLD-tau from pFTLD-TDP (apparent AUC, 0.922; optimism-corrected AUC, 0.866). The outer thickness model yielded higher AUC estimates than the inner thickness model (0.884/0.835 vs. 0.713/0.630), and the individual ONL model showed moderate exploratory discrimination (0.808/0.765). ONL thickness was correlated with cognitive scores in pFTLD-tau (partial r = 0.433–0.483; all P < 0.05), whereas corresponding associations in pFTLD-TDP did not reach statistical significance. ONL thinning was preferentially observed in pFTLD-tau and contributed to exploratory discrimination between PET-supported probable FTLD subtypes. These findings suggest that ONL thickness may provide complementary, noninvasive information for probable FTLD subtype stratification, with potential to facilitate therapeutic trial enrollment and personalized management. Future studies incorporating neuropathological confirmation and fluid biomarkers are warranted to validate these findings.

Perioperative neurocognitive disorder (PND) is a significant neurological complication in aging perioperative patients that impacts post-operative cognition. PND is currently diagnosed through cognitive function testing, which is limited by its subjectivity and time requirements. Thus, the identification of biomarkers to assess PND onset is a priority to identify at-risk individuals and enable interventions and treatments to patient outcomes. This article synthesizes expert perspectives on brain aging and PND, presents the latest clinical evidence on PND biomarkers (imaging, electroencephalography, and molecular biomarkers), and delves into the relationship between PND and other age-related cognitive disorders. Thorough review of PND research identified several biomarkers with high sensitivity and specificity, offering a solid scientific foundation to predict and diagnose PND. These biomarkers not only enhance diagnostic accuracy for clinicians but also provide opportunities for earlier intervention and more effective treatment, potentially enhancing patient outcomes and quality of life.

Histamine H3 receptor (H3R) antagonists regulate histamine release that modulates neuronal activity and cognitive function. Although H3R is elevated in Alzheimer’s disease (AD) patients, whether H3R antagonists can rescue AD-associated neural impairments and cognitive deficits remains unknown. Pitolisant is a clinically approved H3R antagonist/inverse agonist that treats narcolepsy. Here, we find that pitolisant reverses AD-like pathophysiology and cognitive impairments in an AD mouse model. Behavioral assays and in vivo wide-field Ca2+ imaging revealed that recognition memory, learning flexibility, and slow-wave impairment were all improved following the 15-day pitolisant treatment. Improved recognition memory was tightly correlated with slow-wave coherence, suggesting slow waves serve as a biomarker for treatment response and for AD drug screening. Furthermore, pitolisant reduced amyloid-β deposition and dystrophic neurites surrounding plaques, and enhanced neuronal lysosomal activity, inhibiting which blocked cognitive and slow-wave restoration. Our findings identify pitolisant as a potential therapeutic agent for AD treatments.

INTRODUCTION:This study was undertaken to evaluate the diagnostic performance of a novel plasma phosphorylated tau (p-tau) 217/amyloid beta (Aβ) 42 ratio test for Alzheimer's disease (AD). METHODS:The diagnostic performance of the Lumipulse G plasma p-tau217/Aβ42 ratio was evaluated using Aβ and tau positron emission tomography (PET) as reference standards in a clinic cohort (n = 391) and a community cohort (n = 121). RESULTS:Plasma p-tau217/Aβ42 exhibited high performance for abnormal statuses of Aβ PET (area under the curve [AUC]: 0.963 to 0.966) and tau PET (AUC: 0.947 to 0.974), which were clinically equivalent to those of cerebrospinal fluid (CSF) p-tau181/Aβ42 and Aβ42/Aβ40 and higher than those of blood p-tau217, Aβ42/Aβ40, p-tau181, and p-tau181/Aβ42 in both clinic and community cohorts. Applying a two-cutoff approach improved the specificity without reducing sensitivity. The p-tau217/Aβ42 ratio had a lower intermediate percentage than p-tau217 alone in both clinic (10.6% vs 13.0%) and community (16.5% vs 31.4%) cohorts. DISCUSSION:Plasma p-tau217/Aβ42 has high performance in detecting cerebral AD pathologies, thus offering a promising tool for clinical diagnosis and community screening of AD. HIGHLIGHTS:Lumipulse G plasma p-tau217 and the p-tau217/Aβ42 ratio accurately identified abnormal Aβ and tau PET statuses in both clinical and community cohorts. The performance of plasma p-tau217 and p-tau217/Aβ42 ratio were equivalent to CSF tests. Plasma p-tau217/Aβ42 ratio outperformed p-tau217 alone in identifying Aβ PET positivity, and this superiority is more obvious in the community cohort, suggesting an advantage in the early diagnosis of AD. Two cut points of p-tau217/Aβ42 were established in the Chinese population for clinical laboratory and community screening uses.