@article {pmid42322668,
year = {2026},
author = {Tremblay, SA and Tulsi, J and Yang, D and Alsibai, Z and McDonald, I and Aladeeb, R and Novielli, A and Wong, TYM and Freitas, JG and Miller, M and Dhir, V and Natasha Rajah, M and Godard-Sebillotte, C and Altuntur, S and Karunananthan, S and Geddes, MR},
title = {Review of current research practices in social and structural determinants of health data collection in Canadian longitudinal cohorts of aging and dementia.},
journal = {Neurobiology of aging},
volume = {167},
number = {},
pages = {53-75},
doi = {10.1016/j.neurobiolaging.2026.06.005},
pmid = {42322668},
issn = {1558-1497},
abstract = {BACKGROUND: Social and structural determinants of health (SSDH) are key drivers of disparities in cognitive aging and dementia risk, yet their collection in aging and dementia research remains inconsistent. We examined SSDH data collection practices across Canadian longitudinal cohorts of aging and dementia, aiming to identify which SSDH are collected and how they are operationalized.

METHODS: We conducted an environmental scan using three sources: (1) literature databases (Cochrane, Embase, Medline, PubMed, and Web of Science), 2) grey literature (e.g., Alzheimer Society of Canada's website), and 3) key informants. We included Canadian longitudinal cohorts of community-dwelling older adults that assessed at least one cognitive or dementia-related outcome, including seven key cohorts previously identified by our group. For each study, we extracted information from data collection instruments on whether specific SSDH were assessed, and which tools were used.

RESULTS: From 1043 non-duplicated articles identified through database searches, fourteen unique cohorts met inclusion criteria, eleven of which provided data collection instruments. Five additional cohorts were identified from other sources, and together with 7 pre-identified key cohorts, yielded 23 included cohorts. Disability-related measures and ethnicity- and culture-related constructs were among the most comprehensively assessed domains, whereas literacy, environmental context, and economic conditions were among the least frequently assessed.

CONCLUSION: SSDH that shape dementia risk and brain resilience, many modifiable at the community and policy levels, remain unevenly collected in Canadian aging and dementia cohorts. Strengthening and harmonizing SSDH measurement is a critical step toward equitable dementia prevention and reducing health disparities.},
}

@article {pmid42322864,
year = {2026},
author = {Li, L and Gu, Y and Luo, X and Wang, J and Jia, Y and Yan, T},
title = {Chrysin reprograms microglial metabolism and function via targeting SYK to alleviate the symptoms of Alzheimer's disease.},
journal = {Journal of ethnopharmacology},
volume = {370},
number = {},
pages = {122056},
doi = {10.1016/j.jep.2026.122056},
pmid = {42322864},
issn = {1872-7573},
abstract = {Alpiniae Oxyphyllae Fructus, first documented in Bencao Shiyi, is a classical traditional Chinese herb traditionally used to warm the kidney, invigorate the spleen, consolidate essence and relieve chronic diarrhea. Guided by the TCM theory that kidney essence nourishes brain marrow, modern studies have confirmed its notable neuroprotective and anti-neuroinflammatory activities.

BACKGROUND: Neuroinflammation is a key pathological hallmark of Alzheimer's disease (AD), and spleen tyrosine kinase (SYK) serves as a critical signaling regulator. Our previous work confirmed that Alpiniae Oxyphyllae Fructus extract (AE) exerts notable neuroprotection; nevertheless, its blood-brain barrier-permeable components and detailed mechanisms remain poorly clarified.

OBJECTIVE: The purpose of this study is to identify the main active components in AE and clarify its mechanism of improving AD pathology by regulating the SYK signaling pathway.

METHODS: A preliminary dose-finding study with two AE doses (180 mg/kg, 360 mg/kg) was performed via open field test and inflammatory indexes to select the optimal dose for subsequent experiments. Behavioral assays assessed AE-related neurobehavioral improvements. LC-QTOF-MS/MS identified brain-permeable components, while network pharmacology combined with GEO database analysis screened potential targets and underlying mechanisms. Molecular docking was applied to filter SYK-binding candidates, further validated by molecular dynamics simulation and Cellular thermal shift assay (CETSA). In vivo, a piceatannol-induced SYK inhibition model was established to verify whether the candidate component alleviated LPS-triggered behavioral deficits in mice in a SYK-dependent manner. In vitro, BV2 microglia were used to detect microglial polarization, Aβ phagocytosis and migration through qRT-PCR, glucose/ATP/lactate measurement, wound healing assay and immunofluorescence staining.

RESULTS: Chrysin was identified as the primary brain-permeable constituents targeting SYK. In AD mice, it significantly ameliorated cognitive deficits and reduced Aβ accumulation. Mechanistically, Chrysin modulated the SYK/BTK/PLCγ2 and NF-κB axes to trigger a microglial M1-to-M2 phenotypic shift. This phenotypic transition is accompanied by metabolic reprogramming-shifting from glycolysis to oxidative phosphorylation, thereby notably enhancing microglial migration capacity and Aβ phagocytosis. These neuroprotective effects were confirmed to be SYK-dependent.

CONCLUSION: Chrysin is the primary brain-permeable constituent of AE. that targets SYK to restore microglial metabolic homeostasis, offering a promising therapeutic strategy for AD.},
}

@article {pmid42322910,
year = {2026},
author = {Liu, R and Wei, M and Xu, L and Qu, Z and Yu, JQ and Liu, Y and Zhang, WN and Zhang, D and Zhuang, C},
title = {A Keap1-Nrf2 protein-protein interaction inhibitor 4-95 ameliorates cognitive dysfunction by suppressing neuronal ferroptosis.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110134},
doi = {10.1016/j.bioorg.2026.110134},
pmid = {42322910},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder. With current therapies failing to halt clinical progression, identifying novel disease-modifying therapeutics is of paramount urgency. Although ferroptosis has emerged as a crucial driver of AD pathogenesis, effective pharmacological strategies targeting this pathway remain limited. Bioinformatic analysis revealed close associations among ferroptosis, oxidative stress, the Keap1-Nrf2 pathway, and AD. Compound 4-95, a selective Keap1-Nrf2 protein-protein interaction (PPI) inhibitor, significantly alleviated Erastin and RSL-3-induced ferroptosis in SH-SY5Y and HT-22 cells. In Aβ1-42-treated cell models, 4-95 dose-dependently decreased Aβ and p-Tau expression, while increasing the anti-ferroptotic proteins GPX4 and SLC7A11. Keap1 and GPX4 knockdown verified that 4-95 inhibits ferroptosis via the Keap1-Nrf2-GPX4 axis. In vivo, 4-95 markedly improved cognitive and spatial memory deficits in Aβ1-42-induced AD mice, promoted Nrf2 nuclear translocation, upregulated the downstream antioxidant targets HO-1 and NQO1, and attenuated neuronal injury. Collectively, the study reveals a new mechanism of a Keap1-Nrf2 PPI inhibitor that mitigates AD pathogenesis by directly inhibiting ferroptosis. This novel mechanism underscores a new class of disease-modifying candidates for AD treatment, representing a new therapeutic strategy for this devastating disorder.},
}

@article {pmid42322996,
year = {2026},
author = {Hamm, MJ and McNaught, K and Janus, C and Gazarov, EA and Strickland, Z and Shubin, J and Reinhardt, J and Park, J and Rayaprolu, S and Antropov, WV and Miller, DM and Hotop, A and Patel, S and Yuksel, IS and Howard, J and Fromholt, S and Xu, G and Bird, JE and Moehle, M and Borchelt, DR and Lewis, J},
title = {Robust tauopathy and memory deficits in a mouse model constitutively overexpressing human P301L MAPT.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107496},
doi = {10.1016/j.nbd.2026.107496},
pmid = {42322996},
issn = {1095-953X},
abstract = {Mutations in the MAPT gene encoding tau protein can be causative for frontotemporal lobar degeneration, FTLD-tau. Preclinical mouse models expressing these disease-causing MAPT alleles have successfully modeled biochemical and neuropathological phenomena similar to those seen in human FTLD-tau. One such model, rTg4510, features P301L human tau primarily expressed in the forebrain under the control of a Tet-off system, using the CaMKII promoter to drive transgene expression. While this model allows temporal manipulation of the transgenic tau, many experiments do not require such manipulation, and the bigenic tet-off system adds to the costs of simple transgenics, introduces additional genetic variation, and increases animal usage. Here, we have generated and characterized mice that constitutively overexpress P301L human tau under the CaMKII promoter. The initial founder and offspring were produced in the FVB/N background where we identified a line of constitutive "cTau[P301L]" mice that stably expresses the 0N4R isoform of P301L human tau at levels comparable to the rTg4510 mouse. The cTau[P301L] line features a relatively small deletion at the transgene insertion site and demonstrates no overt motor phenotype. There was, however, unexpectedly high early lethality on the FVB background that was mitigated after just one crossing to C57BL/6 mice. In both backgrounds, Tau[P301L] expression resulted in an age-dependent accumulation of tau and gliosis that occur prominently in the forebrain and hippocampus. In transgenic F1 B6/FVB mice, spatial memory deficits were detected by 6 months of age. Overall, this new cTau[P301L] model recapitulates disease-associated pathology and memory deficits, with limited disruption of the murine genome and a lack of longevity-restricting motor phenotypes. The cTau[P301L] mouse is a robust, new alternative to existing mouse models of tauopathy.},
}

@article {pmid42323146,
year = {2026},
author = {Puranik, K and Ranpise, N and Khot, S and Negi, P},
title = {Nose-to-Brain delivery of empagliflozin-loaded nanostructured lipid carriers incorporated In-situ gel: Biopharmaceutical evaluation for Alzheimer's disease.},
journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V},
volume = {},
number = {},
pages = {115161},
doi = {10.1016/j.ejpb.2026.115161},
pmid = {42323146},
issn = {1873-3441},
abstract = {Alzheimer's therapy remains limited by poor drug targeting and multifactorial pathology. The therapeutic potential of SGLT-2 inhibitors like empagliflozin (EGZ) is constrained by poor brain bioavailability. Current study investigates the potential of EGZ-nanostructured lipid carrier (ENLC) for brain delivery via nasal route. The ENLC were prepared using hot melt emulsification technique followed by probe sonication and optimized using Box-Behnken design. ENLC were incorporated into poloxamer 407-chitosan in situ gel (ENPCG) to improve nasal retention, controlled release, and direct brain transport via olfactory and trigeminal uptake. ENPCG demonstrated a sustained drug release of 56.36 ± 3.37 % and enhanced nasal permeation. Nasal kinetics revealed high Cmax[mucosa] (48.2 ± 1.42 µg/cm[2]) relative to plain EGZ-suspension (15.9 ± 0.7 µg/cm[2]) in goat nasal mucosa. ENPCG significantly improved cognitive memory in sporadic AD model, as confirmed by behavioural, biochemical, and histopathological assessments in Wistar rats. Pharmacokinetic study in Sprague Dawley rats revealed a 4.5-fold increase in AUC0-t of intranasal ENPCG (30.56 ± 0.45 μg/mL*h) relative to intravenous ENLC (6.73 ± 0.15 μg/mL*h). ENPCG showed 95.31 ± 3.89 % drug targeting potential. Furthermore, a strong point-to-point ex vivo-in vivo correlation (R[2] = 0.9952) was observed, suggesting a non-invasive potential of ENPCG for translating AD interventions.},
}

@article {pmid42323193,
year = {2026},
author = {Chang, M and Hong, B and Barense, MD},
title = {Improving autobiographical episodic memory, quality of life, and sense of self with a smartphone intervention in early dementia: A case study.},
journal = {Neuropsychological rehabilitation},
volume = {},
number = {},
pages = {1-37},
doi = {10.1080/09602011.2026.2689541},
pmid = {42323193},
issn = {1464-0694},
abstract = {In memory disorders such as Alzheimer's disease, recent autobiographical memories are disproportionately vulnerable to loss, yet most traditional reminiscence therapies focus on remote past events. We present a case study examining whether a digital reminiscence intervention designed to support memory for recent experiences can improve episodic recall and psychosocial outcomes in neurodegenerative memory impairment. G.F., a 79-year-old man with early-stage dementia, completed an 11-week personalized intervention using HippoCamera, a neuroscience-based smartphone application that helps users generate and review multimodal memory cues from everyday events. Events that G.F. reviewed using HippoCamera were recalled with greater episodic detail than events that were recorded but not reviewed. Post-intervention, G.F. reported improvements in quality of life, life satisfaction, self-concept, and perceived episodic and spatial memory abilities, along with reduced depressive symptoms. Qualitative feedback revealed that the intervention helped G.F. regain confidence, re-engage socially, and feel more optimistic about the future. These findings suggest that digital interventions targeting memory for recent experiences - a domain often overlooked in traditional reminiscence therapy - may provide benefits to cognition and quality of life in the early stages of dementia. This work highlights the promise of HippoCamera as an accessible, neuroscience-informed tool to support memory and well-being in those experiencing memory loss.},
}

@article {pmid42323462,
year = {2026},
author = {Chen, Y and Wang, Z and Chen, H and Li, H and Zhang, Z and Cui, H and Li, S and , },
title = {Plasma p-Tau217 and Aβ42/Aβ40 mediate the association between minimal depressive symptoms and cognitive impairment.},
journal = {Journal of neurology},
volume = {273},
number = {7},
pages = {},
pmid = {42323462},
issn = {1432-1459},
support = {82471199//National Natural Science Foundation of China/ ; 82171582//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/blood ; *tau Proteins/blood ; *Cognitive Dysfunction/blood ; *Peptide Fragments/blood ; Female ; Male ; Biomarkers/blood ; *Depression/blood ; Aged ; Aged, 80 and over ; Glial Fibrillary Acidic Protein/blood ; Phosphorylation ; Neurofilament Proteins/blood ; Alzheimer Disease/blood ; },
abstract = {Depression is a recognized risk factor and potential prodromal feature of Alzheimer's disease (AD). While associations between depressive symptoms and AD pathology have been observed using cerebrospinal fluid (CSF) and PET imaging, it remains unclear whether these relationships can be captured by accessible plasma biomarkers, particularly the highly specific phosphorylated tau-217 (p-Tau217). We analyzed 615 participants from Alzheimer's disease Neuroimaging Initiative (ADNI) cohort, of whom 374 had minimal depressive symptoms (MDS). Plasma biomarkers included phosphorylated tau-217 (p-Tau217), amyloid-β 42/40 ratio (Aβ42/Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Linear regression models and mediation analyses were employed to examine associations between MDS, plasma biomarkers (p-Tau217, Aβ42/Aβ40, NfL, and GFAP), and cognitive impairment, with adjustments for age, sex, and APOE ε4 carrier status. Participants with MDS demonstrated significantly elevated plasma p-Tau217 levels (mean difference = 0.105, 95% CI [0.046, 0.163]; P < 0.001) and reduced Aβ42/Aβ40 (mean difference = -0.024, 95% CI [-0.041, -0.006]; P = 0.007) compared with those without MDS. These associations were primarily observed in non-demented individuals and influenced by age, sex, and APOE ε4 status. In mediation analyses, plasma p-Tau217 accounted for 41.57%-42.18% of the association between MDS and cognitive impairment, while Aβ42/Aβ40 mediated 7.13%-8.45% of this relationship. Plasma biomarkers of p-Tau217 and Aβ42/Aβ40 were associated with early depressive symptoms and mediate their associations with cognitive impairment. These findings identify plasma p-Tau217 as a key mediator linking MDS to cognitive impairment, extending evidence from CSF to accessible blood-based biomarkers. This highlights the value of monitoring plasma p-Tau217 and Aβ42/Aβ40 to unravel the pathological basis of depressive symptoms in early AD.},
}

Humans
*Amyloid beta-Peptides/blood
*tau Proteins/blood
*Cognitive Dysfunction/blood
*Peptide Fragments/blood
Female
Male
Biomarkers/blood
*Depression/blood
Aged
Aged, 80 and over
Glial Fibrillary Acidic Protein/blood
Phosphorylation
Neurofilament Proteins/blood
Alzheimer Disease/blood

@article {pmid42323643,
year = {2026},
author = {Bouveret, Z and Pruvost, L and Trédan, O and Le Romancer, M and Poulard, C},
title = {How post-translational modifications impact glucocorticoid receptor function in human pathologies.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-03015-7},
pmid = {42323643},
issn = {1478-811X},
support = {ANR-22-CE13-0001-01//Agence Nationale de la Recherche/ ; },
abstract = {Glucocorticoid receptor (GR) is a member of the nuclear hormone receptor family, which acts as a transcription factor when bound by glucocorticoid (GC) ligands. GR is expressed in nearly all tissue types and regulates essential processes such as inflammation, immune regulation and metabolism. Given its ubiquitous role, GR has frequently been associated with a wide range of illnesses, particularly in the fields of allergy, pulmonary, dermatology, rheumatology, or ophthalmology. It was reported that GCs either contribute to their development or serve as part of their treatment, making them the most prescribed drugs worldwide. GR activity and signaling is finely regulated by a network of post-translational modifications (PTMs). Indeed, PTMs can alter GR behavior and function by modifying its localization, stability, interaction with other proteins and transcriptional activity. Aside from the well-characterized phosphorylation events, additional PTMs are implicated in GR activity and their dysregulation has been described in various diseases. This review provides an integrated overview of current knowledge on GR PTMs, highlighting both mechanistic insights and their relevance in disease. We will present how aberrant PTMs contribute to extremely prevalent diseases, such as cancer, chronic inflammatory diseases, Alzheimer's disease and other neurological diseases. Special attention will be given to the specific readers of these PTMs and to the enzymes catalyzing these modifications, as they represent promising therapeutic targets.},
}

@article {pmid42323655,
year = {2026},
author = {Monteverdi, A and Cotta Ramusino, M and Conca, F and Augello, A and Totaro, C and Grasso, PA and Castelnovo, A and Lorenzi, RM and Terzaghi, M and Farina, LM and Costa, A and Pichiecchio, A and Cappa, SF and Gandini Wheeler-Kingshott, C and Palesi, F and D'Angelo, E},
title = {Virtual brain and electroencephalography explain the variance of memory alterations in mild cognitive impairment.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02114-4},
pmid = {42323655},
issn = {1758-9193},
abstract = {BACKGROUND: Mild Cognitive Impairment (MCI) is a heterogeneous clinical condition characterized by a wide spectrum of cognitive and behavioural manifestations. Despite numerous studies, the link between neuropsychological performance and pathophysiological signatures of the disease-including Aβ and tau accumulation along with altered excitation/inhibition (E/I) balance and brain rhythms-remains elusive.

METHODS: Here Aβ/tau biomarkers were used to distinguish positive (MCI[+]- prodromal Alzheimer's disease) and negative (MCI[-]) subjects in a cohort of 30 MCI patients (18 MCI[+] and 12 MCI[-]). Virtual brain models based on high-field magnetic resonance imaging data were then developed to determine the inter-node coupling and E/I profile in resting-state networks, while node spectral information was obtained from source analysis of high-density electroencephalography (HD-EEG). Finally, virtual brains and HD-EEG parameters, creating brain digital twins of individual subjects, were correlated with cognitive performance.

RESULTS: While virtual brain simulations did not reveal E/I differences between MCI[+] and MCI[-], a positive correlation emerged between synaptic parameters of the limbic network and verbal episodic memory for both groups. EEG power spectral density revealed a lower high-frequency/low-frequency ratio in MCI[+] largely due to a reduced alpha band in the default mode, limbic, attention, frontoparietal, visual and somatomotor networks. A strong correlation emerged between multimodal parameters and memory functions, supporting that brain digital twin simulations can effectively explain the variability of neuropsychological performance in MCI patients beyond the sensitivity of individual techniques alone. In particular, the combination of HD-EEG and virtual brain parameters explained more than 90% of variance for episodic memory patients' scores, confirming the compound origin of memory performance involving network specific E/I levels and electroencephalographic activity acting in concert.

CONCLUSIONS: This multimodal and multiparametric analysis combining virtual brain modelling with HD-EEG and molecular data enhances the stratification of MCI patients and could be used to develop digital biomarkers of progression to dementia, opening new perspectives for personalized prognosis and treatment.},
}

@article {pmid42323731,
year = {2026},
author = {Domingo, J and Alves, A and Sanders, J},
title = {Evaluating the Use of Anxiety Patient-Reported Outcome Measures (PROMs) in Dementia Clinical Trials: A Systematic Review.},
journal = {Health expectations : an international journal of public participation in health care and health policy},
volume = {29},
number = {3},
pages = {e70736},
pmid = {42323731},
issn = {1369-7625},
mesh = {Humans ; *Patient Reported Outcome Measures ; *Dementia/psychology ; *Anxiety/diagnosis ; Randomized Controlled Trials as Topic ; Quality of Life ; *Clinical Trials as Topic ; Female ; },
abstract = {UNLABELLED: Anxiety is a common but underdetected or underdiagnosed symptom in dementia, affecting quality of life and care outcomes. Clinical trials are essential for informing effective management, yet the use of patient-reported outcome measures (PROMs) in dementia trials remains unclear. This review examined how validated PROMs are used to assess anxiety in dementia trials, including measurement tools, methods, demographic representation and evidence gaps.

METHODS: A systematic review was conducted following PRISMA and Cochrane Handbook guidance, with protocol registration on PROSPERO (CRD42025649920). Randomised controlled trials published between January 2015 and February 2025 were included if they assessed anxiety in mild to moderate dementia using validated PROMs within pharmacological or non-pharmacological interventions. Searches were conducted across MEDLINE, Embase, PsycINFO, Cochrane Library and ClinicalTrials.gov, supplemented by citation tracking. Two reviewers independently undertook study selection, data extraction and risk of bias assessment. Due to heterogeneity, findings were narratively synthesised.

RESULTS: Of 2328 records screened, 29 trials (n = 5697) met inclusion criteria. While 93.1% used validated anxiety measurement tools, only 44.4% employed PROMs, most frequently the Hospital Anxiety and Depression Scale, mainly in non-pharmacological trials. Women and individuals of White ethnicity were overrepresented, and no studies examined PROM effectiveness by sex and ethnicity. Most trials showed moderate to high risk of bias, and evidence was confined to high-income countries.

CONCLUSIONS: Anxiety outcomes in dementia trials remain largely proxy-reported. Existing anxiety PROMs are generic and unvalidated for dementia populations. There is a critical need for dementia-specific, culturally sensitive anxiety PROMs, improved demographic reporting and integration of anxiety assessment within dementia core outcome sets.

Feedback from research participants in dementia studies, who reported experiencing anxiety, motivated this systematic review. Patient and public involvement was examined across all included studies. The lack of validated dementia-specific anxiety PROMs identified in this review highlights a broader gap in co-produced outcome development within dementia research. These findings emphasise the need for meaningful involvement of people living with dementia and care partners in the development, validation and cultural adaptation of anxiety PROMs to ensure that trial outcomes are relevant, acceptable and representative.},
}

Humans
*Patient Reported Outcome Measures
*Dementia/psychology
*Anxiety/diagnosis
Randomized Controlled Trials as Topic
Quality of Life
*Clinical Trials as Topic
Female

@article {pmid42323822,
year = {2026},
author = {Pan, JP and Zhang, J and Wang, PJ and Chen, G and Fang, EF},
title = {Mitophagy mitigates tau acetylation via the ULK1-NAD[+]/SIRT1 axis in Alzheimer's disease.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/15548627.2026.2689031},
pmid = {42323822},
issn = {1554-8635},
abstract = {Autophagy preserves neuronal integrity by clearing damaged proteins and other subcellular components, yet it declines with age and exacerbates in Alzheimer's disease (AD). Although autophagy reduces tauopathy, whether it can proactively restrict early tau pathology via post-translational modifications (PTMs) has remained unclear. In a recent paper, we have identified a mitophagy-based metabolic signaling mechanism linking the autophagy-initiating kinase Unc-51-like autophagy activating kinase 1 (ULK1) to the inhibition of pathogenic tau acetylation via the ULK1-NAD[+]/SIRT1 axis. Analyses of human biofluidic to postmortem and transcriptomic data reveal an age-associated decline of ULK1; this situation gets worse in AD with the extent of ULK1 reduction positively correlates with Tau-based Braak stage progression, consistent with a bidirectional vicious cycle in which pathological tau disrupts mitochondrial homeostasis and impairs autophagy. Restoring ULK1-dependent mitophagy breaks this cycle in the upstream: in the hTau.P301S mice, ULK1 overexpression reduces ac‑tauK174 leading to reduced tau pathology and improved cognition. Mechanistically, ULK1 activates PINK1- and FUNDC1- as well as AMBRA1-dependent mitophagy to eliminate damaged mitochondria, restore bioenergetics, and elevate intracellular NAD[+], which activates the deacetylase SIRT1 to directly deacetylate tau at Lys174. Pharmacological ULK1 activation with a small molecule Rac‑BL‑918 phenocopies these protective effects in a mitophagy- and SIRT1-dependent manner. Collectively, our recent findings position mitophagy as a metabolic signaling hub that couples mitochondrial turnover to NAD[+]/SIRT1 activity to shape neuronal tau PTMs, supporting ULK1-mitophagy activation as an upstream strategy to limit tauopathy before overt aggregation.},
}

@article {pmid42324021,
year = {2026},
author = {Yang, LL and Luo, YX and Song, D and Liu, N and Gong, LH and Heng, T and Zhou, XH and Li, YX and Chen, JH and Song, ZX and Li, Y and Wang, YL and Bai, CC and He, R and Hu, P and Zhou, Y and Jia, GW and Yao, XQ},
title = {Physical exercise mitigates amyloid beta-driven muscle degeneration in Alzheimer's disease.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.06.018},
pmid = {42324021},
issn = {2090-1224},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is increasingly recognized as a systemic disorder, with skeletal muscle dysfunction contributing substantially to frailty and functional decline. Although amyloid-β (Aβ) has been detected in peripheral tissues, including skeletal muscle, how it drives muscle degeneration and whether exercise can counteract this process remain to be elucidated.

OBJECTIVES: This study aimed to define the molecular mechanisms underlying Aβ-induced skeletal muscle degeneration in AD and assess the potential of high-intensity interval training (HIIT) to alleviate muscle dysfunction and related pathology.

METHODS: We combined a small-scale exploratory clinical cohort with the 5 × FAD mouse model, integrating transcriptomic and metabolomic profiling with in vitro and in vivo functional assays to dissect Aβ-induced muscle pathology and the protective mechanisms of HIIT.

RESULTS: AD patients in the exploratory cohort showed a trend toward reduced handgrip strength, mirroring the progressive muscle weakness, myofiber atrophy, and intramuscular Aβ accumulation observed in 5 × FAD mice. Mechanistically, Aβ activated RAGE/NF-κB signaling, driving inflammation and oxidative stress in myofibers. HIIT reversed these pathological changes and concomitantly lowered Aβ levels. Transcriptomic profiling identified fibroblast growth factor 10 (FGF10) as a key exercise-induced mediator: FGF10 activated the FGFR2-AKT-ADAM10 axis to promote RAGE ectodomain shedding, generating soluble RAGE that suppressed Aβ-mediated inflammatory and injury signaling.

CONCLUSION: Our findings define an Aβ-RAGE axis driving AD-associated muscle degeneration and reveal an exercise-responsive FGF10-RAGE protective pathway, reframing AD as a brain-muscle axis disorder and highlighting FGF10 as a promising target for systemic therapeutic intervention.},
}

@article {pmid42324031,
year = {2026},
author = {Donepudi, K and Eadha, S and Rodarte, D and Sharma, B and Kumar, S},
title = {Cell-Specific MicroRNA Networks Orchestrate the Pathogenesis of Alzheimer's Disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103211},
doi = {10.1016/j.arr.2026.103211},
pmid = {42324031},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles of hyperphosphorylated tau, synaptic dysfunction, and chronic neuroinflammation. AD pathogenesis involves multiple central nervous system (CNS) cell types-including neurons, astrocytes, microglia, and oligodendrocytes, and, less prominently, neural stem cells (NSCs), ependymal cells, and endothelial cells-which undergo coordinated but cell-type-specific pathological changes. These include neuronal loss, reactive gliosis, impaired myelin maintenance, reduced neurogenesis, and blood-brain barrier (BBB) dysfunction. MicroRNAs (miRNAs), the small non-coding RNAs that regulate post-transcriptional gene expression, have emerged as key modulators of these cell-specific processes and are consistently dysregulated in AD. Across AD-vulnerable brain regions and CNS cell types, miRNAs influence amyloid and tau biology, synaptic resilience, glial activation states, myelin structure, neurogenic potential, and vascular homeostasis. Dysregulated miRNAs also act across cell types through extracellular vesicle (EV) transfer, amplifying or mitigating amyloidogenesis, tauopathy, neuroinflammation, and white-matter injury. This review provides a comprehensive, cell-type-specific analysis of miRNAs involved in AD, detailing their roles in neurons, astrocytes, microglia, oligodendrocytes, NSCs, ependymal cells, and endothelial cells. We highlight common miRNAs that function across multiple CNS cell types and examine the potential of circulating and cerebrospinal fluid (CSF) miRNAs as minimally invasive biomarkers. Finally, we discuss therapeutic strategies aimed at restoring protective miRNAs or inhibiting pathogenic miRNAs, emphasizing the need for targeted interventions. By integrating pathways of miRNA dysregulation across CNS cell types, this review underscores the central role of miRNA networks in AD pathogenesis and the promise of precise, cell-specific miRNA modulation.},
}

@article {pmid42324052,
year = {2026},
author = {Tomyshev, A and Cherkasov, N and Panikratova, Y and Bozhko, O and Kolykhalov, I and Lebedeva, I},
title = {Structural MRI and mild behavioral impairment as complementary predictors of conversion from amnestic MCI to Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.025},
pmid = {42324052},
issn = {1873-7544},
abstract = {Mild Behavioral Impairment (MBI) and amnestic Mild Cognitive Impairment (aMCI) are complementary early markers of Alzheimer's disease (AD), yet their combined neuroanatomical correlates and predictive value for conversion remain underexplored. In this study of 72 community-dwelling older adults (49 aMCI, 23 healthy controls), we retrospectively classified aMCI participants into non-converters (aMCI-NC, n = 31) and converters (aMCI-C, n = 18) based on longitudinal follow-up. Baseline structural MRI revealed that aMCI-C patients exhibited bilateral atrophy in the hippocampus, amygdala, and nucleus accumbens, alongside cortical thinning in temporal-limbic and parietal regions compared to both aMCI-NC and controls. Notably, in the non-converter group, MBI-Checklist scores correlated negatively with temporal-parietal cortical thickness, while Montreal Cognitive Assessment scores correlated positively with subcortical volumes. Cox proportional-hazards regression with supervised principal component analysis revealed that while MBI symptoms alone did not independently predict conversion, they demonstrated significant conditional predictive value when combined with structural MRI markers. Model robustness was confirmed via rigorous internal validation using nested leave-one-out cross-validation with bootstrap aggregation. Furthermore, time-varying analysis indicated that the protective effect of larger medial temporal-limbic subcortical volumes was strong initially but attenuated over follow-up, consistent with a depletable brain reserve. Given the limited conversion events, which constrained statistical power for smaller independent effects and restricted model complexity, replication in larger prospective cohorts is warranted. Despite this limitation, our results underscore the conditional utility of integrating MBI assessment with structural MRI to enhance early detection and risk stratification in memory clinic settings.},
}

@article {pmid42324246,
year = {2026},
author = {Zammit, AR and Yu, L and Poole, VN and Tasaki, S and Vialle, R and Arfanakis, K and Schneider, JA and Petyuk, VA and De Jager, PL and Kaddurah-Daouk, R and Iturria-Medina, Y and Bennett, DA},
title = {Associations of stable psychological traits with multi-omic subtypes of Alzheimer's dementia.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04195-z},
pmid = {42324246},
issn = {2158-3188},
support = {R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG015819//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG064233/AG/NIA NIH HHS/United States ; RF1 NS139975/NS/NINDS NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG015819//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG61356//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG72975//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG015819//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG61356//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG10161//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG72975//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG015819//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG61356//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Psychological traits reflecting neuroticism, depressive symptoms, loneliness, and purpose in life are risk factors of AD dementia; however, the underlying biological mechanisms remain largely unknown. Using multi-omic data from the dorsolateral prefrontal cortex of 822 decedents in the Religious Orders Study and Rush Memory and Aging Project, we utilized a previously derived multi-omic brain molecular pseudotime representing molecular distance from no cognitive impairment (NCI) to AD dementia, and three distinct multi-omic brain molecular subtypes of AD dementia. We first confirmed generalizability of pseudotime and subtypes in two independent samples. We then annotated the subtypes, and explored whether they differed by neuropathologic burden, brain morphology or genetic risk, and found that while these indices differentiated all subtypes from NCI they did not differentiate amongst them. Finally, we tested for differential associations between the psychological traits and the subtypes, adjusting first for age, sex, education, and time to death, and then additionally for 9 common AD and Related Dementias pathologies. We found that in fully adjusted models, neuroticism, loneliness and purpose in life remained differentially associated with some AD subtypes relative to NCI. Our results are consistent with a two-stage model in which (i) upstream genetic risk influences overall disease liability, while (ii) intermediary psychological predispositions align more directly with subtype differentiation capturing AD-related heterogeneity not explained by neuropathology or brain atrophy. These results indicate that psychological risk factors may be associated with AD dementia via multi-omic molecular pathways, predominantly informed by metabolomic dysregulation, capturing heterogeneity not explained by neuropathology.},
}

@article {pmid42324333,
year = {2026},
author = {Lu, Y and Hammonds, SK and Fernandez-Quilez, A},
title = {Clinical pathways matter for multimodal deep learning in early Alzheimer's disease detection.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-57861-z},
pmid = {42324333},
issn = {2045-2322},
abstract = {Identifying individuals at risk of Alzheimer's disease (AD), particularly in the preclinical and early stages, remains challenging. Although deep learning approaches based on structural MRI show promise as a non-invasive biomarker, existing multimodal models require task-specific training and depend on biomarkers that are not routinely available in clinical practice. Here, we propose a zero-shot multimodal feature extraction framework based on SigLIP that combines structural MRI embeddings with text embeddings of routinely collected clinical variables for early AD risk stratification in individuals at preclinical or mild cognitive impairment (MCI) stages. We evaluated the approach in 416 individuals from the ADNI cohort (age: 72.73 ± 6.7). SigLIP was used without fine-tuning to extract MRI and clinical text embeddings, which were combined into multimodal representations for individual-level AD risk prediction within 4 years. We further compared the model performance in a single-visit and two-visit settings to assess the value of longitudinal information and framework scalability. In the 1-visit setting, combining MRI embeddings with MMSE, age, and sex achieved an AUC of 0.91 ± 0.02, showing higher performance than the CSF Aβ42-based model (AUC 0.73 ± 0.08) and MMSE-based model (AUC 0.85 ± 0.22). In the 2-visit setting, performance was maintained or improved, supporting the scalability of the approach to longitudinal data. These findings suggest that multimodal fusion of SigLIP-derived MRI features and routinely collected clinical variables may provide a practical and scalable strategy for early AD risk progression prediction without task-specific training.},
}

@article {pmid42324487,
year = {2026},
author = {Buée, L and Wildsmith, KR and Alladi, S and Bertucci, T and Boche, D and Bowles, KR and Boxer, A and Brummet, J and DeVos, SL and Diaz, K and Dreyer, AJ and Duff, K and Duran-Aniotz, C and Durrant, CS and Farrell, K and Fontana, IC and Franzmeier, N and Frost, B and Horie, K and Kaňovský, P and Kao, AW and Mahinrad, S and Malpetti, M and Morris, HR and Palleis, C and Petrucelli, L and Rexach, J and Reyderman, L and Rommel, A and Rowe, JB and Sanabria Bohórquez, SM and Sato, C and Schöll, M and Schneider, A and de Silva, R and Snyder, HM and VandeVrede, L and Varga, AW and Vogel, JW and Yeh, FL and Yoo, AS and Carrillo, MC},
title = {Emerging directions in tauopathy research.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71431},
doi = {10.1002/alz.71431},
pmid = {42324487},
issn = {1552-5279},
support = {RT/ESG2005C//Alzheimer's Research UK/ ; ART/PG2006/4//Alzheimer's Research UK/ ; ARTEXT2010-1//Alzheimer's Research UK/ ; ARUK-EG2015A-4//Alzheimer's Research UK/ ; ARUK-PG2018A-012//Alzheimer's Research UK/ ; ARUK-RADF2021A-010//Alzheimer's Research UK/ ; MC_UU_00030/14//Medical Research Council UK/ ; MR/T033371/1//Medical Research Council UK/ ; G0501033//Medical Research Council UK/ ; UK DRI-4211//UK Dementia Research Institute/ ; //NIHR Applied Research Collaboration East of England/ ; AS-PG-21-006/ALZS_/Alzheimer's Society/United Kingdom ; //Fogarty International Center (FIC)/ ; R01AG057234//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG075775//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG21051//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG083799//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R21AG081961//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG081394-01//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG078964//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; U01AG072464//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; K01AG070326//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG075802//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R21AG091113//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG080609//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG066870//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R01AG056682//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; R21AG088736//National Institutes of Health (NIH), National Institute on Aging (NIA)/ ; //Rainwater Charitable Foundation/ ; //Global Brain Health Institute/ ; 1210622//ANID/FONDECYT Regular/ ; 1250091//ANID/FONDECYT Regular/ ; 240065//ANID/FOVI/ ; 13240170//ANID/Proyecto Exploracion/ ; CARE-2025-0883490149//Wellcome Leap CARE Program/ ; 101236426//European Union / Horizon Europe/ ; A2026019S//BrightFocus Foundation/ ; 685-2023-06-Pathway//CurePSP/ ; //Eisai, Inc./ ; NW25-04-00194//AZV CR/ ; FNOL 0098892//Czech Republic for the Conceptual Development of a Research Organization/ ; NIHR 203312//National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre/ ; //PSP Association/ ; //Michael J Fox Foundation/ ; //CBD Solutions/ ; //Drake Foundation/ ; /PUK_/Parkinson's UK/United Kingdom ; //Cure Parkinson's Trust/ ; EXC2145SyNergy//Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)/ ; ID390857198//Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)/ ; //Thiemann Stiftung/ ; RF1NS144499//National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1NS139972//National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS)/ ; RF1NS128800//National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS)/ ; 220258/WT_/Wellcome Trust/United Kingdom ; //Cambridge Centre for Parkinson-Plus/ ; KAW2014.0363//Wallenberg Centre for Molecular and Translational Medicine/ ; KAW2023.0371//Wallenberg Centre for Molecular and Translational Medicine/ ; 2017-02869//the Swedish Research Council/ ; 2021-02678//the Swedish Research Council/ ; 2021-06545//the Swedish Research Council/ ; 2023-06188//the Swedish Research Council/ ; 101132933//European Union's Horizon Europe research and innovation program/ ; 101112145//European Union's Horizon Europe research and innovation program/ ; RS-2023-00263612//National Research Foundation of Korea/ ; ALFGBG-813971//Swedish government and the County Councils/ ; ALFGBG-965326//Swedish government and the County Councils/ ; FO2021-0311//the Swedish Brain Foundation/ ; FO2024-0372//the Swedish Brain Foundation/ ; AF-1011738//Swedish Alzheimer Foundation/ ; //JM Dahl Foundation/ ; //Familjen Rönström's Foundation/ ; //Sahlgrenska Academy/ ; VGFOUREG-995510//Västra Götaland Region R&D/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; FZK01EK2102A//German Federal Ministry of Education and Research/ ; PREPARE//German Federal Ministry of Education and Research/ ; FZK01GP2213A//German Federal Ministry of Education and Research/ ; EXC2151-39087304//Cluster of Excellence ImmunoSensation/ ; //Reta Lila Weston Trust for Medical Research/ ; //Merck Investigator Studies Program/ ; //Cure Alzheimer's Fund/ ; //Eisai WashU Research Exchange Program/ ; SG-20-725707/ALZ/Alzheimer's Association/United States ; AARGD-24-1310017;AARG-1027406/ALZ/Alzheimer's Association/United States ; 2018-AARG-589632/ALZ/Alzheimer's Association/United States ; //Innovation platforms, Sahlgrenska Science Park/ ; //Alzheimerfonden/ ; //Swedish government/ ; //Vetenskapsrådet/ ; //Knut och Alice Wallenbergs Stiftelse/ ; //Else Kröner-Fresenius-Stiftung/ ; //National Institute for Health and Care Research/ ; //Ministerstvo Zdravotnictví Ceské Republiky/ ; //Agentura Pro Zdravotnický Výzkum České Republiky/ ; //James Dyson Foundation/ ; //Tau Consortuim/Rainwater Charitable Trust/ ; //Eli Lilly and Company/ ; //PSPA/ ; //UCB/ ; },
mesh = {*Tauopathies/therapy/diagnosis/metabolism ; Humans ; *tau Proteins/metabolism ; Biomarkers ; *Biomedical Research/trends ; Animals ; },
abstract = {The Tau Global Conference 2025, hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation, convened international experts from academia, industry, government, and philanthropy to explore advances and challenges in tauopathy research. The meeting highlighted progress across tau biology, including emerging models of tau regulation, degradation, and propagation; advances in biomarker development for the diagnosis and staging of tauopathies; and evolving therapeutic strategies targeting diverse aspects of tau pathophysiology. Discussions also emphasized the importance of cross-sector collaboration, and global initiatives to address disparities in tau research. This report synthesizes key insights from the conference and underscores the critical role of interdisciplinary, biomarker-driven, and globally inclusive approaches in accelerating the translation of tau research into effective clinical applications.},
}

*Tauopathies/therapy/diagnosis/metabolism
Humans
*tau Proteins/metabolism
Biomarkers
*Biomedical Research/trends
Animals

@article {pmid42324743,
year = {2026},
author = {Sakagami, S and Yoshida, Y and Uemura, S and Kumamoto, T and Tsukamoto, R and Nishi, T and Kawano, S and Fukuoka, K and Ino, H and Hamamura, K and Ohdo, S and Matsunaga, N},
title = {Benzbromarone as a Novel Candidate for Preventing Alzheimer's Disease: Evidence From Real-World Data Screening and in Vitro Validation.},
journal = {Clinical and translational science},
volume = {19},
number = {7},
pages = {e70650},
doi = {10.1111/cts.70650},
pmid = {42324743},
issn = {1752-8062},
mesh = {Humans ; *Benzbromarone/therapeutic use/pharmacology ; *Alzheimer Disease/prevention & control/epidemiology ; *Drug Repositioning ; Female ; Male ; Japan/epidemiology ; *Uricosuric Agents/pharmacology/therapeutic use ; Aged ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Incidence ; Cell Line, Tumor ; },
abstract = {Drug development for Alzheimer's disease (AD) remains challenging, with only a 0.4% success rate from Phase I trials to regulatory approval. Drug repositioning leverages existing approved drugs to identify promising drug alternatives, particularly when combined with real-world data (RWD) and target trial emulation. In this study, we comprehensively screened 1,241 approved drugs using a large-scale Japanese claims database (n = 2,090,465; 2005-2023). We identified patients newly prescribed a study drug and applied an active-comparator, new-user design. We used propensity score-based inverse probability of treatment weighting (IPTW) to balance the covariates. The primary outcome was incident AD, defined using ICD-10 codes (F00 and G30). We estimated cumulative incidence using IPTW-adjusted Kaplan-Meier analysis and Cox proportional hazards models and conducted sensitivity analyses using Fine-Gray competing risk models, empirical calibration with negative control outcomes, and E-value estimation. We performed in vitro validation using Aβ-Tet-ON SH-SY5Y cells and quantified Aβ expression using western blotting. Benzbromarone, a uricosuric agent, was associated with a decreased risk of AD onset (adjusted HR: 0.54, 95% CI: 0.41-0.71, p < 0.05 post-FDR correction); this association remained robust across sensitivity analyses. In vitro, benzbromarone reduced Aβ protein expression in SH-SY5Y cells in a dose-dependent manner, even following transcriptional blockade, suggesting a posttranscriptional regulatory mechanism. In conclusion, using a combined approach of RWD-based pharmacoepidemiology and in vitro validation, we identified benzbromarone as a novel candidate potentially associated with reduced AD risk. Our findings highlight the potential of drug repositioning strategies to accelerate AD drug discovery, promoting further mechanistic and clinical investigations.},
}

Humans
*Benzbromarone/therapeutic use/pharmacology
*Alzheimer Disease/prevention & control/epidemiology
*Drug Repositioning
Female
Male
Japan/epidemiology
*Uricosuric Agents/pharmacology/therapeutic use
Aged
Amyloid beta-Peptides/metabolism
Aged, 80 and over
Incidence
Cell Line, Tumor

@article {pmid42324842,
year = {2026},
author = {Ugale, V and Sharon, N and Salunkhe, C and Salunkhe, J and Lokwani, D and Patil, K and Reddy, PN and Kulkarni, P},
title = {Naphthalene-4H-Chromene Molecular Hybrids as Dual Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70338},
doi = {10.1002/ddr.70338},
pmid = {42324842},
issn = {1098-2299},
support = {RGSTC/File-2024/DPP-309/CR-20/332//Rajiv Gandhi Science and Technology Commission/ ; TAR/2021/000140//Department of Science and Technology (DST)-Science and Engineering Research Board (SERB)/ ; CRG/2022/004365//Department of Science and Technology (DST)-Science and Engineering Research Board (SERB)/ ; KBCNMU/RGSTC/Sanction Order/199//Kavayitri Bahinabai Chaudhari North Maharashtra University (KBCNMU)/ ; },
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis ; Animals ; *Alzheimer Disease/drug therapy ; Mice ; *Naphthalenes/chemistry/pharmacology ; *Benzopyrans/chemistry/pharmacology ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Molecular Docking Simulation ; Male ; Humans ; Scopolamine ; Cell Line ; Structure-Activity Relationship ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with cholinergic dysfunction. Herein, we have designed and synthesized series of 4-(naphthalen-1-yl)-4H-chromene derivatives 4(a-n) by a one-pot three-component reaction with adequate synthetic yield and purity. Naphthalene-chromene hybrids were synthesized by formation of two C─C bonds and one C─O bond in a single synthetic step. All synthesized compounds were tested for safety and efficacy using in vitro and in vivo studies. Compounds were found devoid of cytotoxicity in BV-2 cells. Most of the synthesized compounds have shown moderate to good inhibitory activity against cholinesterase enzymes. These compounds were found to be more selective towards acetylcholinesterase (AChE) compared to butyrylcholinesterase (BuChE). Compound 4 m has shown highest inhibitory potency against AChE (AChE, IC50 = 1.08 µM; BuChE, IC50 = 82.59 µM). The prototype compound (4 m) from in-vitro screening was found to be safe in acute oral toxicity followed by histopathological analysis. Compound 4 m was evaluated for in vivo efficacy in scopolamine-induced cognitive impairment model in mice. It significantly reversed the cognitive deficit in neurobehavioral tests. Pre-treatment with 4 m have balanced key biochemical markers involved in the oxidative stress and cognitive functions. The compound 4 m alleviated neuronal tissue damage caused by scopolamine as indicated in the histological study. Molecular docking analysis also reconfirmed the binding affinity of 4 m at cholinesterase enzymes. Taken together, these findings supported the emergence of 4 m as a potential cholinesterase inhibitor for the treatment of AD.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis
Animals
*Alzheimer Disease/drug therapy
Mice
*Naphthalenes/chemistry/pharmacology
*Benzopyrans/chemistry/pharmacology
Acetylcholinesterase/metabolism
Butyrylcholinesterase/metabolism
Molecular Docking Simulation
Male
Humans
Scopolamine
Cell Line
Structure-Activity Relationship

@article {pmid42324916,
year = {2026},
author = {Yin, J and Srivastava, S and Tang, X and Galbraith, C and Uchenunu, O and Miller, J and Liu, Y and Crescenzi, I and Kiyota, T and Kurinov, I and Costa-Mattioli, M and Laufer, R and Aman, A and Rottapel, R and Ramnauth, J and Haakonsen, DL and Uehling, DE and Sicheri, F},
title = {Structural Transformation of a BRAF Inhibitor into a Selective PKR Inhibitor.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c03664},
pmid = {42324916},
issn = {1520-4804},
abstract = {The RNA-dependent protein kinase PKR regulates responses to viral infection and has emerging roles in memory formation. Inhibition of PKR enhances long-term memory in mice and reverses cognitive decline in models of aging and Alzheimer's disease. However, existing PKR inhibitors have poor selectivity and pharmacokinetic properties, limiting therapeutic development. Here, we describe the transformation of dabrafenib, an FDA-approved oncogenic BRAF inhibitor, into a selective PKR inhibitor. Dabrafenib was identified by screening as a promising PKR lead with similar potency against BRAF and PKR. Guided by X-ray cocrystal structures, we introduced modifications that removed BRAF while retaining PKR inhibition. This optimization yielded OICR-403184, which shows markedly reduced BRAF activity, improved PKR selectivity (IC50 > 10,000 nM against BRAF vs IC50 = 263 nM against PKR in vitro), and minimal activity against related eIF2α kinases in cells. These findings establish OICR-403184 as a promising chemical starting point for further PKR inhibitor optimization.},
}

@article {pmid42324989,
year = {2026},
author = {Carriere, L and Minyo, M and Bass, D and Possin, KL and Samper-Ternent, R and Salinas, J and Deaner, N},
title = {Bridging the diagnostic gap: Expanding dementia care navigation for timely diagnosis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71619},
doi = {10.1002/alz.71619},
pmid = {42324989},
issn = {1552-5279},
support = {/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Dementia/diagnosis/therapy ; *Patient Navigation ; *Delayed Diagnosis/prevention & control ; Treatment Delay ; },
abstract = {Over half of dementia cases remain undiagnosed, with persistent disparities across racial, ethnic, and socioeconomic groups. Dementia care navigation (DCN) has demonstrated value in post-diagnosis settings. If implemented earlier, DCN could address diagnostic delays and care gaps. We define the diagnostic window as the period from initial symptom awareness through diagnosis and early care planning. Drawing on deliberations from the Alzheimer's Association Dementia Care Navigation Roundtable, we present a pre-diagnosis DCN framework organized across six domains and describe navigator roles across three phases: pre-evaluation, diagnostic assessment, and immediate post-diagnosis and transition. We address special considerations, including people without a care partner and those with unmet care needs. The framework complements federal initiatives such as the Guiding an Improved Dementia Experience (GUIDE) Model and the National Alzheimer's Project Act and identifies existing reimbursement pathways for pre-diagnostic navigation activities. Generating evidence to refine these models across diverse settings will be essential to inform policy action and system-level integration.},
}

Humans
*Dementia/diagnosis/therapy
*Patient Navigation
*Delayed Diagnosis/prevention & control
Treatment Delay

@article {pmid42325000,
year = {2026},
author = {Chen, Y and Duggan, MR and Timsina, J and Xu, Y and Western, D and Gong, K and Liu, M and Budde, J and Schindler, SE and Morris, JC and Holtzman, DM and Benzinger, TLS and Gordon, BA and Moqri, M and , and Ibanez, L and Walker, KA and Cruchaga, C and Ali, M},
title = {Blood-based proteomic signature of amyloidosis: identification of novel regulators of amyloid load.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71611},
doi = {10.1002/alz.71611},
pmid = {42325000},
issn = {1552-5279},
support = {ZEN-22-848604/ALZ/Alzheimer's Association/United States ; R01AG044546//Foundation for the National Institutes of Health/ ; },
mesh = {Humans ; *Proteomics/methods ; *Amyloidosis/blood/diagnostic imaging ; *Alzheimer Disease/blood ; Biomarkers/blood ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; Female ; Male ; Aged ; Brain/diagnostic imaging/metabolism ; },
abstract = {INTRODUCTION: Cerebral amyloidosis is a defining feature of Alzheimer's disease (AD), yet the molecular heterogeneity among amyloidbeta-positive (Aβ+) individuals remains poorly defined. We aimed to map the proteomic correlates of cerebral amyloidosis and link them to clinical variability within Aβ+ individuals.

METHODS: We integrated quantitative amyloid PET with large-scale plasma proteomics (∼7000 proteins; SomaScan version 4.1) in Knight Alzheimer's Disease Research Center and Bio-Hermes cohorts (n = 1429). Proteome-wide association analyses identified proteins associated with amyloid load, followed by unsupervised clustering and pathway enrichment analyses.

RESULTS: We identified 454 amyloid-associated proteins, of which 54 replicated cross-cohort. A derived 54-protein proteomic score correlated with amyloid burden, AD biomarkers, and clinical severity. Pathway analyses of clinically distinct protein clusters revealed coordinated enrichment of intracellular signaling, immune, and proteostasis modules.

DISCUSSION: These findings delineate the circulating proteomic signature of cerebral amyloidosis and support plasma proteomics as a complementary approach to phosphorylated tau at threonine 217 and amyloid PET for biological stratification and characterization of disease heterogeneity in AD.},
}

Humans
*Proteomics/methods
*Amyloidosis/blood/diagnostic imaging
*Alzheimer Disease/blood
Biomarkers/blood
Positron-Emission Tomography
*Amyloid beta-Peptides/metabolism
Female
Male
Aged
Brain/diagnostic imaging/metabolism

@article {pmid42325001,
year = {2026},
author = {Yin, H and Deng, Y and Lu, Z and Jiang, Y and Zuo, C and Li, J and Guo, L and Ying, B and Battaglia, G and Tian, X and Gong, Q and , },
title = {Choroid plexus remodeling linked to impaired CSF-mediated clearance and Alzheimer's disease progression.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71606},
doi = {10.1002/alz.71606},
pmid = {42325001},
issn = {1552-5279},
support = {ZYGD23007//1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University/ ; ZYYC24011//1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University/ ; },
mesh = {*Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging ; *Choroid Plexus/pathology/diagnostic imaging ; Animals ; Humans ; Disease Progression ; Positron-Emission Tomography ; Mice, Transgenic ; Mice ; Magnetic Resonance Imaging ; Male ; Female ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Aged, 80 and over ; Diffusion Tensor Imaging ; tau Proteins/cerebrospinal fluid/metabolism ; Amyloid beta-Protein Precursor/genetics ; Biomarkers/cerebrospinal fluid ; Disease Models, Animal ; },
abstract = {INTRODUCTION: Impaired cerebrospinal fluid (CSF) -mediated clearance has been implicated in Alzheimer's disease (AD), but how choroid plexus (ChP) remodeling relates to these processes in vivo remains incompletely understood.

METHODS: In a large ADNI cohort, we integrated structural magnetic resonance imaging (MRI), amyloid/tau positron emission tomography (PET), and diffusion tensor imaging (DTI) -derived analysis along the perivascular space (ALPS) to characterize ChP changes and their associations with ventricular measures, glymphatic marker, CSF biomarkers, and cognition across diagnostic stages. Our experiments in APP/PS1 mice complemented human analyses.

RESULTS: ChP volume increased with disease stage, while PET signal decreased. Larger ChP volume was associated with ventricular enlargement, a lower ALPS index, higher cortical amyloid/tau burden, and worse cognitive performance. Glymphatic impairment partially mediated ChP effects on cognition and pathology. APP/PS1 mice recapitulated the key ChP and glymphatic MRI phenotypes observed in humans, alongside altered expression and localization of key proteins.

DISCUSSION: ChP remodeling linked to impaired CSF-mediated clearance, highlighting its role as an early diagnostic and therapeutic target.},
}

*Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging
*Choroid Plexus/pathology/diagnostic imaging
Animals
Humans
Disease Progression
Positron-Emission Tomography
Mice, Transgenic
Mice
Magnetic Resonance Imaging
Male
Female
Aged
Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Aged, 80 and over
Diffusion Tensor Imaging
tau Proteins/cerebrospinal fluid/metabolism
Amyloid beta-Protein Precursor/genetics
Biomarkers/cerebrospinal fluid
Disease Models, Animal

@article {pmid42325010,
year = {2026},
author = {Perović, M and Phillips, NA and Einstein, G},
title = {Sex differences in the association of adverse childhood experiences with brain and cognition along a continuum of risk for Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71612},
doi = {10.1002/alz.71612},
pmid = {42325010},
issn = {1552-5279},
support = {MFE-201012//Canadian Institutes of Health Research Postdoctoral Fellowship/ ; //Jacqueline Ford Gender and Health Fund/ ; //Wilfred and Joyce Posluns Chair in Women's Brain Health and Aging/ ; //Alzheimer's Society of Canada/ ; //Ontario Graduate Scholarship - International/ ; WJP-150643//Ontario Brain Institute/ ; CCNA 049-04//Consortium canadien en neurodégénérescence associée au vieillissement/ ; CNA-163902//Consortium canadien en neurodégénérescence associée au vieillissement/ ; },
mesh = {Humans ; Female ; *Alzheimer Disease/psychology/pathology/diagnostic imaging ; Male ; *Adverse Childhood Experiences ; *Sex Characteristics ; *Cognitive Dysfunction/psychology/pathology ; Aged ; *Brain/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; *Cognition/physiology ; Risk Factors ; Aged, 80 and over ; Neuropsychological Tests ; Canada ; Prefrontal Cortex/pathology ; },
abstract = {INTRODUCTION: Women make up two-thirds of people with Alzheimer's disease (AD). Research has focused on biological explanations for this sex difference, while contributions of psychosocial risk factors are less well understood.

METHODS: We examined sex differences in the effects of adverse childhood experiences (ACEs) on late-life cognition in groups along a continuum of AD risk: cognitively unimpaired controls (CU; n = 128), subjective cognitive decline (SCD; n = 113), mild cognitive impairment (MCI; n = 241), and AD (n = 77), from the Canadian Consortium on Neurodegeneration in Aging Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study.

RESULTS: Women reported more ACEs than men. There were negative associations between ACEs and hippocampal and prefrontal cortical volumes in CU men and prefrontal volumes in men with SCD. In MCI, ACEs were linked to poorer executive function and associative memory in women. No ACE-related effects were found in AD.

DISCUSSION: ACEs may have enduring effects on late-life cognition that differ between men and women and vary by cognitive status.},
}

Humans
Female
*Alzheimer Disease/psychology/pathology/diagnostic imaging
Male
*Adverse Childhood Experiences
*Sex Characteristics
*Cognitive Dysfunction/psychology/pathology
Aged
*Brain/pathology/diagnostic imaging
Magnetic Resonance Imaging
*Cognition/physiology
Risk Factors
Aged, 80 and over
Neuropsychological Tests
Canada
Prefrontal Cortex/pathology

@article {pmid42325211,
year = {2026},
author = {Laham, MS and Ackerman-Berrier, MS and Alam, F and Turner, S and Velma, GR and Penton, C and Musku, SR and Rana, M and Thulasingam, S and Annadurai, A and Sulaiman, MI and Ma, N and Thatcher, GRJ},
title = {Exploration of precision coregulator TR-FRET identifies diverse signatures for LXR ligands relevant to discovery of nonlipogenic ABCA1 inducers.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
doi = {10.7554/eLife.109146},
pmid = {42325211},
issn = {2050-084X},
support = {T32GM008804/NH/NIH HHS/United States ; U01AG076450/NH/NIH HHS/United States ; },
mesh = {*Liver X Receptors/metabolism/agonists ; Humans ; *ATP Binding Cassette Transporter 1/metabolism ; Ligands ; Fluorescence Resonance Energy Transfer/methods ; },
abstract = {APOE4, the major genetic risk factor for Alzheimer's disease (AD), and ATP-binding cassette-A1 (ABCA1), required for lipidation of APOE are gene products of the liver X receptor (LXR) receptor. LXR agonists have been validated in animal models as therapeutics for AD, atherosclerosis, and many other diseases. Clinical progress has been thwarted by unwanted hepatic lipogenesis. Structurally diverse LXR ligands were profiled in coregulator TR-FRET (CRT) assays analyzing ligand-induced coactivator recruitment, coactivator selectivity, corepressor dissociation, and LXR isoform selectivity. A multiplex CRT assay was developed to measure synchronous ligand-induced displacement of corepressor by coactivator. Potency for coactivator recruitment to LXRβ correlated with induction of ABCA1 in human astrocytoma cells. Correlation with lipogenic activation of sterol response element (SRE) in hepatocarcinoma cells, was more complex. CRT response was diverse revealing ligands with theoretical full agonist, partial agonist, antagonist, inverse agonist, and other signatures within the same chemical series, suggesting the scope for precision CRT to guide nonlipogenic LXR agonist design.},
}

*Liver X Receptors/metabolism/agonists
Humans
*ATP Binding Cassette Transporter 1/metabolism
Ligands
Fluorescence Resonance Energy Transfer/methods

@article {pmid42325223,
year = {2026},
author = {Thia, BWQ and Tan, DYZ and Wong, BWX and Shen, L and Gong, L and Ling, LH and Chen, CL and Yong, EL},
title = {Indices of Arterial Stiffness and the Alzheimer's Disease Biomarker, p-tau217, in Non-Demented Midlife Women.},
journal = {Pulse (Basel, Switzerland)},
volume = {14},
number = {1},
pages = {78-92},
pmid = {42325223},
issn = {2235-8676},
abstract = {INTRODUCTION: The association between indices of arterial stiffness and/or pressure wave reflection with Alzheimer disease amyloid-β accumulation and tau pathology in the brain is unclear. Deficiency of estrogen post-menopause may be an important contributor to changes in these indices to affect Alzheimer's disease progression. We aimed to assess the associations between indices of arterial stiffness and/or pressure wave reflection and the Alzheimer's disease blood biomarker, p-tau217, in midlife women without dementia.

METHODS: This cross-sectional analysis of participants from the Integrated Women's Health Program (IWHP) enrolled community-dwelling midlife women without dementia attending routine health screening at the National University Hospital in Singapore. Fasted blood p-tau217 was measured using the Simoa® ALZpath p-tau217 Advantage PLUS (Quanterix, MA, USA). Aortic augmentation index (AIx) and reflection index (RI) were obtained from peripheral arterial pressure waveforms and cardio-ankle vascular index (CAVI) measured using pressure cuffs on the extremities and a phonocardiogram. Multivariable linear regression was used to examine the independent associations between indices of arterial stiffness and serum levels of p-tau217.

RESULTS: Among 871 participants (mean age: 62.80 ± 6.02 years), every SD increase in AIx and RI scores was both associated with 0.010 pg/mL (95% CI: 0.003-0.017, p = 0.004) higher blood p-tau217 levels after adjustment for age, employment status, BMI, mild cognitive impairment, hypertension, cholesterol-HDL ratio, renal function, and ApoE4 carrier status. With natural logarithmic transformed p-tau217, RI remained significantly associated with ln(p-tau217), β = 0.026 (0.007, 0.045), p = 0.007, after covariate adjustment. For AIx, the association was attenuated but remained directionally consistent. Trends for the association between CAVI and blood p-tau217 level were not statistically significant after adjustment for covariates.

CONCLUSION: Increases in indices of arterial stiffness and pressure wave reflection were associated with higher blood p-tau217 levels in community-dwelling midlife women without dementia. These indices may be markers of risk for tau-related pathologies in the brain.},
}

@article {pmid42325225,
year = {2026},
author = {Mukherjee, D and Raghul Kannan, S and Tamizhselvi, R},
title = {N-terminal modifications as fate switches in neurodegeneration: a mechanistic review.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1809812},
pmid = {42325225},
issn = {1663-4365},
abstract = {The accumulation of aberrant proteins or their impaired clearance leads to neurodegenerative diseases (NDs). The protein amino terminus (Nt) and its modifications determine the fate of proteins and their cellular effects. Nt acetylation, Nt methylation, and Nt myristoylation are protein Nt modifications implicated in the pathogenesis of proteinopathies like Alzheimer's, Parkinson's, and Huntington's diseases by regulating the protein lifespan, folding, and interaction with protein/DNA. In particular, Nt acetylation shields proteins from degradation or targets them for the same, thereby affecting their fate. Distinct enzymes catalyze Nt acetylation, Nt methylation, and Nt myristoylation, and these modifications compete for the nascent polypeptide at the ribosomal exit tunnel. Dysregulation of Nt modifications initiates the protein aggregation cascade and could potentially induce neuroinflammation and neurodegeneration. Here, we review Nt modifications and their emerging roles in the pathogenesis of NDs. Further, we highlight the crosstalk among distinct Nt modifications and explore how their convergence may shape disease vulnerability and progression.},
}

@article {pmid42325226,
year = {2026},
author = {Alhowail, AH and Al Mouslem, AK and Almatrafi, MA and Aldubayan, MA},
title = {Semaglutide in cognitive dysfunction: neuroprotective potential, clinical trial limitations, and a prevention-focused framework.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1851072},
pmid = {42325226},
issn = {1663-4365},
abstract = {Metabolic dysfunction is increasingly recognized as a pivotal factor in cognitive decline and neurodegenerative diseases, such as Alzheimer's disease (AD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs), notably the long-acting agonist semaglutide, exhibit significant metabolic efficacy and pronounced neuroprotective effects across a broad spectrum of preclinical models. This is corroborated by extensive epidemiological studies that consistently link GLP-1RA use with a decreased incidence of dementia. Nevertheless, promising preclinical and observational findings have not been mirrored in clinical success for the treatment of established AD. Recent negative outcomes from the pivotal phase 3 EVOKE and EVOKE+ trials, which demonstrated no clinical benefit of oral semaglutide in patients with early AD, have resulted in a notable translational paradox. This review critically examines the mechanistic, preclinical, epidemiological, and clinical evidence concerning the impact of semaglutide on cognitive function to reconcile these conflicting findings. Preclinical studies have revealed complex neuroprotective mechanisms, including suppression of neuroinflammation, restoration of metabolic function, and activation of pro-survival pathways. Conversely, clinical trials in symptomatic AD have been unsuccessful, although modest and clinically insignificant changes in cerebrospinal fluid biomarker levels have been observed. We propose the hypothesis that the current body of evidence is consistent with a prevention-focused model, wherein semaglutide's primary value may lie in modifying the upstream metabolic and inflammatory drivers of neurodegeneration, such as those prevalent in vascular and metabolic cognitive impairment, rather than reversing established amyloid-driven AD pathology. This hypothesis, however, remains speculative and requires prospective validation in appropriately designed trials. This review seeks to resolve the apparent contradictions in the literature and propose future research directions centered on appropriate patient populations and therapeutic windows.},
}

@article {pmid42325271,
year = {2026},
author = {Liang, C and Jiang, W and Chen, J and Turner, JA and Calhoun, VD and Abbott, CC and Jiang, R and Fu, Z and Wu, L and Wang, X and Qi, S and Yuan, Y},
title = {Longitudinally altered default mode network and insula multimodal brain pattern in end-stage renal disease during sustained hemodialysis treatment.},
journal = {iScience},
volume = {29},
number = {6},
pages = {116008},
pmid = {42325271},
issn = {2589-0042},
abstract = {Hemodialysis (HD) is the predominant treatment for end-stage renal disease (ESRD). Despite the efficacy of HD, the neurobiological underpinnings underlying high-risk complications remain unclear. In this study, using unsupervised fusion of functional and structural MRI, we identified a longitudinally altered default mode network (DMN)-insula pattern in ESRD receiving HD over 1-year follow-up (n = 39). This pattern was associated with cognition, and its related genes were enriched in biological processes involving DNA damage and repair, energy metabolism, and cellular activation. The baseline DMN-insula pattern demonstrated potential predictive value for follow-up cognition in ESRD. More importantly, these brain-cognition associations were validated in independent high-risk complications cohorts, including major depressive disorder (n = 60), mild cognitive impairment (n = 291), and Alzheimer's disease (n = 77) by extracting the corresponding brain features and assessing their correlations with cognition. Collectively, this study may help researchers better understand the underlying mechanisms of ESRD receiving HD from a multimodal neuroimaging and molecular perspective.},
}

@article {pmid42325273,
year = {2026},
author = {Hao, W and Yu, X and Zhou, Q and Jia, Y and Su, X and Yu, Y and Wang, Y and Wang, J and Liu, C},
title = {Different modulation patterns of theta and gamma dual-site HD-tACS on cognitive impairment.},
journal = {iScience},
volume = {29},
number = {6},
pages = {116138},
pmid = {42325273},
issn = {2589-0042},
abstract = {Alzheimer's disease (AD) is characterized by impaired local network integration and long-range connections. Theta and gamma oscillations are critical for cognitive function, so this study used dual-site fronto-temporoparietal junction (TPJ) high-density transcranial alternating current stimulation (HD-tACS) to explore its frequency-specific effects on brain networks and cognition. Thirty-six AD patients were randomized 1:1:1 to 6Hz-tACS, 40Hz-tACS and sham stimulation targeting bilateral fronto-TPJ cortex for four weeks. Cognitive functions were assessed at baseline, post-treatment and 8-week follow-up. TMS-EEG and voxel-based distance-related functional connectivity analysis evaluated network changes. Both active stimulation groups showed sustained cognitive improvements for eight weeks compared to the sham stimulation group (all p < 0.017). 40Hz-tACS also enhanced language function (p < 0.025). 6Hz-tACS increased anterior functional connections and anterior-to-posterior information flow, while 40Hz-tACS increased posterior connections and posterior-to-anterior flow, closely linked to cognitive improvements. These effects are oscillation frequency-dependent, supporting cognitive improvement in AD.},
}

@article {pmid42325435,
year = {2026},
author = {Liu, C and Zhu, Z and Lin, H and Bush, WS and Jenq, RR and Cominelli, F and Pillai, JA and Haines, JL and Zhu, X and Xu, R and Williams, SM and Cheng, F and Zhang, L},
title = {The gut-brain axis in Alzheimer's disease: early detection, microbial metabolites, mechanisms, and therapeutic opportunities.},
journal = {Frontiers in molecular biosciences},
volume = {13},
number = {},
pages = {1735332},
pmid = {42325435},
issn = {2296-889X},
abstract = {Alzheimer's disease (AD), the leading cause of dementia worldwide, imposes a growing clinical and societal burden, yet no therapies have been proven to alter its progression despite decades of intensive research. As traditional targets have yielded limited success, attention has shifted to modifiable upstream pathways, notably the gut-brain axis, a bidirectional system linking gut microbiota with CNS function. Emerging evidence indicates that microbial dysbiosis may influence key processes leading to AD, including neuroinflammation, amyloid and tau pathology, and cognitive decline. While microbiome composition is associated with AD, it remains unclear at which stage-preclinical, mild cognitive impairment (MCI), or AD dementia-these differences first arise, or how specific risk bacteria and metabolites contribute to progression. The precise roles of these microbes and metabolites in AD pathology or brain resilience also remain poorly understood, and few microbiome-targeted treatments have been validated in humans. Existing reviews often overlook host-specific factors that influence microbiome composition and confound associations with AD. To bridge these gaps, we summarize human studies published in the past 5 years. The literature suggests that gut microbial changes may precede clinical symptoms, with consistent dysbiosis observed in AD patients. We adopt a microbiome-centered perspective emphasizing bacteria-driven and metabolite-driven mechanisms, each playing distinct yet complementary roles in neural and bloodstream pathways. These pathways offer potential targets for microbiome-based prevention and treatment but require more human validation. Future studies should leverage longitudinal, multi-omics approaches and artificial intelligence (AI) tools while rigorously accounting for confounders to improve early detection and develop personalized therapies for AD.},
}

@article {pmid42325550,
year = {2026},
author = {Li, X and Chen, H and Xu, P and Guo, X and Gao, J and Yao, D and Wang, Y and Wang, T and Liu, B and Yuan, J},
title = {Exosomes: A new frontier in the treatment of neurological diseases.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116331},
pmid = {42325550},
issn = {2589-0042},
abstract = {Exosomes (Exos) are an essential class of extracellular vesicles enriched with a wide range of biologically active molecules, which gives them a unique advantage in participating in intercellular signaling and communication and serving as carriers for drug delivery. Exo-based diagnostic and therapeutic strategies are currently hot topics in disease research. Owing to their naturally low immunogenicity, good biocompatibility, ability to penetrate the blood‒brain barrier (BBB), and engineered modifications, exos have significant advantages and possible applications in the treatment of nervous system diseases. Due to the serious harm of neurological diseases to human health, they have been widely studied by researchers. Exos can be administered in a variety of ways, including intranasal administration, intracranial administration, local stereotactic injection, and encapsulation in biomaterials, each of which has its own advantages and disadvantages. However, several requirements need to be met before exo-based therapies can be implemented, such as the standardization of isolation and purification techniques, an in-depth understanding of the mechanism of action, and safety assessments and regulation for clinical translation. The aim of this review is to provide a comprehensive overview of the biogenesis, molecular composition, function, and delivery modes of exos and their therapeutic roles and mechanisms in neurological diseases (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and stroke) and to discuss the current challenges and future perspectives to support ongoing research and clinical applications.},
}

@article {pmid42325556,
year = {2026},
author = {Xiong, D and Liu, M and Xie, J and Liu, Z and Wang, J},
title = {A dual space MRI radiomic network signature for risk stratification and subtyping of mild cognitive impairment.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116394},
pmid = {42325556},
issn = {2589-0042},
abstract = {Mild cognitive impairment (MCI) is a clinically heterogeneous prodromal stage of Alzheimer's disease (AD) in which accurate risk stratification could support earlier intervention and more efficient trial design. Using baseline T1-weighted MRI from the Alzheimer's Disease Neuroimaging Initiative and the National Alzheimer's Coordinating Center cohorts, we developed a dual-space anatomical radiomic-network signature that integrates regional radiomic features and radiomics similarity network metrics extracted in standard and native spaces. The signature improved prediction of MCI-to-AD conversion relative to regional volumetric and clinical models, achieved consistent external validation performance, and separated participants into high- and low-risk groups. The same feature set identified five imaging-defined MCI subtypes with distinct anatomical patterns, conversion risks, and clinical, APOE ε4, and cerebrospinal fluid biomarker profiles; fronto-parietal and parahippocampal-temporal subtypes showed the highest risk. These findings support structural MRI radiomic-network profiling as a complementary framework for individualized prognosis and cohort stratification in AD research.},
}

@article {pmid42325559,
year = {2026},
author = {Wei, Z and Yang, J and Qiao, Y and Wang, S and Cai, Y and Gao, L},
title = {Sleeve gastrectomy improves cognition by enhancing central ERK/CREB/BDNF pathway through increased GIP secretion.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116292},
pmid = {42325559},
issn = {2589-0042},
abstract = {Sleeve gastrectomy (SG) was used to probe the gut-brain axis in Alzheimer's disease (AD). In APP/PS1/Tau triple transgenic mice, SG improved glucose tolerance and insulin sensitivity without lasting effects on body weight or food intake. SG significantly improved cognitive performance and reduced anxiety-like behavior, attenuated neuronal damage and pTau accumulation in the hippocampal CA3 region, and increased both peripheral levels and hippocampal immunoreactivity of GIP and GLP-1 along with ERK/CREB/BDNF pathway activity. In HT22 cells, GIP receptor knockdown exacerbated Aβ-induced pTau and suppressed this pathway, whereas GLP-1 acted synergistically. These findings indicate that SG could improve cognition in non-obese AD mice largely through GIP/GLP-1 signaling rather than metabolic changes, supporting dual incretin targeting as a therapeutic strategy for AD.},
}

@article {pmid42325569,
year = {2026},
author = {Sebastian, RM and Kupp, R and Nanavati, D and Parfentev, I and Krzystek, TJ and Romanul, N and Yanamandra, K and Preiss, CN and Manos, JD and Wu, HY and Volkova, A and Crescenti, S and Titterton, K and Welker, AM and Townsend, M and Karran, E and Langlois, X and Wu, JW},
title = {SynCAR platform for capturing neuronal synaptic proteopathic seeds.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116362},
pmid = {42325569},
issn = {2589-0042},
abstract = {Synaptic proteins are critical for maintaining healthy neuronal transmission but can also drive prion-like trans-synaptic spreading of pathological aggregated proteins found in many neurodegenerative diseases, including Alzheimer's disease. Recognizing technological limitations for in situ identification of synaptic proteins, we built a modular synaptic chimeric antigen receptor (synCAR) for capture of synaptic proteins by fusing a single-chain antibody fragment with the post-synaptic protein neurolignin-1 (NLGN1). Using our synCAR platform, we show that anchoring the tau antibody PHF1 to the synapse effectively captures pathogenic synaptic tau species. Expressing PHF1 synCAR at synapses in mouse primary and human neuronal tau seeding models results in increased tau aggregation, likely due to concentrating pathological tau seeds at the synapse. These findings provide the first published method for the isolation and modulation of synaptic protein function within relevant biological contexts, highlighting synCAR as a relevant instrumental platform for synaptic protein research and neurodegenerative disease drug development.},
}

@article {pmid42325592,
year = {2026},
author = {Bellaver, B and Povala, G and De Bastiani, MA and Pola, I and Ferreira, PCL and Bauer-Negrini, G and Ferrari-Souza, JP and Leffa, DT and Lussier, FZ and Therriault, J and Rahmouni, N and Stevenson, J and Servaes, S and Patira, R and Gauthier, S and Tudorascu, DL and Karikari, TK and Ashton, N and Blennow, K and Zetterberg, H and Zimmer, ER and Benedet, AL and Rosa-Neto, P and Pascoal, TA},
title = {Aβ- and tau-associated neuroinflammatory signatures in Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70275},
pmid = {42325592},
issn = {2352-8737},
abstract = {INTRODUCTION: Neuroinflammation is increasingly recognized as a key contributor to Alzheimer's disease (AD) progression, with distinct responses linked to amyloid beta (Aβ) and tau pathology. Two detrimental waves of neuroinflammation have been proposed, the first during early Aβ accumulation, and the second during widespread tau deposition. However, the neuroinflammatory signatures associated with each phase remain unclear.

METHODS: We studied 63 individuals who underwent Aβ and tau positron emission tomography imaging along with cerebrospinal fluid profiling of 368 inflammation-related proteins. Protein contrasts between cognitively unimpaired Aβ-negative and Aβ-positive individuals defined the signature of the Aβ phase, while comparisons between cognitively impaired Aβ-positive individuals with early versus late tau pathology characterized the tau phase. Gene Ontology enrichment identified biological processes associated with differentially expressed proteins.

RESULTS: During the Aβ phase, 34 proteins were downregulated and mapped to 157 biological processes, including Toll-like receptor signaling, nuclear factor kappa beta activation, and cytokine production. The tau phase showed upregulation of 23 proteins associated with 82 biological processes enriched in adaptive immune responses. A set of 48 biological processes and three proteins including interleukin 4 receptor, cystosolic phospholipidase A2, and secretoglobin family 3A member 2 showed opposite regulation patterns, being downregulated in the Aβ phase and upregulated in the tau phase.

DISCUSSION: Our results revealed distinct neuroinflammatory signatures and biological processes associated with Aβ- and tau-dominant stages of AD. The reversal in protein expression patterns across these stages underscores the need for stage-specific neuroimmune therapeutic strategies.},
}

@article {pmid42325779,
year = {2026},
author = {Zhang, L and Ikeda, N and Takeda, S and Oikawa, N and Murayama, S and Koshimizu, U and Yabe, I and Kondo, T},
title = {Plasma ECRG4 as a novel diagnostic marker for Alzheimer's disease associated with oligodendrocyte dysfunction.},
journal = {American journal of translational research},
volume = {18},
number = {5},
pages = {3765-3782},
pmid = {42325779},
issn = {1943-8141},
abstract = {Current treatments for Alzheimer's disease (AD) primarily focus on slowing disease progression, emphasizing the urgent need for a reliable diagnostic method for early-stage Alzheimer's (EAD). Our investigation, which is based on the finding that the secretory protein Esophageal Cancer Related Gene 4 (ECRG4) is elevated in the hippocampus of AD patients, led to the creation of a novel ELISA system for ECRG4 detection. We observed that ECRG4 peptides, particularly the fragment spanning amino acids 108-132, were elevated in the plasma of approximately 25% of patients with mild cognitive impairment (MCI) and 50% of those with AD, compared to individuals without dementia. RNA sequencing of plasma samples revealed decreased levels of carbohydrate sulfotransferase 3 (CHST3) mRNA, which is mainly expressed in oligodendrocyte (OLG)-lineage cells, in ECRG4-positive patients. Functional analyses demonstrated that the ECRG4 (71-107) peptide induced cytotoxicity in oligodendrocytes in vitro and reduced the expression of the OLG marker galactocerebroside in the corpus callosum following intracerebral injection. Additionally, peptide injection resulted in extravascular IgG leakage and the accumulation of OLG precursor cells (OPCs), which are crucial for myelin regeneration, around the blood vessels. These phenomena were similarly observed in the hippocampi of patients with EAD. Collectively, these findings establish ECRG4 as a novel serum marker for AD and suggest its association with ECRG4-dependent OLG dysfunction.},
}

@article {pmid42325796,
year = {2026},
author = {Wang, C and Song, B and Wang, G and Yan, X and Wu, X and Zhou, S and Hu, P and Wang, K and Ji, G and Wang, Z and Xu, S},
title = {Non-invasive neuromodulation techniques for cognitive impairment intervention.},
journal = {American journal of translational research},
volume = {18},
number = {5},
pages = {3700-3714},
pmid = {42325796},
issn = {1943-8141},
abstract = {Cognitive impairment involves sustained deficits across several key domains: memory, executive function, attention, and behavioral regulation. The condition encompasses cognitive dysfunction linked to Alzheimer's disease, mild cognitive impairment, vascular cognitive impairment, and other forms of neurodegeneration. Existing pharmacotherapies frequently yield inconsistent clinical benefits, are often accompanied by side effects, and generally lack disease-modifying properties. These limitations have spurred increasing attention toward safe, repeatable non-pharmacological strategies. Non-invasive brain stimulation, a central non-pharmacological tool, can regulate excitability in targeted brain regions, shape network-level connectivity, and facilitate activity-dependent neuroplasticity. Evidence from multiple clinical settings supports its potential to improve cognitive outcomes. This review centers on major NIBS techniques: repetitive transcranial magnetic stimulation, transcranial electrical stimulation, gamma-frequency sensory stimulation, photobiomodulation, and transcranial ultrasound stimulation. We synthesize their underlying mechanisms, clinical applications, and supporting evidence, aiming to provide an evidence-based framework to guide standardized clinical implementation and future research design in this area.},
}

@article {pmid42325951,
year = {2026},
author = {Zhao, W and Liu, X and Yao, Y and Yu, Y and Hu, Z},
title = {Exploring ceramide as a novel biomarker and therapeutic target for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1771302},
pmid = {42325951},
issn = {1662-4548},
abstract = {Metabolic dysregulation is increasingly being recognized as a hallmark across various neurodegenerative diseases. While Alzheimer's disease (AD) is well-established as a dual proteinopathy characterized by amyloid-beta (Aβ) deposition and tau protein tangles, the specific mechanisms mediating lipid homeostasis imbalance have garnered increasing attention. However, translating these findings into safe clinical therapeutic targets remains a formidable challenge, primarily hindered by the pleiotropic roles of ceramides in maintaining neural and immune homeostasis, as well as the blood-brain barrier (BBB) penetration issues and systemic safety limitations of current sphingolipid-targeting strategies. We conducted a comprehensive search of electronic databases, including PubMed, Web of Science, and Google Scholar, to identify relevant studies published from database inception through March 2026. The search term combinations included: "Alzheimer's disease," "AD," "ceramide," "sphingolipid metabolism," "biomarker," "therapeutic target," "neuroinflammation," and "mitochondrial dysfunction." To ensure the depth and rigor of this review, priority was given to peer-reviewed original research, systematic reviews, and meta-analyses. The search was restricted to English-language literature. Additionally, the reference lists of retrieved articles were manually screened to identify further relevant studies. This narrative review aims to comprehensively elucidate the potential roles of ceramides in AD pathogenesis, exploring their associations with triggering inflammatory responses, mediating apoptosis, interfering with signal transduction, and inducing mitochondrial dysfunction.},
}

@article {pmid42325956,
year = {2026},
author = {Zhang, Z and Bai, Y and Zhang, X and Zhang, J and Yang, G},
title = {ALDOC modulates astrocytic glycolysis and AMPK/mTOR/HIF-1α signaling in Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1847340},
pmid = {42325956},
issn = {1662-4548},
abstract = {AIMS: Astrocytes provide crucial metabolic support for neurons and undergo significant metabolic changes in Alzheimer's disease (AD). Aldolase C (ALDOC), an astrocyte-enriched glycolytic enzyme, may play a role in this process. This study aimed to investigate whether ALDOC modulates astrocytic metabolism to support neuronal energy supply in patients with AD and to assess its therapeutic potential.

METHODS: Hippocampal and cortical tissues from 6-month-old APP/PS1 and wild-type mice were subjected to western blotting, qPCR, and immunofluorescence staining for ALDOC and glycolytic proteins. An in vitro AD model was created using oligomeric β-amyloid (oAβ)-treated SVGp12 astrocytes. ALDOC was overexpressed or knocked down via plasmid or siRNA. Downstream effects on AMPK/mTOR/HIF-1α signaling and the expression of glycolytic markers (LDHA and PKM2) were evaluated by western blot and qPCR, as well as by lactate/ATP assays and extracellular acidification rate (ECAR) measurements. Neuron-astrocyte interactions were assessed in an SVGp12/SH-SY5Y coculture. Furthermore, the ability of magnesium ions to restore ALDOC expression was tested.

RESULTS: ALDOC was specifically expressed in astrocytes but was downregulated in APP/PS1 mice, accompanied by reduced HIF-1α and LDHA levels, suggesting glycolytic impairment. Similar downregulation occurred in oAβ-treated SVGp12 cells. ALDOC overexpression was associated with altered AMPK/mTOR/HIF-1α signaling, enhanced glycolysis, and increased lactate and ATP production, whereas its knockdown had the opposite effects. These outcomes appeared to depend on HIF-1α, as suggested by the rescue experiments. In coculture, ALDOC overexpression in astrocytes supported neuronal metabolic function. Moreover, magnesium ions restored ALDOC activity and glycolysis in oAβ-treated astrocytes.

CONCLUSION: These results suggest that ALDOC is downregulated in APP/PS1 mice and is associated with glycolytic impairment. In oAβ-treated astrocytes, ALDOC appears to regulate glycolysis through the AMPK/mTOR/HIF-1α axis and may support neuronal energy via the lactate shuttle. Magnesium ions appear to offer a potential strategy for addressing the metabolic deficits in AD.},
}

@article {pmid42325964,
year = {2026},
author = {Lou, L and Zhou, Y and Zhu, H and Zheng, K and Ji, Y},
title = {Multimodal non-invasive approaches for early Alzheimer's disease detection: a review of neuroelectrophysiological and neuroimaging techniques.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1824430},
pmid = {42325964},
issn = {1664-0640},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized primarily by a gradual decline in cognitive function and specific pathological changes in the brain. In recent years, although various neuroelectrophysiological and neuroimaging techniques have greatly advanced the mechanistic study of abnormal brain function in AD, an integrative discussion of these technologies remains fragmented. This paper primarily summarizes and interactively analyzes the research progress of several non-invasive neuroimaging and neuroelectrophysiological techniques-event-related potential (ERP), electroencephalogram (EEG), transcranial magnetic stimulation-electroencephalogram (TMS-EEG), functional near-Infrared spectroscopy (fNIRS), magnetoencephalography (MEG), structural magnetic resonance imaging (structural MRI) and functional magnetic resonance imaging (fMRI)-to depict a panoramic view of AD pathology from a microscopic to a macroscopic scale from a multimodal perspective. It further compares the advantages and limitations of various technologies for detecting early AD biomarkers, emphasizing the synergistic value of multimodal integration in capturing changes in dynamic functional and structural brain networks. Additionally, we explore the potential of these technologies in clinical translation, particularly when combined with machine learning and deep learning approaches, to enhance the accuracy of early diagnosis and the depth of mechanism analysis. Through the above discussion, this review aims to provide new insights for the early identification of AD and advance our understanding of the neural mechanisms underlying AD.},
}

@article {pmid42326442,
year = {2026},
author = {Bhuiyan, MR and Reza, MS and Shuvo, SR and Yilmaz, MA and Siam, SMM and Sakib, MS and Cakir, O and Durjoy, MNI and Tarhan, A and Eruygur, N and Shahid Ud Daula, AFM},
title = {Potential of Aeginetia indica for Alzheimer's Disease Management: In Vitro, In Vivo, and Computational Insights.},
journal = {Food science & nutrition},
volume = {14},
number = {6},
pages = {e71886},
pmid = {42326442},
issn = {2048-7177},
abstract = {The 2023 Alzheimer's Disease International report warns that Alzheimer's disease (AD) is an escalating global challenge, with estimates suggesting more than 150 million cases worldwide by 2050 and about 13.8 million in the United States by 2060. AD is often linked with cholinergic dysfunction and increased acetylcholinesterase (AChE) activity, exacerbated by chronic neuroinflammation and oxidative stress. This study investigates the potential of Aeginetia indica whole plant methanolic extract (AiME) and its phytochemicals as natural AChE inhibitors (AChEIs) for AD management. AiME (IC50 = 176.586 ± 5.96 μg/mL) exhibited moderate, dose-dependent antioxidant activity compared to standard ascorbic acid (IC50 = 38.866 ± 10.059 μg/mL) in the DPPH antioxidant assay. The other two antioxidant assays, reducing power activity (RPA) and ferric-reducing antioxidant power (FRAP), also followed a similar trend (AiME: EC50 = 358.249 ± 16.605 μg/mL, EC50 = 39.467 ± 9.046 μg/mL), respectively, compared to standard ascorbic acid (Std: EC50 = 53.778 ± 0.624 μg/mL, Std: EC50 = 48.986 ± 0.512 μg/mL). AiME at all doses showed significant inhibition (p < 0.001) of paw edema in animals (in vivo) compared to the negative control group. Notably, AiME displayed better AChE inhibitory activity (IC50 = 1.636 ± 0.067 mg/mL) compared to standard rivastigmine (IC50 = 2.344 ± 0.151 mg/mL) in the acetylcholinesterase assay. LCMS/MS analysis identified 16 phenolic compounds, and GCMS analysis revealed 23 phytoconstituents in AiME. Molecular docking studies revealed acteoside, acacetin, and luteolin as promising leads, exhibiting favorable binding affinities and hydrogen bond interactions with the AChE active site. The structural stability and rigidity of our top two lead compounds, acteoside and acacetin, were evaluated using 100 ns molecular dynamics simulations, where they exhibited lower root mean square deviation values, with the acteoside-AChE complex ranging from 0.1 to 0.35 nm and the acacetin-AChE complex ranging from 0.1 to 0.4 nm, indicating notable stability. This study highlights the potential of A. indica and its phenolic constituents as natural alternatives for AD management, offering a multi-pronged mechanistic pathway through AChE inhibition, anti-inflammatory, and antioxidant properties.},
}

@article {pmid42326467,
year = {2026},
author = {Gomes, BF and Sauer, M and Montoliu-Gaya, L and Franquesa-Mullerat, M and Bejanin, A and Alcolea, D and Lleó, A and Illán-Gala, I and Fortea, J and Blennow, K and Zetterberg, H and Nilsson, J and Belbin, O and Ashton, NJ},
title = {Cerebrospinal fluid NPTX2/p-tau ratio as a biomarker for cognitive decline in neurodegenerative diseases.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70391},
pmid = {42326467},
issn = {2352-8729},
abstract = {INTRODUCTION: Neuronal pentraxin 2 (NPTX2) and its use as a ratio with other synaptic proteins has emerged as a prognostic cerebrospinal fluid (CSF) biomarker across neurodegenerative diseases.

METHODS: Using a single molecule array (Simoa) method, CSF NPTX2 was measured in 688 individuals from the Sant Pau Initiative on Neurodegeneration, including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration-related disorders (FTLDrs), and cognitively unimpaired (CU) participants. NPTX2/phosphorylated-tau (p-tau)181 performance was compared to standalone NPTX2 and p-tau181.

RESULTS: The NPTX2/p-tau ratio enhanced diagnostic performance of standalone NPTX2 and p-tau, particularly for DLB and FTLDrs (area under the curve [AUC]NPTX2/p-tau = 0.78-0.79 vs. AUCNPTX2 = 0.63-0.70 and AUCp-tau = 0.59-0.75), and was more strongly associated with cognition. It also better predicted progression to dementia across the cohort (hazard ratio [HR] = 1.63), especially in AD (HR = 1.84) and DLB (HR = 1.50).

DISCUSSION: NPTX2/p-tau may improve prognostic assessments in patients with cognitive impairment, outperforming standalone biomarkers.},
}

@article {pmid42326469,
year = {2026},
author = {Michaelian, JC and Feizpour, A and Vickers, JC and Alty, JE and Collins, JM and Doré, V and Ireland, C and King, AE and Martins, RN and Woodward, M and Naismith, SL and Rowe, CC},
title = {Impact of plasma pTau181 levels on clinician diagnostic confidence and management in memory and cognition clinics: A multi-site before-and-after study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70386},
pmid = {42326469},
issn = {2352-8729},
abstract = {INTRODUCTION: Recent advances allow blood tests to detect key proteins linked to Alzheimer's disease (AD).

METHODS: In this before-and-after study across three Australian memory and cognition clinics, we evaluated the impact on clinicians' diagnostic confidence and management following disclosure of routine patients' AD probability, using predefined plasma phosphorylated tau 181 (pTau181) thresholds set at 90% sensitivity and 90% specificity for amyloid-beta (Aβ) positron emission tomography (PET) positivity.

RESULTS: One hundred thirteen participants (mean age: 71.2 ± 8.4; mean Mini-Mental State Examination score: 27.7 ± 2.5) with dementia (n = 17, 15.0%), mild cognitive impairment (n = 48, 42.5%), and subjective cognitive decline (n = 48, 42.5%) were enrolled. Blood test results were "probably negative," n = 81, 71.7%; "indeterminate", n = 24, 21.2%; and "probably positive," n = 8, 7.1%. In 12 cases (10.6%), pTau181 changed clinician diagnosis and increased mean diagnostic confidence from low-to-moderate (61%) to moderate-to-high (80%). Aβ PET in 40 participants showed plasma pTau181 improved diagnostic accuracy by 5%.

DISCUSSION: This study demonstrates the benefits of plasma pTau181 in real-world clinical practice particularly when diagnostic confidence is only low-to-moderate.},
}

@article {pmid42326470,
year = {2026},
author = {Hokkanen, H and Hintsala, E and Hotta, J and Rantamäki-Häkkinen, T},
title = {Transient plasma p-tau217 elevations after electroconvulsive therapy: A two-case report.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70405},
pmid = {42326470},
issn = {2352-8729},
abstract = {INTRODUCTION: Plasma phosphorylated tau (p-tau217) is increasingly used in the evaluation of Alzheimer's disease (AD). However, factors influencing its interpretation in real-world settings remain incompletely defined.

METHODS: We describe a patient with repeated measurements of p-tau217 after an acute course of electroconvulsive therapy (ECT), complemented by a second patient with repeated measurements obtained during maintenance ECT.

RESULTS: In the primary case, p-tau217 was markedly elevated 3 weeks after completion of an acute ECT course (5.360 pg/mL; normal < 0.185 pg/mL), followed by a decline toward normal levels within weeks and normalization at follow-up. Cerebrospinal fluid biomarkers and neuropsychological assessment were normal. A second patient undergoing maintenance ECT demonstrated fluctuating levels of p-tau217.

DISCUSSION: ECT may induce transient elevations of p-tau217 that could be misinterpreted as suggestive of AD pathology. The temporal profile suggests a reversible process distinct from amyloid-driven tau pathology. Deferring p-tau217 testing after ECT may reduce false-positive results.},
}

@article {pmid42326471,
year = {2026},
author = {Argenti, L and Cirone, A and Massa, F and Sentieri, E and Losa, M and Lorenzini, L and Garbarino, S and Sofia, L and Raffa, S and Bauckneht, M and Sambuceti, G and Kreshpa, W and Bozzo, G and Tomassini, G and De Cesari, F and Pelagotti, V and Pulze, M and Gualco, L and Hamedani, M and Razzetta, C and Brugnolo, A and Girtler, N and Caneva, S and Mattioli, P and Morbelli, S and Ali, S and Piana, M and Serrati, C and Uccelli, A and Chincarini, A and Arnaldi, D and Roccatagliata, L and Bandini, F and Orso, B and Pardini, M},
title = {Exploring the spatial covariance of cerebral vascular density and amyloid burden in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70390},
pmid = {42326471},
issn = {2352-8729},
abstract = {INTRODUCTION: Regional patterns of amyloid beta (Aβ) deposition in Alzheimer's disease (AD) may be influenced by cerebrovascular architecture. We examined the relationship between normative arterial and venous density maps and cortical Aβ burden.

METHODS: Seventy-four amyloid-positive AD patients underwent amyloid positron emission tomography (PET) and magnetic resonance imaging. Regional Aβ uptake was quantified; spatial associations with normative arterial (time-of-flight magnetic resonance angiography) and venous (susceptibility-weighted imaging) density maps were assessed using correlation analyses and partial least squares (PLS) regression, controlling for early-frame PET as a proxy for perfusion.

RESULTS: Higher arterial density was associated with lower Aβ uptake (r = -0.68, p < 0.001), independent of venous density and perfusion. PLS explained 71% of regional variance, highlighting temporo-limbic regions. Subject-level analyses showed heterogeneous vascular-amyloid coupling, related to education and global Aβ burden.

DISCUSSION: Arterial architecture may contribute to regional amyloid vulnerability through vascular clearance mechanisms.},
}

@article {pmid42326500,
year = {2026},
author = {Kim, Y and Heo, W and Park, SJ and Kim, Y and Cho, YE and Lee, YW and Kim, J},
title = {A biphasic astrocytic PTGDS trajectory marks a metabolic vulnerability stage in prodromal Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9499795/v2},
pmid = {42326500},
issn = {2693-5015},
abstract = {Alzheimer's disease shows prolonged prodromal stability before accelerating decline, yet molecular markers resolving this heterogeneity are limited. Using pseudo-progression analysis of 1.3 million SEA-AD single nuclei (84 donors), we identify a reproducible biphasic astrocytic trajectory anchored to prostaglandin D2 synthase (PTGDS), with a statistically resolved donor-level inflection (quadratic β2 = -2.27, p = 0.006; vertex CPS 0.47). The same directional change is independently reproduced in external brain proteomics (ROSMAP and Banner; AD versus control p = 3.4 × 10[-3]), and the biphasic pattern reconciles previously conflicting CSF reports as stage-dependent. In ADNI CSF, downstream NEFL tracks cognitive decline strongly and LCN2 weakly, whereas PTGDS itself is tissue-restricted and not a stand-alone predictor. We propose, but do not establish, that post-inflection PTGDS attenuation accompanies LCN2-linked inflammation and NGFR suppression. These data position astrocytic PTGDS as a candidate stage marker, not a causal driver, of the compensatory-to-vulnerable shift in the aging brain - the astrocytic PTGDS inflection (CPS 0.47).},
}

@article {pmid42326524,
year = {2026},
author = {Lee, SY and Nashiro, K and Min, J and Yoo, HJ},
title = {Effects of a 5-week heart rate biofeedback randomized intervention on texture in the Alzheimer's Disease signature cortical region.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9828565/v1},
pmid = {42326524},
issn = {2693-5015},
abstract = {Using data from a randomized clinical trial, we examined whether daily biofeedback training that modulates heart rate oscillations is associated with changes in microstructural brain texture in Alzheimer's disease-signature cortical (ADSC) and hippocampal regions. Younger and older adults were randomly assigned to one of two daily biofeedback practices for five weeks: slow-paced breathing designed to increase heart rate oscillations (Osc+) or self-selected strategies aimed at decreasing oscillations (Osc-). Intervention effects were observed in both ADSC and hippocampus regions and were confined to a composite texture factor dominated by uniformity and entropy. Across regions, effects were expressed primarily as Time × Condition interactions, indicating differential texture trajectories between Osc + and Osc-. In the hippocampus, this pattern was further qualified by a Time × Condition × Age Group interaction, reflecting more pronounced effects in older adults, whereas younger adults showed no reliable texture modulation. Partial least squares correlation analyses further demonstrated that training-related texture changes in the left hippocampus, right fusiform gyrus, and right entorhinal cortex covaried with concurrent changes in plasma AD-related biomarkers, with tau- and p-tau-related measures contributing most strongly to the multivariate association. Together, these findings suggest that HRV biofeedback may selectively influence specific dimensions of brain microstructural texture and that such changes are meaningfully coupled with plasma AD-related biomarker profiles.},
}

@article {pmid42326531,
year = {2026},
author = {Meikle, P and Wang, T and Beyene, H and Yi, C and Duong, T and Mellett, N and Meikle, T and Wu, J and Dakic, A and Cinel, M and Watts, G and Hung, J and Hui, J and Beilby, J and Blangero, J and Salim, A and Moses, E and Arnold, M and Kastenmüller, G and Han, X and Blach, C and Yu, C and McNeil, J and Lacaze, P and Nho, K and Saykin, A and Shaw, J and Magliano, DJ and Kaddurah-Daouk, R and Giles, C and Huynh, K},
title = {A lipidomic based metabolic age score for monitoring the effects of lifestyle and diet on metabolic disease risk.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-9239578/v1},
pmid = {42326531},
issn = {2693-5015},
abstract = {Biological age scores capture ageing heterogeneity beyond chronological age but are often dominated by lifestyle and environmental exposures, limiting clinical interpretability. We developed an environmentally adjusted metabolic age score (EAmAge) to isolate intrinsic ageing biology relevant to neurodegeneration and chronic disease. Major environmental influences were statistically removed from plasma lipidomic profiles before constructing an age-prediction model using ridge regression. EAmAge was derived in the AusDiab cohort (n = 10,339) and validated across three independent cohorts (BHS, ADNI and ASPREE; total n = 9,835). Compared with an unadjusted lipidomic age model (mAge_orig), EAmAge showed stronger and more consistent associations with incident Alzheimer's disease-related dementia, cardiovascular events and all-cause mortality. EAmAge was also associated with Alzheimer's disease-related biomarkers, including amyloid burden, reduced glucose metabolism and hippocampal atrophy. These findings establish EAmAge as a robust and partially modifiable biomarker that improves risk stratification by disentangling intrinsic metabolic ageing from environmental confounding.},
}

@article {pmid42326821,
year = {2026},
author = {Williams, ME and Arrotta, K and Bangen, KJ and Reyes, A and Stasenko, A and Zawar, I and Punia, V and Wang, I and Shin, W and Su, TY and Shih, JJ and Farid, N and Kapur, J and Struck, AF and Iragui-Madoz, VJ and Bekris, LM and Ferguson, L and Almane, DN and Jones, JE and Hermann, BP and Busch, RM and McDonald, CR and , },
title = {Alzheimer's disease neuroimaging signature aids identification of cognitive impairment in older adults with early-onset epilepsy.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.05.26354952},
pmid = {42326821},
abstract = {BACKGROUND AND OBJECTIVES: Older adults with epilepsy are at increased risk for Alzheimer's disease (AD), yet the mechanisms underlying this association remain poorly understood. We applied a validated AD neuroimaging signature to older adults with epilepsy to examine 1) whether older adults with epilepsy mirror AD-related changes, 2) associations with clinical, cognitive, and plasma biomarker outcomes, and 3) utility for identifying subgroups at heightened risk for cognitive decline. Our multicenter, prospectively enrolled cohort allowed for direct examination of differences in AD signatures between those with early-onset and late-onset unexplained epilepsy.

METHODS: Participants included 449 older adults: 87 with focal epilepsy from the multicenter Brain Aging and Cognition in Epilepsy (BrACE) cohort (age=66.10 [SD=6.86], including early-onset (<55 years at seizure onset) and late-onset (≥55 years at seizure onset) epilepsy); 362 from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU) healthy controls and individuals with mild cognitive impairment (MCI) or AD dementia. An AD signature was derived from regional cortical thickness and hippocampal volume weighted by their sensitivity to AD-related neurodegeneration in prior work. Associations between the AD signature, epilepsy characteristics, plasma biomarkers (β-amyloid 42/40, phosphorylated tau [pTau217, pTau181], neurofilament light chain [NfL]), and cognition were evaluated in BrACE.

RESULTS: Participants with epilepsy demonstrated more AD-like signatures compared to ADNI CU controls (β= -0.43, p adj <0.001), reflecting reduced thickness/volume in AD-vulnerable regions. This effect was stronger among early-onset (β= -0.57) versus late-onset (β= -0.26) epilepsy. In BrACE, the AD signature correlated with NfL (β= -0.30, p adj =0.050), memory performance (β= 0.30, p adj =0.006), and predicted greater odds of cognitive impairment specifically among those with early-onset, but not late-onset, epilepsy (interaction p adj =0.043). Further, among those with early-onset epilepsy, the AD signature significantly improved identification of cognitive impairment over and beyond the effects of plasma AD biomarkers (p =0.041). Findings were similar when examining the effects of epilepsy duration rather than epilepsy onset age.

DISCUSSION: AD neuroimaging signatures may help identify clinically meaningful subgroups among older adults with epilepsy, particularly when integrated with AD biomarkers. Findings support a multimodal framework for assessing AD-related risk in epilepsy and highlight interactive effects of epilepsy chronicity and AD-related processes that can influence cognitive outcomes.},
}

@article {pmid42326827,
year = {2026},
author = {Hartz, SM and Jackson, S and Benzinger, TLS and Bierut, L and Evans, A and Goswami, S and Gordon, BA and Hassenstaab, J and Hayibor, L and Linnenbringer, E and Morris, JC and Moulder, KL and Oliver, A and Sun, L and Schindler, SE and Xiong, C and Mozersky, J},
title = {No cognitive or psychological impact from returning research Alzheimer disease biomarkers: A delayed-start, noninferiority, randomized clinical trial.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.22.26353881},
pmid = {42326827},
abstract = {IMPORTANCE: Little is known about the impact of returning Alzheimer disease (AD) biomarkers to cognitively unimpaired (CU) research participants.

OBJECTIVE: Determine whether return of research results (RoRR) negatively impacts longitudinal symptoms of depression and cognition.

DESIGN: Randomized, noninferiority, delayed-start clinical trial, 2021-2025.

SETTING: AD biomarker research results offered to CU participants in a longitudinal cohort of community-dwelling older adults.

PARTICIPANTS: 341 CU research participants age ≥65 with available biomarkers (APOE genotype and either plasma Aβ42/40 or amyloid PET and MRI hippocampal volume) were recruited.

Participants were offered their research AD biomarker results (RoRR) with an estimated 5-year risk of symptomatic AD. After consenting, participants were randomized to either receiving results within several weeks (RoRR arm) or 1 year later (delayed-start arm).

MAIN OUTCOMES AND MEASURES: Longitudinal change in Geriatric Depression Scale (GDS), Clinical Dementia Rating® sum of boxes (CDR-SB), and global cognitive composite. Outcomes were measured at annual assessments for a longitudinal study of aging.

RESULTS: 147 participants received results after randomization: 70 in RoRR arm (average age 75, 60% female), 66 in delayed-start arm (average age 73, 53% female). The observed changes in annual measures did not differ between arms in both those with elevated amyloid (Aβ+) and in those without elevated amyloid (Aβ-) for GDS (Aβ+ difference 0.7, 95% CI 0.0-1.3; Aβ-difference -0.1, 95% CI -0.7-0.5; clinically significant decline >4.0), CDR-SB (Aβ+ difference 0.0, 95% CI -0.1-0.1; Aβ-difference 0.0, 95% CI 0.0-0.1; clinically significant decline >0.5), and cognitive composite (Aβ+ difference -0.10, 95% CI -0.25-0.06; Aβ-difference - 0.05, 95% CI -0.17-0.07; clinically significant decline < -0.26). Secondary analyses found no evidence of association between RoRR and proximity to follow-up testing.

CONCLUSIONS AND RELEVANCE: In the first randomized, delayed-start clinical trial of returning AD research results to CU older-adult participants, no effect was seen on longitudinal changes in symptoms of depression or cognition. This supports evidence that there are no harms to returning AD research results, although the results may not apply to more diverse populations not included in this study.

TRIAL REGISTRATION: NCT04699786.

KEY POINTS: Question: Does return of Alzheimer's disease (AD) research biomarker results to cognitively unimpaired older adults negatively impact longitudinal symptoms of depression and cognition?Findings: In this randomized, delayed-start clinical trial, no effect of returning research AD biomarkers was seen on longitudinal changes in symptoms of depression or cognition.Meaning: This supports evidence that there are no harms to returning AD research results, although the results may not apply to more diverse populations not included in this study.},
}

@article {pmid42326829,
year = {2026},
author = {Ruffini, N and Fischer, FU and Subirana Slotos, R and Goschke, J and Scholz, L and Knaepen, K and Hüttelmaier, S and Morrison, H and Steffan, T and Pabst, AS and Winter, J and Baier, B and Mierau, A and Binder, H and Drzezga, A and Teipel, S and Fellgiebel, A and Endres, K and Tüscher, O and , },
title = {TACR3 variant confers resilience to aging and Alzheimer's disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.06.26355071},
pmid = {42326829},
abstract = {BACKGROUND: While genetic factors strongly influence brain aging trajectories, variants conferring cognitive resilience remain poorly characterized. The neurokinin-3 receptor (NK3-R), encoded by Tachykinin Receptor 3 (TACR3) , modulates cholinergic signaling in memory circuits vulnerable to aging. Previous studies linked the non-WT expression of the TACR3 variant rs2765 with cognitive decline and reduced volume of the hippocampus and basal forebrain, but systematic replication and mechanistic validation were lacking.

METHODS: We investigated rs2765 in the preregistered AgeGain cohort of cognitively healthy older adults (n=188) with independent validation in the ADNI cohort (n=809) which includes persons with and without Alzheimer's Disease (AD) that show healthy cognition, mild cognitive impairment or dementia. Analyses integrated structural neuroimaging, longitudinal cognitive assessments, epigenetic aging (PhenoAge), genome-wide methylation profiling, and mechanistic validation through luciferase assays and cross-species protein expression studies.

RESULTS: The infrequent protective rs2765 WT variant, found in 12.8% of Europeans, conferred 49% slower cognitive decline (p = 0.002) for amyloid-positive individuals of the ADNI cohort and 3.7 years younger epigenetic age (p = 0.013, 95% CI: 0.79-6.67 years) in the cognitively healthy AgeGain cohort. WT carriers showed larger hippocampal and basal forebrain volumes across cohorts, with Allen Brain Atlas integration revealing these outcomes to occur exclusively in regions where TACR3 expression positively correlated with gray matter volume. Mechanistically, the non-WT variant ameliorated RBMX-mediated post-transcriptional regulation, reducing NK3-R protein expression by 25-40% in vitro and ex vivo murine brain slice models. Senescence-accelerated mice exhibited reduced endogenous NK3-R expression, phenocopying the predicted functional consequences of the variant. In AgeGain participants, genome-wide methylation profiling identified 2,313 differentially methylated CpGs affecting 228 pathways spanning glutamatergic signaling, acetylcholine receptor pathways, chromatin remodeling, and angiogenesis, suggesting coordinated molecular reprogramming from synaptic function to systemic aging.

CONCLUSIONS: rs2765 WT confers resilience to age- and AD-related cognitive decline through RBMX-dependent regulation of NK3-R expression, with effects of remarkable size cascading from memory to systemic aging. rs2765 genotyping could stratify individuals for NK3-R modulator therapy (e.g., fezolinetant or senktides) and identify those maintaining function despite pathological burden, complementing APOE-based risk assessment in precision geromedicine.},
}

@article {pmid42326920,
year = {2026},
author = {Oliveira, M and Freitas, A and Teodoro, AC and Gonçalves, H},
title = {Spatio-temporal patterns of neurodegenerative disease hospitalizations in mainland Portugal.},
journal = {Frontiers in public health},
volume = {14},
number = {},
pages = {1767007},
pmid = {42326920},
issn = {2296-2565},
mesh = {Portugal/epidemiology ; *Hospitalization/statistics & numerical data ; Humans ; *Neurodegenerative Diseases/epidemiology ; Retrospective Studies ; Spatio-Temporal Analysis ; Male ; Female ; Aged ; Bayes Theorem ; },
abstract = {BACKGROUND: Neurodegenerative diseases are an increasing concern for the aging population worldwide. In Portugal, as in many other developed countries, the population is aging rapidly. Understanding temporal and spatial patterns is of utmost relevance to help manage the burden these diseases place on the healthcare system.

METHODS: In this retrospective study, we analyzed over 500,000 hospitalizations discharged between 2000 and 2016. We used the empirical Bayes method to compute the smoothed age-standardized hospitalization rates for each neurodegenerative disease, for all hospitalizations per year, and across administrative divisions (districts and municipalities). We then searched for data clusters using both global and local spatial autocorrelation methods based on the Moran index.

RESULTS: A steady increase in age-standardized hospitalization rates was observed throughout the study period. Statistically significant global spatial autocorrelation was found when considering all diseases per municipality (Moran's I = 0.010, p-value < 0.001). In addition, when considering the districts, only Alzheimer's disease, dementia, and basal ganglia disorders did not show significant spatial autocorrelation. When considering municipalities, all diseases showed significant positive global spatial autocorrelation.

CONCLUSION: Temporal analysis showed increasing age-standardized hospitalization rates over time, likely reflecting the aging population in Portugal. The spatial analysis showed significant clustering, which may reflect geographic differences in hospitalization practices, access to care, population structure, or other contextual factors. Through this study, we hope to enlighten future research by providing insights into the anticipated spatio-temporal patterns.},
}

Portugal/epidemiology
*Hospitalization/statistics & numerical data
Humans
*Neurodegenerative Diseases/epidemiology
Retrospective Studies
Spatio-Temporal Analysis
Male
Female
Aged
Bayes Theorem

@article {pmid42327033,
year = {2026},
author = {Mostowfi, N and Foreman, R and Wang, J and Khoury, R and Albanese, A and Ma, QL and Cohn, W and Petzinger, G and Jakowec, M and Ahmed, SK and Seidler, PM},
title = {Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.09.731185},
pmid = {42327033},
issn = {2692-8205},
abstract = {Pathological tau aggregates drive neuronal dysfunction in Alzheimer's disease (AD) and related tauopathies, yet no approved therapy eliminates existing tau neurofibrillary tangles. Here, we report the development of a coumarin-based small-molecule series that disaggregates tau fibrils and oligomers through a stacking-driven co-assembly mechanism. Structure-activity relationships identified PT-13 as a lead compound that inhibits tau seeding by AD brain-derived matter and reduces aggregate burden measured across both fibrillar and oligomeric tau species. Mechanistic studies demonstrate that disaggregation does not generate soluble oligomeric intermediates, addressing a central question in the field. PT-13 is brain-penetrant and well tolerated in vivo. In a tauopathy mouse model, PT-13 treatment reduces tau pathology while preserving behavioral function, proteasome capacity, and synaptic integrity. These findings establish small-molecule tau disaggregation as a viable therapeutic strategy and provide a molecular framework for the design of aggregate-directed therapeutics in neurodegeneration.},
}

@article {pmid42327071,
year = {2026},
author = {Kaikini, A and Shi, A and Francis, P and Swerdlow, R and Troakes, C and Kennedy, J and Hodgkinson, A and Malik, AN},
title = {Why diabetes matters in dementia studies: Excluding diabetes status masks regional mitochondrial DNA copy number changes in human hippocampus, amygdala, and cerebellum in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.03.729204},
pmid = {42327071},
issn = {2692-8205},
abstract = {INTRODUCTION: Diabetes is a major risk factor for Alzheimer's disease (AD), and both diseases involve mitochondrial dysfunction. We hypothesised that AD is associated with reduced mitochondrial DNA copy number (mtDNA-CN) in vulnerable brain regions, and that diabetes modifies these changes.

METHODS: Post-mortem hippocampus, amygdala, and cerebellum samples (N=66-77) from non-cognitively impaired (NCI) and AD donors, with and without diabetes, were analysed. mtDNA-CN was quantified by absolute quantification.

RESULTS: Overall, mtDNA-CN was lower in AD. However, stratification by diabetes revealed opposite changes: non-diabetic AD cases showed reduced mtDNA-CN, whereas diabetic cases showed higher mtDNA-CN across all regions irrespective of cognitive status.

DISCUSSION: These findings confirm multiregional loss of mtDNA-CN in the AD brain, most evident in the absence of diabetes. The functional significance of higher mtDNA-CN in the diabetic brain remains unclear, but evidence that diabetes can mask effects has important implications for dementia studies.},
}

@article {pmid42327086,
year = {2026},
author = {Yang, NV and Hodgson, D and Jang, TM and Kim, JJ and Gottschalk, WK and Yassine, HN and Chiba-Falek, O and Krauss, RM},
title = {TOMM40 '523' genotype induces sex- and tissue- specific differences in cholesterol and triglyceride levels in an APOE-TOMM40 humanized mouse model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.09.731195},
pmid = {42327086},
issn = {2692-8205},
abstract = {INTRODUCTION: Genetic variants within the APOE-TOMM40 locus are associated with Alzheimer's disease (AD). A specific role for TOMM40 is indicated by the finding that '523' poly-T variants are associated with AD risk, but the mechanism for this effect has not been established. Our studies have shown that suppression of Tomm40 in mice increased brain cholesterol content, an AD risk factor, and thus the present study sought to assess whether major '523' poly-T variants (Short [S] and Very Long [VL]) are associated with altered lipid content of brain and other tissues.

METHODS: We utilized a mouse model containing the entire human APOE3-TOMM40 locus to quantify cholesterol and triglyceride levels in brain, liver, and white adipose tissue (WAT), as well as brain content of the AD biomarkers Aβ 42 and tau, in mice carrying two homozygous TOMM40 '523' poly-T genotypes (S/S and VL/VL).

RESULTS: Male mice carrying the '523'-S/S genotype, but not females, showed higher brain cholesterol and triglyceride levels than VL/VL carriers, together with greater brain Aβ 42 content. WAT showed similar lipid differences as in the brain, while hepatic lipid content was broadly similar between '523'-S/S and -VL/VL genotypes, though there was a trend for higher triglycerides in VL/VL mice in a sex- and age-dependent manner.

DISCUSSION: These results demonstrate that TOMM40 '523' poly-T variants drive tissue-specific, sex-, and age-dependent lipid differences in humanized APOE3-TOMM40 mice, with the S/S genotype linked to elevated brain cholesterol and Aβ 42 levels, effects that link this locus to AD pathogenesis.},
}

@article {pmid42327098,
year = {2026},
author = {Doddi, AD and Dawes, P and Chan, Y and Lim, ET},
title = {MipSScs: Artificial neural network-based data integration of 2D/3D single-cell spatial RNA sequence data from virus-infected human cerebral organoids.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.08.727881},
pmid = {42327098},
issn = {2692-8205},
abstract = {There is interest in the use of recent single-cell spatial transcriptomic technologies to gain biological insights into disease mechanisms. Previously, we characterized the use of herpes simplex virus 1 (HSV-1) induced neuroinflammation in 2D dissociated cells from human cerebral organoids (dcOrgs) to model molecular and transcriptomic readouts associated with Alzheimer's disease (AD). In this work, we generated two datasets by using single-cell non-spatial RNA sequencing and single-cell spatial RNA sequencing technologies on HSV-1-infected 2D dcOrgs and HSV-1-infected 3D cerebral organoids (cOrgs). We conducted cell type assignment for the cells in the 2D dcOrgs and 3D cOrgs, by using single-cell non-spatial RNA sequence data from human fetal brains and adult post-mortem brains, to infer the transcriptomic effects of AD-associated in-vitro perturbations through viral infections linked to AD. We evaluated computational and machine learning methods, including the use of multi-layer perceptrons (MLPs), and we used cross-2D/3D platform comparisons as a benchmark to evaluate the artificial neural network models. In the process, we found that the use of MLPs can lead to high validation rates for assigning cell type identities from 2D and 3D human cerebral organoids to cell types found in human adult post-mortem brain samples. Furthermore, the use of these technologies and systems enabled the identification of pseudotime trajectories and cell clusters associated with the viral transcriptional life cycle. We identified several cell types, including endothelial cells and astrocytes, with significantly more clustered cell-cell nearest neighbor distances in infected 3D cOrgs compared to mock 3D cOrgs. Permutation tests revealed that these differences in nearest neighbor distances are unlikely to be driven by overall structural differences between individual infected 3D cOrgs and mock 3D cOrgs, such as differences in the density of cells. Given that there are more large-scale single-cell non-spatial (2D) RNA sequence datasets that had been generated from human post-mortem brain samples, compared to single-cell spatial (3D) RNA sequence datasets from human post-mortem brain samples, the development of data integration approaches by using artificial neural networks such as MLPs, across 2D and 3D single-cell transcriptomics datasets generated from human post-mortem brain samples and human in-vitro systems such as brain organoids is likely to be critical to gain novel insights into neurodegenerative diseases such as AD.},
}

@article {pmid42327192,
year = {2026},
author = {Fulghum, K and Hayir, A and Ankeriasniemi, R and Shaddy-Gouvion, C and Vang, CM and Salathe, SF and Queathem, ED and Hughey, CC and Haeri, M and Thyfault, JP and Puchalska, P and Crawford, PA},
title = {Diet-Dependent Cognitive Benefits of Exogenous Ketone Body Precursor, (R,S)-1,3,-Butanediol, in a Mouse Model of Tauopathy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.03.729999},
pmid = {42327192},
issn = {2692-8205},
abstract = {Alzheimer's disease and related tauopathies are escalating public health threats, particularly in the context of obesity and metabolic dysfunction, which accelerate cerebral glucose hypometabolism, tau pathology, neurodegeneration, and cognitive decline. Ketogenic therapies reconfigure systemic fuel metabolism, with emerging evidence for neuroprotection. (R,S)-1,3-butanediol (BD) raises circulating D- and L-β-hydroxybutyrate (βOHB) concentrations. To evaluate whether BD improves cognitive function across dietary contexts, male and female tau-transgenic mice and littermate controls received 10% BD in drinking water for 20 or 30 weeks starting at 6 weeks of age. BD rapidly induced ketosis (1.5-3.0 mM βOHB) in chow-fed mice, with L-βOHB contributing to ∼75% of the circulating βOHB pool. Despite minimal effects of BD on body weight and glucose homeostasis, and no effect on histopathological tau signal, 20-week BD treatment improved memory to control levels in chow-fed female tauopathy mice. Isotope-tracing untargeted metabolomics revealed that BD-treatment differentially affected glucose-derived [13] C-enrichment of metabolites in brains of male and female mice. BD-induced cognitive benefits in tau-transgenic mice were abrogated when mice were maintained on BD for 30 weeks on standard chow or when mice were administered BD over 20 weeks while maintained on a high-fat, Western diet, Notably, BD-induced ketosis was blunted in mice consuming Western diet. Moreover, intermittent ketogenic diet-induced ketosis failed to improve cognition in Western diet-fed tauopathy mice. These results suggest BD-induced ketosis extends cognitive benefits in a manner dependent on biological sex and nutritional metabolic status. Taken together, these data contextualize the roles of βOHB as modulators of cognitive resilience in tauopathy.},
}

@article {pmid42327204,
year = {2026},
author = {Jackson, RJ and Dierksmeier, S and Nishtar, M and Meltzer, J and Balduin, F and Beaumont, B and Fan, Z and Sergienko, E and Olson, S and Jackson, MR and Hyman, BT},
title = {Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.09.730809},
pmid = {42327204},
issn = {2692-8205},
abstract = {Apolipoprotein E (ApoE) is the primary genetic risk modifier of late-onset Alzheimer's disease, with the ε4 allele increasing risk up to 15-fold relative to ε3. The structural differences between isoforms are thought to underlie their distinct effects on lipid transport, receptor binding, and disease risk. ApoE4 exhibits reduced thermodynamic stability compared to ApoE3, but prior characterisation has relied on purified recombinant protein, leaving open whether these differences are preserved in native cellular environments and how they relate to rare disease-associated variants. Here, we employed the cellular thermal shift assay (CETSA) and a bioluminescence-based thermal stability assay (BiTSA) to systematically characterise ApoE thermal stability across isoforms and variants. Using CETSA on brain tissue from humanised APOE knock-in mice and post-mortem human brain, we confirm that ApoE4 exhibits significantly reduced thermal stability compared to ApoE3 in native tissue, with this difference conserved across species despite variation in absolute melting temperatures. We developed BiTSA, which leverages a split-luciferase HiBiT tag to quantify soluble ApoE across a thermal gradient in living cells, providing a higher-throughput platform that faithfully recapitulates isoform stability differences. Applying BiTSA to rare AD-associated variants, we found that L28P exerts divergent, isoform-dependent effects, destabilising ApoE3 while paradoxically stabilising ApoE4-a finding supported by AlphaFold modelling revealing isoform-specific differences in helix 1 architecture. These results establish BiTSA as a robust cellular tool for ApoE variant characterisation and demonstrate that isoform background critically modulates the structural consequences of rare mutations.},
}

@article {pmid42327232,
year = {2026},
author = {Libby, JB and Mahoney, ER and Drucker, B and De Jager, PL and Menon, V and Oveisgharan, S and Schneider, JA and Barnes, LL and Bennett, DA and Petyuk, VA and Hohman, TJ},
title = {Post-translational modifications in the brain are critical contributors to Alzheimer's disease neuropathology and cognitive decline.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.13.732018},
pmid = {42327232},
issn = {2692-8205},
abstract = {Post-translational modifications (PTMs) in APP and MAPT contribute to plaques and tangles in Alzheimer's disease (AD). Yet broader proteome-wide PTMs in the AD brain are relatively unexplored. Therefore, this study highlights associations between PTMs, quantified by mass spectrometry in prefrontal cortex tissue, and Alzheimer's disease neuropathology and cognition. Leveraging PTMs quantified from prefrontal cortices in 101 Rush Memory and Aging Project participants. We assessed associations with post-mortem amyloid-β and tau burden, global cognition, and cognitive decline. First, APP and MAPT PTM associations were assessed on these outcomes given their known relevance in AD, followed by assessment of protein-wide effects of PTMs. Then, kinase enrichment analysis was performed on each outcome to assess which kinases might contribute to the results. We observed a novel association of APP-K687 acetylation, a known mutation hotspot driving pathology, with amyloid-β load (β=0.44, P=3.9e-8), while confirming known MAPT PTMs with tangle burden. Further, we identified 20+ novel PTMs' associations with AD neuropathology, including ENO2-K256 ubiquitination (β=0.353, P=1.13e-6), PSMD13-K31 ubiquitination (β=0.568, P=1.34e-6), and PLXND1-K1826 ubiquitination (β=0.577, P=7.08e-8) for tangle burden and SYP-K23 ubiquitination (β=1.50, P=4.7e-8), TMEFF2-C80 cysteine oxidation (β=1.64, P=1.1e-8), and STX1B-T121 phosphorylation (β=0.898, P=3.3e-7) for amyloid-β load. Further, kinase enrichment analyses highlight the complexity of disease-related proteome changes with some kinases like CDK5 showing expected over-enrichment (amyloid z=3.44, P=3.0e-4; tau z=4.98, P=3.3e-7) but others like PKC family kinases showing divergent enrichment between amyloid (z=8.98-11.55, P<1.0e-18) and tau (z=-2.83--3.88, P<0.006). This study provides an atlas of brain PTMs within crucial proteins like MAPT and APP and at the proteome-wide level, that impact AD neuropathology and clinical presentation. Further, we explored what kinases might be driving phosphorylation results, emphasizing the complex proteome changes which impact AD. In sum, these results highlight robust post-translational alterations in the AD brain and provide novel targets for future mechanistic studies.},
}

@article {pmid42327234,
year = {2026},
author = {Fernanda Schuck, P and da Costa Ferreira, G and Rezende Freitas, H},
title = {Astrocyte subtype-specific expression of the sodium-coupled citrate transporter SLC13A5 and citrate metabolism genes across Alzheimer's disease pseudoprogression: a single-nucleus RNA sequencing analysis of the human middle temporal gyrus.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.05.730472},
pmid = {42327234},
issn = {2692-8205},
abstract = {The sodium-coupled citrate transporter NaCT (SLC13A5) imports extracellular citrate into cells. In the CNS, SLC13A5 is described to be expressed predominantly in neurons. Cytosolic citrate levels rely on citrate generated in mitochondria and imported from other CNS cells, regulating intermediary metabolism and supplying acetyl-CoA for lipid synthesis and histone acetylation. Despite evidence for NaCT's role in neurometabolic homeostasis, its transcriptional behavior across Alzheimer's disease (AD) progression and across astrocyte subtypes remains uncharacterized at single-cell resolution. We analyzed single-nucleus RNA sequencing data from 1,378,211 nuclei across 84 donors in the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) Middle Temporal Gyrus dataset to profile SLC13A5 and seven citrate metabolism genes across a continuous AD pseudoprogression score. SLC13A5 expression was restricted to astrocytes (∼20% prevalence) and concentrated in the Astro 2 supertype (24.0%), a homeostatic subtype characterized by low C3 (1.6%) and CD44 (5.5%), which expanded with pseudoprogression (Spearman rho = +0.345, FDR < 0.001). The A1-reactive Astro 3 supertype, where SLC13A5 prevalence was 0.87%, declined concordantly (rho = -0.393). Opposing compositional and transcriptional forces produced apparent stability in overall SLC13A5 prevalence. SLC13A3 and ACO1 showed progressive donor-level declines correlating with Braak stage and Thal phase (rho range: -0.307 to -0.349, FDR < 0.01). APOE4 carriers exhibited lower SLC13A5 prevalence specifically within Astro 2 nuclei (median 17.6% vs. 25.9%; Wilcoxon p = 0.025), though this association did not survive multivariate regression. No difference in Astro 2 SLC13A5 expression was detected between cognitively resilient and expected-AD donors with equivalent high Braak burden (p = 0.888). Contrary to the prevailing description of NaCT as a neuronal transporter, SLC13A5 expression in the SEA-AD MTG dataset is restricted to astrocytes, concentrated in the homeostatic Astro 2 subtype, and maintained as this subtype expands with advancing AD pathology. Supertype-resolved SLC13A5 and SLC13A3 expression provide more informative readouts of astrocytic metabolic state than bulk measurements.},
}

@article {pmid42327253,
year = {2026},
author = {Zhu, K and Sanfilippo, M and Oh, MA and Ahmed, M and Aldrich, A and Nyberg, D and Sauteraud, R and Dalva, N},
title = {Gateway: patient olfactory neurons for large-scale discovery in neurodegenerative disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.10.731272},
pmid = {42327253},
issn = {2692-8205},
abstract = {An estimated 42% of Americans over age 55 will develop dementia, but the molecular understanding of dementia and neurodegenerative disease is constrained because the living human brain cannot be routinely sampled during disease progression. Olfactory sensory neurons provide a clinically accessible neuronal tissue source with developmental, transcriptional, and disease-relevant links to the central nervous system. Here we describe Gateway, a platform that combines device guided olfactory epithelium biopsy, onsite fixation, and 10x Genomics FLEX RNA profiling to generate single-cell transcriptomic data from living patient neurons. We present a 4-million-cell atlas representing 202 human donors, including healthy controls and individuals with neurodegenerative diseases, and release it as an open resource through CELLxGENE. We define the cellular composition of the human olfactory epithelium and show that Gateway captures neuronal functional and compartmental programs and detects more brain-enriched genes than other clinically accessible transcriptomic sample types. In exploratory analyses of Alzheimer's Disease and Parkinson's Disease, we identify dys-regulation of pathways and GWAS-implicated genes related to key neurodegenerative mechanisms such as neuroinflammation, endolysosomal biology, proteostasis, and synaptic maintenance. Together, this atlas and clinical workflow establish living patient olfactory neurons as a scalable complementary modality for neuroscience research, target discovery, and biomarker development in neurodegenerative disease.},
}

@article {pmid42327258,
year = {2026},
author = {Powers, AE and Kamble, K and Nair, MG and Windham, IA and Miner, GE and Prim, CE and Mills, CA and Lyons, SP and Herring, LE and Chirasani, VR and Johnson, LA and Cohen, S},
title = {APOE interacts with COX-2 on lipid droplets to modulate inflammatory lipid signaling.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.09.730852},
pmid = {42327258},
issn = {2692-8205},
abstract = {Alzheimer's Disease (AD) is the leading cause of dementia worldwide. Expression of the E4 variant of apolipoprotein E (APOE) greatly increases individuals' risk of developing AD. In response to lipogenesis in astrocytes, APOE can escape secretion and traffic to the cytoplasmic surface of lipid droplets (LDs), but protein interactors of APOE at the LD were unknown. Here we find that LD-localized APOE physically interacts with the inflammatory lipid signaling enzyme cyclooxygenase-2 (COX-2). Like APOE, COX-2 can avoid the secretory pathway and traffic to LDs in response to lipogenesis. APOE3, but not APOE4, increases COX-2 localization to LDs. Computational modeling, microscopy-based assays, and targeted lipidomics reveal that APOE3 promotes while APOE4 suppresses COX-2 enzymatic activity at LDs and intracellular prostaglandin production. This work identifies a novel and targetable protein-protein interaction of APOE and provides a mechanistic link between APOE4 and dysregulated inflammatory lipid signaling.},
}

@article {pmid42327307,
year = {2026},
author = {Lin, Y and Lin, KZ},
title = {High-Dimensional Sensitivity Analysis for Genomic Studies: An Adversarial Framework for Learning Worst-Case Latent Confounders.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.27.728283},
pmid = {42327307},
issn = {2692-8205},
abstract = {High-dimensional genomics studies are frequently confounded by unmeasured biological processes that obscure disease-specific signals. While existing workflows can estimate these latent confounders, they fail to quantify how robust a discovery is to varying levels of hypothetical confounding. We introduce sensGAN, a deep-learning adversarial framework that systematically explores the confounding spectrum by learning "worst-case" latent variables that nullify the most gene associations under novel predictive-gain constraints. By identifying the minimum confounding strength required to explain away an observed effect, our method shifts the paradigm toward a formal, quantitative sensitivity analysis. In diverse simulations, sensGAN accurately recovers latent structures and outper-forms existing methods in identifying confounder-sensitive genes. Applied to human Alzheimer's disease microglia, our framework prioritizes robust disease pathways while successfully isolating signals driven by unmeasured co-occurring neurodegenerative pathologies. Our method is publicly available, deposited at the GitHub repository yifanlinz/AD_sensitivity_ICML .},
}

@article {pmid42327368,
year = {2026},
author = {Gatt, A and Buhidma, Y and Fodder, K and Humphrey, J and Foti, SC and Frias, B and Benson, BC and Gami-Patel, P and Gittings, LM and Toomey, CE and Lashley, T},
title = {Transcriptomic and pathological analysis of the hnRNP network reveals glial involvement in frontotemporal lobar degeneration pathological subtypes.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag197},
pmid = {42327368},
issn = {2632-1297},
abstract = {Frontotemporal dementia is a neurodegenerative disorder with a strong heritable component. Frontotemporal lobar degeneration refers to the pathological changes seen in frontotemporal dementia, characterized by atrophy of the frontal and temporal lobes and the presence of abnormal protein inclusions. In the case of frontotemporal lobar degeneration with hyperphosphorylated TDP-43 positive inclusions (FTLD-TDP), five pathological subtypes (A, B, C, D and E) are observed based on the types and distribution of inclusions found in the brain. In all subtypes, there tends to be a large variability in the number of pathological inclusions observed between cases, with limited correlation to clinical manifestations. TDP-43 is an RNA-binding protein belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family, which along with other hnRNPs, modulates multiple aspects of RNA processing. HnRNPs other than TDP-43 have been implicated in several neurological diseases, including Amyotrophic Lateral Sclerosis, FTLD-TDP, frontotemporal lobar degeneration with fused in sarcoma (FTLD-FUS) and Alzheimer's disease. Multiple hnRNPs have been found in pathological inclusions in specific subtypes of FTLD-TDP, suggesting potential roles in the disease process. The role of the hnRNP network in frontotemporal lobar degeneration disease pathogenesis, however, has not yet been investigated. This study aimed to comprehensively evaluate the presence and expression of hnRNP proteins in two pathological subtypes of sporadic FTLD-TDP (A and C) as well as the genetic form FTLD-TDP A C9orf72 using immunohistochemistry and gene expression analysis by single-nuclei RNA-sequencing. We found that there was great variability in the frequency of TDP-43 pathology across and within FTLD-TDP pathological subtypes. Our findings suggest that distinct global transcriptomic profiles may underlie the different pathological subtypes of FTLD-TDP. The most prominent transcriptomic changes were observed in oligodendrocytes and astrocytes, involving multiple hnRNPs across frontotemporal lobar degeneration subtypes compared to controls. Transcriptomic co-expression analysis further revealed that glial clusters were more strongly associated with RNA-processing dysfunction and contributed to disease classification. Together, these findings highlight the involvement of the hnRNP network and glial-specific RNA-processing alterations in FTLD-TDP pathophysiology, offering new insight into the molecular distinctions between pathological subtypes and potential targets for future investigation.},
}

@article {pmid42327424,
year = {2026},
author = {Jiakponnah, NN and Curran, J and Watermeyer, T and Shah, J and Musili, L and Onyango, S and Aliwa, B and Mackelfresh, A and Bubu, OM and Onyike, C and Okonkwo, O and Merali, Z and Akinyemi, R and Hughes, T and Saleh, M and Petersen, M and Blackmon, K and Ogunniyi, A and Hendrie, H and Udeh-Momoh, C},
title = {Contextual variability in under-diagnosed cardiometabolic disease and cognitive vulnerability among populations at high risk for Alzheimer's disease and related dementias.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {48},
pmid = {42327424},
issn = {3005-1940},
abstract = {Underdiagnosis of cardiometabolic risk factors (CMRFs) may represent an unrecognised biological pathway contributing to dementia risk; yet remains poorly characterised in African and African diaspora populations. We quantified the prevalence and determinants of underdiagnosed hypertension and abnormal glycaemia across four cohorts comprising up to 7000 adults aged ≥40 years from Nigeria, Kenya, and The United States: Indianapolis, and North Texas. Underdiagnosis was defined as absence of self-reported diagnosis despite elevated systolic blood pressure (≥130 mmHg) or fasting blood glucose (≥100 mg/dL). Cohort-stratified analyses examined demographic, socioeconomic, cognitive, Alzheimer's genetic, and blood-based biomarker correlates. Underdiagnosis was pervasive in African cohorts. Elevated fasting glucose was associated with cognitive impairment in Kenya and North Texas, while severe hypertension and diabetes were linked to Alzheimer's disease-related biomarkers [pTau217/181, NFL and Aβ42/40] in North Texas (all p ≤ 0.05). These findings identify context-specific diagnostic gaps in populations at high dementia risk and highlight cardiometabolic detection as a mechanistic target for prevention.},
}

@article {pmid42327426,
year = {2026},
author = {Genner, RM and Meredith, M and Daida, K and Moller, A and Weller, C and Ayuketah, A and Jerez, PA and Akeson, S and Malik, L and Baker, B and Kouam, C and Paquette, K and Catching, A and Bromberek, S and Hu, F and Reed, X and Marenco, S and Auluck, P and Mandal, A and Paten, B and Gibbs, JR and Jain, M and Cookson, MR and Singleton, AB and Nalls, M and Blauwendraat, C and Billingsley, KJ},
title = {Haplotype-resolved DNA methylation at the APOE locus identifies allele-specific epigenetic signatures relevant to Alzheimer's disease risk.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {45},
pmid = {42327426},
issn = {3005-1940},
abstract = {The APOE gene encodes a lipid transport protein central to Alzheimer's disease (AD) pathogenesis. Three common alleles-ε2 (rs7412(C > T)), ε3 (reference), and ε4 (rs429358(T > C))-arise from two coding variants in exon 4 and confer distinct AD risk profiles, with ε4 increasing risk and ε2 being protective. The ε3-linked APOE variant rs769455[T] has also been associated with increased AD risk among individuals of African ancestry who also carry the APOE ε4 allele. Determining how genetic variation influences CpG methylation requires methQTL-type analyses, but conventional bisulfite and array-based approaches offer limited resolution for distinguishing allele-specific effects. Here, we use high-accuracy long-read sequencing to generate haplotype-resolved methylation profiles across the APOE locus in 332 postmortem brain tissue samples from ancestrally diverse cohorts, including 201 samples from individuals of European ancestry and 131 samples from individuals of African and African admixed ancestry. Treating each haplotype as an independent observation, OLS regression identified 18 novel differentially methylated CpG sites associated with ε2, ε4, and rs769455[T] across the APOE locus (TOMM40, APOE, APOC1, and APOC4-APOC2 genes). These findings reveal distinct allele-specific methylation signatures and demonstrate the utility of long-read sequencing for resolving epigenetic variation relevant to AD risk.},
}

@article {pmid42327427,
year = {2026},
author = {Katsumi, Y and Eckbo, R and McGinnis, SM and Sepulcre, J and Rabinovici, GD and La Joie, R and Dickerson, BC and Putcha, D},
title = {Functional network contributions to longitudinal tau spread in Posterior Cortical Atrophy.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {46},
pmid = {42327427},
issn = {3005-1940},
abstract = {In this study, we investigated longitudinal tau spreading in 23 amyloid-positive individuals with early-stage posterior cortical atrophy (PCA), a clinical syndrome typically characterized by progressive visual cognitive deficits emerging largely from underlying Alzheimer's disease-related tau deposition in posterior cortical areas. Each PCA participant underwent structural MRI and [18]F-Flortaucipir PET at baseline and follow-up (mean interval between baseline and follow-up PET = 1.17 ± 0.29 years). Using directional regression analysis (i.e., a regression-based model testing temporal directionality in tau spread), we quantified how tau epicenters (top 10% regions by baseline tau) predicted longitudinal tau accumulation. Seed-based analysis revealed evidence supporting the role of posterior cortical epicenters in the visual and dorsal attention networks (DAN), showing directional spreading of tau to anterior DAN nodes and the default mode network (DMN), with the largest effects in anterior DAN regions. Complementary graph theory analysis identified the visual network and posterior DMN as hubs of tau spread. These findings collectively suggest that longitudinal tau spread in PCA follows hierarchical progression from primary epicenters within the visual network and DAN to secondary epicenters, including the posterior DMN, possibly mediated by dynamic connectivity reorganization as primary epicenters become saturated with tau pathology.},
}

@article {pmid42327728,
year = {2026},
author = {Maiese, K},
title = {Agitation, Alzheimer's disease, and autophagy: mechanistic insights into aging pathways, gut microbiome, and artificial intelligence.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1846280},
pmid = {42327728},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/metabolism/therapy/psychology/etiology ; *Aging ; *Autophagy ; *Gastrointestinal Microbiome ; Animals ; *Artificial Intelligence ; },
abstract = {The presentation of mood disorders that involve agitation and anxiety in patients with cognitive loss represent significant challenges for the care of patients with Alzheimer's disease (AD). Additional concerns rest with the rising lifespan and aging of the global population with expectations that over the next two decades more than 50 percent of the elderly population will suffer from mental health disease and at least 30 million of these individuals will also succumb to cognitive loss with AD. Although current treatments for mood disorders and cognitive loss can have a multi-modal approach with behavioral therapy, cognitive training sessions, physical exercise, nutritional care, environmental changes, and disease modifying agents, these therapies are primarily symptomatic in nature that do not halt disease progression and possess risks for further nervous system insults. Given these consideration, novel work that addresses the shared underlying pathways for mood disorders and cognitive loss with autophagy and related mechanisms of programmed cell death, aging and cellular senescence, perivascular system dysfunction, inflammatory microglial cell dynamics, oxidative stress, metabolic pathways that involve diabetes mellitus and apolipoprotein E, the gut microbiota, glucagon-like peptide-1 receptor agonism, innovative diagnostic strategies, artificial intelligence, and machine learning can offer rewarding avenues for the innovative development of therapeutic strategies that address disease onset and progression of these disorders. These pathways that oversee mood disorders and cognitive are both critical and complex in their intimate relationships and warrant in-depth knowledge of the mechanisms that can influence biological outcome for clinical translation.},
}

Humans
*Alzheimer Disease/metabolism/therapy/psychology/etiology
*Aging
*Autophagy
*Gastrointestinal Microbiome
Animals
*Artificial Intelligence

@article {pmid42327828,
year = {2026},
author = {Chen, C and Jose, D and Cheng, PK and Massa, JJ and Li, W},
title = {Linking EEG markers of oscillopathy and default mode network dysfunction in Alzheimer's disease.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1750878},
pmid = {42327828},
issn = {1662-5161},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and multifaceted neuropathology. Although fluid biomarkers cerebrospinal fluid (CSF) amyloid-β and tau and imaging biomarkers positron emission tomography (PET) have substantially advanced AD diagnostics, electroencephalography (EEG) remains a comparatively underutilized tool despite its unique potential. EEG biomarkers capture oscillatory abnormalities (oscillopathies), providing a dynamic window into network-level dysfunction in AD pathophysiology that is not accessible through static molecular or structural measures. Of particular interest are EEG indices linked to dysfunction in the default mode network (DMN), a large-scale intrinsic network increasingly recognized as an epicenter of AD vulnerability. This review synthesizes evidence for key EEG oscillopathy markers in AD-including spectral slowing, gamma deficits, and reduced long-range synchrony-and maps these alterations onto DMN dysfunction within a hierarchical cascade spanning molecular pathology to cognitive impairment. We further explore how frequency-specific transcranial alternating current stimulation (tACS) may both mechanistically interrogate and therapeutically target the oscillopathy-DMN link, drawing on causal evidence from combined EEG-fMRI studies and emerging clinical trials. Finally, we discuss how artificial intelligence (AI), applied to large-scale multimodal datasets, may transform oscillopathy markers into tools for personalized diagnosis, prognosis, and closed-loop neuromodulation. By integrating EEG, network neuroscience, and targeted stimulation, this narrative review positions oscillopathy as a central and clinically accessible feature of AD-related network dysfunction.},
}

@article {pmid42328129,
year = {2026},
author = {Yang, Z and Chen, Y and Li, S and Lei, X and Wu, X and Wang, Y and Deng, S},
title = {Overcoming Biological Barriers: A Comprehensive Review of Advanced Melatonin Delivery Systems for Therapeutic Applications.},
journal = {International journal of medical sciences},
volume = {23},
number = {7},
pages = {2462-2485},
pmid = {42328129},
issn = {1449-1907},
mesh = {*Melatonin/administration & dosage/pharmacokinetics/chemistry/therapeutic use ; Humans ; *Drug Delivery Systems/methods ; Animals ; Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/drug effects/metabolism ; Drug Carriers/chemistry ; Neoplasms/drug therapy ; Antioxidants/administration & dosage/pharmacokinetics ; Nanoparticles/chemistry ; },
abstract = {Melatonin is a pleiotropic hormone with well-documented antioxidant, anti-inflammatory, neuroprotective, and immunomodulatory properties, making it a promising candidate for the treatment of diverse diseases including neurodegenerative disorders, cardiovascular diseases, cancer, and sleep disturbances. However, its clinical translation has been hampered by several biopharmaceutical limitations, including poor aqueous solubility, extensive hepatic first-pass metabolism, rapid systemic clearance, and low oral bioavailability. Additionally, physiological barriers such as the blood-brain barrier, stratum corneum, and mucosal epithelia restrict its accumulation at target sites. In recent years, nanotechnology-based drug delivery systems have emerged as powerful tools to overcome these challenges. This review provides a comprehensive overview of advanced melatonin nanocarriers with a focus on their design principles, formulation strategies, and therapeutic applications. A central theme of this review is the integration of carrier design with biological barrier circumvention and administration routes-elucidating how specific nanocarrier platforms address the shortcomings of conventional immediate- and prolonged-release melatonin formulations through spatial and temporal control over drug distribution. We summarize recent preclinical progress in melatonin nanocarriers for a wide range of disease models, including Alzheimer's disease, Parkinson's disease, myocardial infarction, retinal degeneration and glaucoma, depression, and various cancers, with emphasis on the relationship between administration routes and therapeutic outcomes. Finally, critical challenges in clinical translation are addressed, including large-scale manufacturing, long-term toxicity evaluation, regulatory considerations, and the development of chronotherapy-compatible delivery systems. By integrating insights from materials science, pharmaceutics, and nanomedicine, this review aims to provide a rational framework for the future design and clinical application of melatonin-based nanotherapeutics.},
}

*Melatonin/administration & dosage/pharmacokinetics/chemistry/therapeutic use
Humans
*Drug Delivery Systems/methods
Animals
Neurodegenerative Diseases/drug therapy
Blood-Brain Barrier/drug effects/metabolism
Drug Carriers/chemistry
Neoplasms/drug therapy
Antioxidants/administration & dosage/pharmacokinetics
Nanoparticles/chemistry

@article {pmid42328206,
year = {2026},
author = {Okochi, Y and Matsui, T and Sakaguchi, S and Kondo, T and Naoki, H},
title = {Zero-shot reconstruction of mutant spatial transcriptomes.},
journal = {Patterns (New York, N.Y.)},
volume = {7},
number = {6},
pages = {101521},
pmid = {42328206},
issn = {2666-3899},
abstract = {Mutant analysis is the core of biological/pathological research, and measuring spatial transcriptomes can facilitate the understanding of the disorganized tissue phenotype. However, the high cost and technical challenges of spatial transcriptome experiments hinder the investigation of large numbers of mutants. Spatial transcriptomes have also been computationally predicted from single-cell RNA sequencing data using teaching data of spatial expression of certain genes, but the lack of teaching data for most mutants remains challenging. In various machine-learning tasks, zero-shot learning offers potential for predictions without teaching data. Here, we provided ZENomix, the zero-shot framework for predicting mutant spatial transcriptomes without teaching data (e.g., mutant spatial atlases). ZENomix accurately predicted spatial transcriptomes in Alzheimer's model mice, Alzheimer's human brains, and Nodal-signaling-deficient mutant zebrafish embryos. We proposed a ZENomix-based screening approach, identifying Nodal-downregulated genes in zebrafish. We expect that ZENomix offers phenotypic insights by leveraging the enormous amount of mutant/disease single-cell RNA sequencing data.},
}

@article {pmid42328289,
year = {2026},
author = {Wang, Z and Huang, Y and Bian, J},
title = {OmniBioTwin: A System-of-Twinned-Systems Framework for Health Digital Twins.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {42328289},
issn = {2331-8422},
abstract = {Health digital twins (HDTs) promise patient-specific modeling and decision support but current approaches remain structurally fragmented: monolithic models that address a single organ or task lack cross-scale fidelity, while system-level twins lack generalizable architectural frameworks. We propose OmniBioTwin, a System-of-Twinned-Systems (SoTS) framework that organizes HDTs as modular computational entities coupled through explicit interaction operators within a multi-layer network architecture. The framework comprises seven coordinated layers - spanning data integration, autonomous twin modeling, cross-scale coupling, temporal synchronization, and human-in-the-loop decision support. We demonstrate OmniBioTwin by instantiating a multiscale twin for glucagon-like peptide-1 (GLP-1) signaling pathways in Alzheimer's disease, illustrating how molecular, cellular, and organ-level twins can be composed and coupled within a unified system.},
}

@article {pmid42328310,
year = {2026},
author = {Hosseinpoor-Dashatani, S and Ebrahimi, N},
title = {Global trends in Alzheimer's disease randomized controlled trials: a bibliometric analysis.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250423},
pmid = {42328310},
issn = {1980-5764},
abstract = {UNLABELLED: Alzheimer's disease (AD) is the most common form of dementia worldwide, creating substantial clinical and socioeconomic burdens. Randomized controlled trials (RCTs) provide the highest level of evidence to evaluate interventions, yet global publication trends and thematic evolution have not been systematically analyzed.

OBJECTIVE: As far as we are aware, there has been no bibliometric analysis that has thoroughly assessed RCTs in AD, despite their pivotal influence on the development of treatment and prevention strategies. Therefore, in this study, we conducted a bibliometric mapping analysis of global RCTs on AD.

METHODS: A bibliometric analysis of human RCTs on AD from September 2010 to September 2025 was conducted using PubMed and Web of Science. VOSviewer was employed for keyword co-occurrence, co-authorship mapping, and co-citation analyses to identify research themes, collaborations, and temporal trends.

RESULTS: A total of 4,482 RCTs were identified, revealing five main themes: pharmacological interventions, lifestyle and prevention strategies, pathophysiological mechanisms, cognitive and behavioral interventions, and clinical trial methodology. After 2015, focus shifted from traditional pharmacology to multidomain, prevention-oriented, and precision-driven approaches. Emerging topics included digital health, gut microbiome, and machine learning. Collaboration networks highlighted the dominance of the US and Europe, with rapid growth in Asia and emerging regions.

CONCLUSION: Findings indicate a paradigm shift in AD RCTs toward integrative, technology-enabled designs, emphasizing both pharmacological and non-pharmacological strategies. These trends can guide future global research priorities and intervention development.},
}

@article {pmid42328628,
year = {2026},
author = {Castro E Silva, JH and Marangon, D and Boccazzi, M and Raffaele, S and Cignitti, N and Bavetta, M and Arisi, I and Fumagalli, M and Abbracchio, MP and Lecca, D},
title = {The GPR17 agonist galinex restores oligodendrocyte maturation under inflammatory conditions.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1838997},
pmid = {42328628},
issn = {1663-9812},
abstract = {INTRODUCTION: Chronic neuroinflammation disrupts oligodendrocyte differentiation and limits effective remyelination across multiple neurological disorders. Among the molecular regulators integrating inflammatory cues with oligodendrocyte maturation, G protein-coupled receptor 17 (GPR17) has emerged as a critical checkpoint. Physiologically, GPR17 expression is low in early oligodendrocyte precursor cells (OPCs), peaks in immature oligodendrocytes, and is subsequently downregulated to allow terminal maturation. Under neuroinflammatory conditions, GPR17 expression persists, suggesting a possible role in impaired oligodendrocyte maturation and defective myelination. Here, we tested whether receptor modulation by the selective GPR17 agonist Galinex (GAL) can support oligodendrocyte maturation under inflammatory conditions.

METHODS: Differentiating oligodendroglial cultures were exposed to a pro-inflammatory cytokine cocktail composed of TNFα, IL-1β, and IFNγ. We first identified a subtoxic inflammatory condition, defined as cytokine exposure that did not cause overt loss of cell viability, and assessed oligodendrocyte maturation, myelin-associated marker expression, GPR17 expression, and transcriptional remodelling. Publicly available transcriptomic signatures from neuroinflammatory mouse models and human Alzheimer's disease and multiple sclerosis brains were used for cross-comparison. The effect of GAL was then evaluated by molecular, morphological, and functional readouts, including a synthetic nanofiber myelination assay.

RESULTS: Subtoxic cytokine exposure consistently impaired oligodendrocyte morphological maturation, reduced the expression of myelin-associated markers, and was accompanied by increased GPR17 expression. Transcriptomic analysis revealed coordinated remodelling of pathways related to protein synthesis and proteostasis, mitochondrial metabolism, lipid homeostasis, and inflammatory/immunogenic-like responses, together with senescence- and DNA damage-associated features. Cross-comparison with disease-associated transcriptomic signatures showed significant overlap with neuroinflammatory modules, supporting the relevance of the inflammatory pathways engaged in our model. GAL treatment partially restored terminal maturation-associated features and oligodendrocyte morphology. Moreover, in the nanofiber assay, GAL significantly increased the length of MBP-positive segments compared with CTK-treated cells, suggesting improved wrapping/myelination-like capacity after inflammatory challenge.

DISCUSSION: Together, this study establishes a controlled in vitro model linking inflammatory cytokine exposure, disease-associated transcriptional alterations, and impaired oligodendrocyte differentiation. Our findings indicate that pharmacological modulation of GPR17 can promote oligodendrocyte maturation and wrapping features under non-permissive inflammatory conditions. This strategy should be considered as an oligodendroglial-directed approach that may complement anti-inflammatory or immunomodulatory interventions.},
}

@article {pmid42328658,
year = {2026},
author = {Ariaei, A and Zamiri, R and Ghasemi, A and Rezayani, B and Rezayani, S and Ezatpour, A and Farshidi, N and Sheikhi, EA and Roghanian, A and , and , },
title = {Metabolic profile association with white matter hyperintensity in patients with mild cognitive impairment.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {76-85},
pmid = {42328658},
issn = {2667-2421},
abstract = {Brain vasculopathy, including cerebral white matter hyperintensity (WMH), is highly associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD) pathology. Metabolite levels provide clues to illuminate the mechanism of WMH in MCI. Therefore, the current study investigated the association between metabolite profile and WMH in MCI. Metabolite profiles and WMH data of MCI patients with three consecutive years of follow-up were retrospectively extracted from the ADNI database. Multivariate logistic regression and mixed model regression adjusted for age, gender, education, and ADAS-Cog13 were used to evaluate the association between metabolite levels and WMH. A total number of 189 subjects were included in this study, allocated into three groups of healthy individuals (n = 67), mild cognitive impairment (n = 112), and AD (n = 10). Based on the multivariate logistic regression, methionine, deoxycholic acid, trimethylamine N-oxide, glutamic acid, and alanine, palmitoylethanolamide, and arachidonic acid positively correlated with WMH (OR:4.014 [95% CI: 1.329-12.128]; OR: 1.272 [95% CI: 1.076-1.504]; OR: 1.839 [95% CI: 1.007-1.390]; OR: 8.474 [95% CI: 2.730-26.300]; OR: 3.532 [95% CI: 1.544-8.076]; OR: 2.486 [95% CI: 1.152-5.364]; OR:2.110 [95% CI: 1.003-4.440], respectively), while tyrosine, proline, histidine, and beta-aminobutyric acid negatively correlated with WMH (OR:0.287 [95% CI:0.092-0.894]; OR:0.381 [95% CI:0.162-0.894]; OR:0.240 [95% CI:0.059-0.982]; OR: 0.598 [95% CI: 0.382-0.939], respectively). The association of metabolite levels with WMH in the MCI group is complex. One of the suggested mechanisms is amino acid overconsumption in the MCI group, resulting in decreasing their detected level in the serum while accumulation of their metabolites in the brain increases the risk of WMH.},
}

@article {pmid42328930,
year = {2026},
author = {Zeng, Y and Cook, N and Yang, C and Sivasankaran, SK and Fujita, M and Gardell, ZA and Le Guen, Y and Shigemizu, D and Ozaki, K and Morizono, T and Hara, N and Miyashita, A and Ikeuchi, T and Pottier, C and Cruchaga, C and Napolioni, V and Corces, MR and Menon, V and Greicius, MD and Belloy, ME},
title = {APOE*4 risk-modifying genes and drug targets in Alzheimer's disease through cell-type-specific genomic analyses.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71552},
doi = {10.1002/alz.71552},
pmid = {42328930},
issn = {1552-5279},
support = {R00AG075238/AG/NIA NIH HHS/United States ; JP25dk0207060//Japan Foundation for Aging and Health/ ; //Knight Family Early Stage Investigator Program/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy ; Genome-Wide Association Study ; *Apolipoprotein E4/genetics ; *Genetic Predisposition to Disease/genetics ; Genomics ; Brain ; },
abstract = {INTRODUCTION: Genetics studies can identify drug targets that counteract the effects of the apolipoprotein E ε4 allele (APOE*4) on Alzheimer's disease (AD) but have remained limited in power and crucially did not assess genetic findings with regard to APOE*4's cell-type-specific impact on pathobiology.

METHODS: We conducted a novel APOE*4-stratified genome-wide association study (GWAS) of AD (N = 447,669) and integrated results with brain cell-type-specific multi-omics data to identify APOE*4 and cell-type-specific AD genes, followed by compound and drug repurposing.

RESULTS: In APOE*4 non-carriers (APOE*4-) and carriers (APOE*4+), we respectively identified 33 and 11 cell type-gene pairs with strong prioritization support. Oligodendrocytes displayed the largest proportion of APOE*4+ genes. Several genes were druggable and pinpointed APOE*4-stratified drugs or compounds.

DISCUSSION: We identified a set of APOE*4-stratified genes that may be causal for AD through brain cell-type-specific mechanisms. We additionally identified compounds that may shed light on therapeutic avenues for treating AD based on an individual's APOE*4 status.},
}

Humans
*Alzheimer Disease/genetics/drug therapy
Genome-Wide Association Study
*Apolipoprotein E4/genetics
*Genetic Predisposition to Disease/genetics
Genomics
Brain

@article {pmid42328935,
year = {2026},
author = {Dvorak, NM and Noebels, JL},
title = {mTORC2-Nav1.2 signaling drives early hyperexcitability in Alzheimer's disease mouse model.},
journal = {Channels (Austin, Tex.)},
volume = {20},
number = {1},
pages = {2687246},
doi = {10.1080/19336950.2026.2687246},
pmid = {42328935},
issn = {1933-6969},
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; Mice ; *Signal Transduction ; Disease Models, Animal ; *Mechanistic Target of Rapamycin Complex 2/metabolism ; *NAV1.2 Voltage-Gated Sodium Channel/metabolism ; Humans ; },
abstract = {Hyperexcitability is a biomarker of early-stage Alzheimer's Disease (AD) and hastens cognitive decline later in its course. Mechanistic target of rapamycin (mTOR) signaling contributes to the slope of this trajectory, as evidenced by early increased brain expression and the rescue of hyperexcitability by genetic deletion of mTOR complex 2 (mTORC2); however, a molecular mechanism directly linking mTOR signaling to membrane hyperexcitability in early-stage AD remains elusive. Here, we show that hyperactive mTOR signaling stimulates the voltage-gated Na[+] channel 1.2 (Nav1.2), a previously identified downstream phosphorylation target of mTORC2 and a key regulator of membrane electrogenesis. Augmented Nav1.2 channel function induced by hyperactive mTOR signaling requires the action of mTORC2 and is selective among major brain Nav channel isoforms. In a murine AD model, neocortical pyramidal neurons display augmented Nav1.2 channel function and hyperexcitability through a mechanism that requires mTORC2 activity. These results highlight the mTORC2-Nav1.2 interaction as a therapeutic target for attenuating pathogenic hyperexcitability in early-stage AD.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology
Mice
*Signal Transduction
Disease Models, Animal
*Mechanistic Target of Rapamycin Complex 2/metabolism
*NAV1.2 Voltage-Gated Sodium Channel/metabolism
Humans

@article {pmid42329045,
year = {2026},
author = {Yang, H and Niu, Z and Li, M and Zhou, H and Xiao, Y and Zhou, S and Zhan, Z and Liu, Y and Liu, S and Tignanelli, CJ and Melton, GB and Zhang, R},
title = {Benchmarking information extraction of physical activity from electronic health record with large language models: an natural language processing pipeline and comparative evaluation.},
journal = {Journal of the American Medical Informatics Association : JAMIA},
volume = {},
number = {},
pages = {},
doi = {10.1093/jamia/ocag101},
pmid = {42329045},
issn = {1527-974X},
support = {R01AT009457//National Institutes of Health's National Center for Complementary and Integrative Health/ ; U01AT012871//National Institutes of Health's National Center for Complementary and Integrative Health/ ; R01AG078154/AG/NIA NIH HHS/United States ; R01CA287413/CA/NCI NIH HHS/United States ; R01DK115629/DK/NIDDK NIH HHS/United States ; R21MD019134-01/MD/NIMHD NIH HHS/United States ; U01FD008720-01/FD/FDA HHS/United States ; //University of Minnesota Clinical and Translational Science Institute (CTSI)/ ; UL1TR002494/TR/NCATS NIH HHS/United States ; /NH/NIH HHS/United States ; },
abstract = {OBJECTIVES: We aimed to develop a data model and a natural language processing (NLP) pipeline for representing physical activity (PA) in Electronic Health Records (EHRs), and to evaluate transformer- and Large Language Model (LLM)-based classifiers for sentence-level PA attribute classification.

MATERIALS AND METHODS: We analyzed PA documentation across three patient cohorts (cancer, COVID, and Alzheimer's disease) using structured and unstructured EHR data. A conceptual schema was developed to represent PA and its linguistic attributes. Five BERT models and three modern LLMs (Llama3-8B, MedAlpaca-13B, and PMC-Llama-13B) were evaluated for classifying PA attributes (binary status, negation, exclusion, and an eleven-class Category) on pre-extracted PA-related sentences.

RESULTS: Clinical notes were a richer source of PA information than structured ICD or SDoH data. On binary tasks, the best BERT model reached F1 0.619 (Exclusion); with Supervised Fine-Tuning (SFT), Llama3-8B reached F1 0.689 (Exclusion). On the 11-class Category task, performance was modest (best macro-F1 0.262, ROC-AUC 0.803, by Llama3-8B).

DISCUSSION: In-Context Learning (ICL) was highly variable: while Llama3-8B-ICL achieved the best ROC-AUC on Category, the domain-specific MedAlpaca-13B and PMC-LLaMA-13B essentially failed. These results, together with sparsely represented PA elements (Amount, Frequency, Assessment) and the absence of a downstream evaluation, position this work as an initial proof of feasibility, with supervised domain adaptation still required for reliable clinical PA extraction.

CONCLUSION: We contribute a PA data model, annotation schema, and a working NLP pipeline with a BERT/LLM benchmark for sentence-level PA attribute classification. The pipeline supports future end-to-end PA extraction and downstream applications such as phenotyping, risk prediction, and cohort identification.},
}

@article {pmid42329240,
year = {2026},
author = {Xu, Z and Ding, J and Su, X and Wang, G and Xie, K and Zhao, Y and Xiong, C and McDade, E and Schneider, LS and Liu, L},
title = {Subgroup identification via Interaction Tree and Mixed Model for Repeated Measures with application to Alzheimer's disease.},
journal = {Biometrics},
volume = {82},
number = {2},
pages = {},
doi = {10.1093/biomtc/ujag104},
pmid = {42329240},
issn = {1541-0420},
support = {UL1 TR002345/GF/NIH HHS/United States ; R21 AG084054/GF/NIH HHS/United States ; 5928//Washington University CTFRP/ ; },
mesh = {*Alzheimer Disease/drug therapy/therapy ; Humans ; Computer Simulation ; *Models, Statistical ; *Precision Medicine/methods ; Treatment Effect Heterogeneity ; Longitudinal Studies ; Algorithms ; },
abstract = {In precision medicine, subgroup identification is crucial for designing personalized treatments. This research focuses on subgroup identification in longitudinal clinical trials by integrating the Interaction Tree (ITree) with the Mixed Model for Repeated Measures (MMRM). Our ITree-MMRM approach retains the flexibility of tree-based methods in capturing nonlinear treatment interactions for heterogeneous treatment effects, while adhering to Food and Drug Administration guidelines for assessing treatment effects at the conclusion of longitudinal studies using MMRM. Additionally, we explore various options for tuning parameters and employ bootstrap methods to prune trees, reducing the risk of overoptimism. We demonstrate that our method outperforms existing subgroup identification techniques in simulations. The ITree-MMRM model is applied to an Alzheimer's disease clinical trial to identify subgroups with long-term treatment responses.},
}

*Alzheimer Disease/drug therapy/therapy
Humans
Computer Simulation
*Models, Statistical
*Precision Medicine/methods
Treatment Effect Heterogeneity
Longitudinal Studies
Algorithms

@article {pmid42329254,
year = {2026},
author = {Paliwal, S and Bhardwaj, JS and Taliyan, R},
title = {Exploring the Neuroprotective Potential of 5-Azacytidine on the Streptozotocin-Induced Rat Model of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00234},
pmid = {42329254},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) associated with insulin resistance represents a major challenge in sporadic neurodegeneration, where impaired neuronal survival and synaptic plasticity are compounded by aberrant DNA methylation. Epigenetic silencing of Wnt pathway genes under insulin-resistant conditions exacerbates β-amyloid accumulation, tau hyperphosphorylation, and oxidative stress. The present study aimed to establish insulin-resistant AD models and evaluate the mechanistic potential of DNA methyltransferase (DNMT) inhibition, with a specific focus on canonical Wnt/β-catenin restoration. An in vitro AD model was generated by exposing SHSY-5Y cells to streptozotocin (STZ, 400 μM), resulting in elevated DNMT1, Aβ1-42, and sFRP1 levels, alongside reduced β-catenin and survivin expression. Treatment with the DNMT1 inhibitor 5-azacytidine (5-AZA), employed here as a mechanistic probe rather than a therapeutic candidate, reversed these changes, restoring Wnt signaling and attenuating amyloid burden. In vivo, intracerebroventricular administration of STZ (3 mg/kg) in rats induced an insulin-resistant AD-like pathology characterized by cognitive decline, increased pTau and acetylcholinesterase activity, and reduced neuroprotective markers. 5-AZA treatment improved memory and behavior, decreased pTau and AChE levels, and enhanced ADAM10, TREM2, BDNF, and antioxidant activity. Histological analysis further revealed preservation of neuronal layers and structural integrity. Collectively, these findings demonstrate that DNMT inhibition, exemplified by 5-AZA as a mechanistic tool, can mitigate STZ-induced molecular and behavioral alterations by relieving hypermethylation-mediated repression and supporting partial reactivation of canonical Wnt/β-catenin signaling. While 5-AZA itself is not a viable therapeutic option, the results highlight DNMT inhibition as a promising disease-modifying strategy in insulin resistance-associated AD.},
}

@article {pmid42329291,
year = {2026},
author = {Sathick Batcha, BR and Amarnath, DP and Srinivasan, D and Ramakrishnan, P},
title = {Targeting mitochondrial dysfunction and neuroprotection in neurodegenerative disorders: emerging therapeutic potential of berberine and polymeric nanoparticle-based delivery systems.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42329291},
issn = {1568-5608},
abstract = {Major neurodegenerative disorders, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are pathologically driven by mitochondrial failure and persistent neuroinflammation. Defects in oxidative phosphorylation, excess Reactive Oxygen Species (ROS), and impaired mitophagy cause an imbalance in neuronal energy and promote the release of mitochondrial Damage-Associated Molecular Patterns (DAMPs) that activate microglial inflammasomes and enhance inflammatory signalling. Current therapeutic strategies have largely targeted individual pathways and have been unable to effectively modulate this interrelated mitochondrial immune axis or achieve efficient delivery to the Central Nervous System (CNS). This review addresses the dual promise of berberine therapy, a biologically active plant alkaloid that enhances mitochondrial production via AMPK/PGC-1α and SIRT1, restores membrane potential, promotes mitophagy, and inhibits NF-κB and NLRP3-mediated inflammation. Nevertheless, this compound's weak solubility, limited bioavailability, and extremely poor Blood-Brain Barrier (BBB) penetration limit its therapeutic application. Encapsulation of berberine in polymeric nanoparticles, including Polyethylene glycol (PEG)-based polymeric nanoparticle systems, offers improved stability, bioavailability, and targeted mitochondrial delivery. An effective method for reducing neuroinflammation and mitochondrial dysfunction is this comprehensive phytochemical nanotechnology technique.},
}

@article {pmid42329333,
year = {2026},
author = {da Silva, AMP and Leite, M and Menegucci, G and Negreli, MFLA and Valverde, MES and Menezes, IR and Gonçalves, OR and da Silva Lapa, JD and Noleto, G and Santos, DH and Duarte, FS and Perry, G and de Souza Franco, E and de Sousa Maia, MB},
title = {Gabapentinoid Use and Risk of Alzheimer's Disease-Related Dementias: A Systematic Review and Meta-analysis of Observational Studies.},
journal = {Drugs & aging},
volume = {},
number = {},
pages = {},
pmid = {42329333},
issn = {1179-1969},
abstract = {BACKGROUND AND OBJECTIVE: Gabapentinoids, particularly gabapentin and pregabalin, are widely prescribed for neuropathic pain and other chronic conditions, including in populations at risk for cognitive decline. Their long-term cognitive safety and potential association with Alzheimer's disease and related dementias (ADRD) remain uncertain. We examined whether gabapentinoid use is associated with ADRD risk and assessed between-study heterogeneity and potential study-level modifiers.

METHODS: PubMed, Embase, and the Cochrane Library were searched from inception through November 2025. We included observational studies comparing gabapentinoid users with non-users or non-gabapentinoid comparators and reporting incident ADRD. Risk of bias was assessed using ROBINS-E. A random-effects meta-analysis was performed using odds ratios. Subgroup and meta-regression analyses explored study-level modifiers. Certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). The protocol was registered in PROSPERO (CRD420251240055).

RESULTS: Five observational studies (325,245 participants) were included. Gabapentinoid use was associated with modestly higher estimated odds of ADRD (odds ratio, 1.28; 95% confidence interval 1.10-1.50; P = 0.002), with high heterogeneity (I[2] = 90.3%). This association was attenuated when restricted to studies with a low risk of bias (odds ratio, 1.23; 95% confidence interval 0.83-1.84). Studies enrolling younger populations yielded larger estimates than those with older cohorts, though the subgroup difference was not statistically significant. Meta-regression identified mean age as a study-level moderator, accounting for 60.2% of between-study variance. Certainty of evidence was low overall.

CONCLUSIONS: Gabapentinoid use was associated with modestly higher estimated odds of ADRD in pooled observational data. High heterogeneity, residual confounding, and confounding by indication preclude causal inference. These findings support cautious prescribing, particularly for off-label and long-term use, and underscore the need for prospective studies.

CLINICAL TRIAL REGISTRATION: PROSPERO protocol number: CRD420251240055.},
}

@article {pmid42329483,
year = {2026},
author = {Kumar, N and Mir, PA and Bhutia, GT and Chaudhary, P and Kaur, G and Alam, Q and Pawar, SD and Gupta, SK},
title = {Reprogramming Neuroinflammation: Mitochondrial Targets and Immune Checkpoint Inhibitors in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42329483},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology/metabolism/pathology ; *Mitochondria/drug effects/metabolism ; Animals ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; *Neuroinflammatory Diseases/drug therapy/pathology/metabolism ; Microglia/metabolism/drug effects/pathology ; },
abstract = {Mitochondrial dysfunction and dysregulated microglial phenotypes are central contributors to the pathogenesis of Alzheimer's disease (AD), driving persistent neuroinflammation, synaptic loss, and impaired clearance of amyloid and tau aggregates. Disruptions in microglial mitochondrial metabolism lead to bioenergetic deficits, elevated oxidative stress, and shifts into maladaptive reactive states that exacerbate neuronal vulnerability. Recent insights into immune checkpoint pathways, including programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), highlight their roles in maintaining neuroimmune balance within the central nervous system (CNS). Although sustained engagement of these pathways in the peripheral compartment may contribute to immune exhaustion and reduced debris clearance, their CNS-resident roles in microglial homeostasis are protective, and this compartment-specific duality must be carefully considered in the design of targeted therapeutic strategies. Immune checkpoint inhibitors (ICIs), initially developed for oncology, are now being explored for their potential to modulate microglial responses, enhance amyloid removal, and mitigate neuroinflammation in AD. Emerging evidence suggests that combining ICIs with mitochondrial modulators may cooperatively support microglial homeostasis and potentially reprogram dysfunctional neuroimmune circuits, though direct combinatorial evidence in AD remains limited. Together, these findings provide a conceptual basis for considering a dual-targeted therapeutic framework for modulating neuroinflammation in AD. This review integrates current mechanistic insights into mitochondrial dysfunction and immune checkpoint signaling in AD and evaluates their translational potential as combined therapeutic strategies.},
}

Humans
*Alzheimer Disease/drug therapy/immunology/metabolism/pathology
*Mitochondria/drug effects/metabolism
Animals
*Immune Checkpoint Inhibitors/therapeutic use/pharmacology
*Neuroinflammatory Diseases/drug therapy/pathology/metabolism
Microglia/metabolism/drug effects/pathology

@article {pmid42329624,
year = {2026},
author = {Hsiao, JK},
title = {Stopping Alzheimer Disease: 50 Years of Progress.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.10969},
pmid = {42329624},
issn = {1538-3598},
}

@article {pmid42329632,
year = {2026},
author = {Olzinski, M and Downer, J and Cobigo, Y and Rajbanshi, B and Li, J and Loureiro, J and Worringer, KA and Heuer, H and Ljubenkov, P and Vandevrede, L and Staffaroni, A and Lario-Lago, A and Leichter, D and Wolf, A and Wise, A and Sanderson-Cimino, M and Barragan, E and Spina, S and Grinberg, LT and Seeley, WW and Casaletto, KB and Kramer, J and Ramos, EM and Geschwind, D and Cook, C and Petrucelli, L and Forsberg, LK and Gendron, T and Boeve, BF and Perneel, J and Rademakers, R and Rosen, HJ and Saloner, R and Boxer, AL and Rojas, JC and , },
title = {Clinical Associations of Cerebrospinal Fluid TMEM106B in Familial and Sporadic Frontotemporal Dementia.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.1927},
pmid = {42329632},
issn = {2168-6157},
abstract = {IMPORTANCE: TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown.

OBJECTIVE: To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD.

This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72, GRN, or MAPT; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls.

EXPOSURES: CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]).

MAIN OUTCOMES AND MEASURES: Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume.

RESULTS: In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, -0.15; 95% CI, -0.24 to -0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P < .001), and faster clinical progression (β, -2.21; 95% CI, -3.70 to -0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD.

CONCLUSIONS AND RELEVANCE: Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.},
}

@article {pmid42329766,
year = {2026},
author = {Metodieva, V and Marchese, S and Esposito, P and Danial, JSH and Di Falco, A and De, S and Klenerman, D and Varela, JA},
title = {Divergent toxicity mechanisms of amyloid-beta aggregates arising from a single aggregation reaction.},
journal = {Cell reports},
volume = {45},
number = {7},
pages = {117595},
doi = {10.1016/j.celrep.2026.117595},
pmid = {42329766},
issn = {2211-1247},
abstract = {Amyloid-β 1-42 (Aβ42) aggregation is among the earliest pathological signs in Alzheimer's disease (AD). Here, we characterized Aβ42 species at several aggregation stages at the single-molecule level and examined their toxicity in murine organotypic brain slices, where we observed a stage-dependent recapitulation of multiple aspects of the cellular phase of AD. Aggregates formed during the lag phase of the Aβ42 aggregation elevated neuronal baseline Ca[2+] levels and impaired long-term potentiation (LTP), while promoting microglial homeostatic exit and transition to disease-associated microglia (DAM) state. In contrast, aggregates enriched during the growth phase downregulated homeostatic microglial markers and induced TLR4-mediated microglial activation, cytokine production, and complement activation, leading to synaptic engulfment and severe disruption of neuronal activity. Together, these findings reveal that structurally distinct Aβ42 aggregate species engage different cellular and molecular pathways. This framework advances mechanistic understanding of amyloid toxicity in neurodegeneration and could inform the design of combination therapeutic strategies.},
}

@article {pmid42330346,
year = {2026},
author = {Nie, C and Yang, R and Wang, X and Jia, P and Zhang, X and Dai, Y and Bai, X and Duan, S and Li, Y and Zheng, P and Tian, X and Jiang, L and Wang, C},
title = {Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4-Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR-Linked Pro-Clearance State.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e24167},
doi = {10.1002/advs.202524167},
pmid = {42330346},
issn = {2198-3844},
support = {82271470//National Natural Science Foundation of China/ ; LG-GG-202401-ADA010100//Lingang Laboratory AD Special Project/ ; 2023NSCQ-MSX3605//Natural Science Foundation of Chongqing Municipal Bureau of Science and Technology/ ; //National Science Fund for Excellent Young Scholars/ ; KZD-JI202400406//Scientific and Technological Research Program of Chongqing Municipal Education Commission/ ; STI2030-Major Projects 2021ZD0202400//Key Technologies Research and Development Program/ ; },
abstract = {The mouse gene Lilrb4a, an ortholog of human leukocyte immunoglobulin-like receptor B4 (LILRB4), is markedly upregulated in microglia in Alzheimer's disease models and has been implicated in Apolipoprotein E (APOE)-related signaling. However, its contribution to amyloid pathology under an APOE4 background remains unclear. Here, 5xFAD mice carrying human APOE4 were used to assess the impact of Lilrb4a reduction by genetic deletion or antisense oligonucleotide treatment. Both approaches significantly reduced cortical amyloid plaque burden and APOE4-associated cerebral amyloid angiopathy without altering amyloid-β (Aβ) production. Bulk RNA sequencing identified enrichment of peroxisome proliferator-activated receptor (PPAR)-related and broader metabolic pathways in Lilrb4a-deficient mice. Consistently, biochemical analyses showed reduced p-SHP-2, NF-κB-p65, and p-STAT1, increased p-STAT3, and induction of anti-inflammatory and clearance-associated effectors, including Arg-1, TGF-β, and Cyp2e1. In primary microglia, pharmacological interrogation supported a functional contribution of PPAR-γ signaling to the enhanced Aβ uptake and degradation associated with Lilrb4a suppression, whereas PPAR-γ agonism recapitulated key pro-clearance phenotypes in vitro and attenuated amyloid pathology in vivo. Together, these data support Lilrb4a as an APOE4-associated microglial checkpoint candidate linked to impaired amyloid clearance and identify a PPAR-linked pro-clearance program as a potential downstream component of this response.},
}

@article {pmid42330435,
year = {2026},
author = {Gallay, C and Soldevila-Domenech, N and López-Martos, D and Sanchez-Benávides, G and Huguet, J and Suárez-Calvet, M and Gispert, JD and Salvadó, G and Sundermann, EE and Grau-Rivera, O and Brugulat-Serrat, A and , },
title = {Effect of Parity and β-Amyloid on Cognition and Hippocampal Volume in Postmenopausal Women.},
journal = {Neurology},
volume = {107},
number = {1},
pages = {e218153},
doi = {10.1212/WNL.0000000000218153},
pmid = {42330435},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Epidemiologic studies exploring the effect of parity on Alzheimer disease (AD) yield mixed results, and little is known about how parity may modify the impact of AD pathology on brain and cognitive aging. We examined the effect of parity and AD pathology on hippocampal volume (HV) and cognitive changes in cognitively unimpaired (CU) postmenopausal women.

METHODS: Analysis was performed on CU postmenopausal women from the ALFA+ observational cohort based in the BarcelonaBeta Brain research center, who completed 1 or 2 visits spaced by ∼3 years (mean = 3.38, SD = 0.55) with reproductive data, cognitive testing (modified Preclinical Alzheimer's Cognitive Composite), CSF biomarkers (Aβ42 and Aβ40), and structural MRI. We used linear mixed-effects models to investigate the interactive effects of parity, time, and Aβ status (based on CSF Aβ42/Aβ40) on cognition and HV. APOE-ε4 status, age, and total intracranial volume were included as covariates.

RESULTS: A total of 254 women were included in our analyses ranging from 49.2 to 73.4 years (mean age = 61.2) at visit 1. A significant interaction between parity and Aβ status was observed for cognitive decline and HV. In women with positive amyloid status, higher parity was associated with steeper cognitive decline (β = -0.035, 95% CI -0.068 to -0.003, p = 0.033) and lower HV across time points (β = -0.134, 95% CI -0.263 to -0.005, p = 0.036).

DISCUSSION: In CU postmenopausal women, higher parity interacts with AD pathology to influence cognitive decline and HV reductions. These findings suggest that parity may affect resilience to AD pathology in preclinical AD stages.},
}

@article {pmid42330806,
year = {2026},
author = {Maeda, K and Ichimura, H and Ogawa, S and Ito, E and Sugimoto, S and Sasahara, T and Kawamura, S and Matsunaga, K and Higashi, T},
title = {A method for quantifying non-esterified cis-9,trans-11-conjugated linoleic acid in finger-prick plasma by LC/ESI-MS/MS with isotope-coded derivatization.},
journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences},
volume = {1281},
number = {},
pages = {125194},
doi = {10.1016/j.jchromb.2026.125194},
pmid = {42330806},
issn = {1873-376X},
abstract = {cis-9,trans-11-Conjugated linoleic acid (c9,t11-CLA) is the major CLA consumed from ruminant-derived foods and exhibits anti-carcinogenic, anti-atherogenic and anti-Alzheimer's disease effects for humans. Determination of the circulating non-esterified c9,t11-CLA helps provide a better understanding of its health benefits, but very few methods are available for this purpose. In this study, a liquid chromatography/electrospray ionization-tandem mass spectrometry-based method was developed and validated for quantifying non-esterified c9,t11-CLA in plasma. The DEMECAL device enabled not only the minimally invasive collection of finger-prick blood, but also an easy and rapid preparation of the plasma sample. The developed method employed the derivatization with 4-(4-dimethylaminophenyl)-1,2,4-triazoline-3,5-dione (DAPTAD), which achieved the complete separation of c9,t11-CLA from its positional and geometric isomers on an octadecylsilyl silica column (resolution, ≥ 1.92), elimination of the negative influence from linoleic acid, and a higher sensitivity (limit of detection, 210 amol) than any methods currently available. In addition, high precision (relative standard deviations in five repetitive measurements, ≤ 6.1%) and accuracy (analytical recovery rates, 99.4-103.7%) were obtained by the isotope-coded derivatization using deuterium-labeled DAPTAD. This method also had a sufficient applicability to real sample analysis; we successfully determined the plasma non-esterified c9,t11-CLA concentrations of Japanese healthy subjects and detected their changes due to the CLA supplementation.},
}

@article {pmid42319929,
year = {2026},
author = {Pan, W and Yang, L and Zhang, Y and Chen, Y and Xu, Y and Li, Y and Fu, Y and Ma, C and Liu, C and Li, Q and Liu, H and Wang, H and Xu, Q and Tong, WM and Niu, Y},
title = {Neuronal YTHDF2 suppresses innate immune activation in Aβ pathology by promoting m[6]A-dependent decay of cytosolic mitochondrial mRNAs.},
journal = {Science advances},
volume = {12},
number = {25},
pages = {eadz0887},
doi = {10.1126/sciadv.adz0887},
pmid = {42319929},
issn = {2375-2548},
mesh = {Animals ; *Immunity, Innate ; *Amyloid beta-Peptides/metabolism ; *RNA-Binding Proteins/metabolism/genetics ; *RNA, Messenger/metabolism/genetics ; *Neurons/metabolism/pathology ; Cytosol/metabolism ; RNA Methylation ; *RNA, Mitochondrial/genetics/metabolism ; Mice ; *Nerve Tissue Proteins/metabolism/genetics ; Humans ; Mitochondria/metabolism/genetics ; *Adenosine/analogs & derivatives/metabolism ; *Alzheimer Disease/metabolism/pathology/genetics/immunology ; *RNA Stability ; Microglia/metabolism ; },
abstract = {Dysregulation of RNA m[6]A modification has been implicated in Alzheimer's disease (AD), but the molecular mechanisms remain largely unclear. Here, we identified the presence of m[6]A on mitochondria-encoded messenger RNAs (mt-mRNAs) in the brain, with elevated levels correlated with amyloid-β (Aβ) deposition. Under physiological conditions, cytosolic m[6]A-modified mt-Nd4 is recognized and degraded by the m[6]A reader protein YTHDF2, thereby preventing aberrant activation of the RIG-I-MAVS innate immune pathway in neurons. Under Aβ-associated pathological conditions, YTHDF2 expression is markedly down-regulated in neurons, leading to the accumulation of m[6]A-modified mt-Nd4 in the cytosol. This accumulation triggers RIG-I-MAVS activation and type I interferon (IFN) responses. Neuron-derived IFN-β then amplifies neuroinflammation by activating surrounding microglia through a paracrine mechanism. Furthermore, neuronal Ythdf2 deficiency exacerbates Aβ-associated neuroinflammation and cognitive decline. Together, these findings reveal a previously unrecognized m[6]A/YTHDF2-dependent regulatory axis that links mitochondrial RNA metabolism to innate immune activation and neuroinflammation in Aβ pathology.},
}

Animals
*Immunity, Innate
*Amyloid beta-Peptides/metabolism
*RNA-Binding Proteins/metabolism/genetics
*RNA, Messenger/metabolism/genetics
*Neurons/metabolism/pathology
Cytosol/metabolism
RNA Methylation
*RNA, Mitochondrial/genetics/metabolism
Mice
*Nerve Tissue Proteins/metabolism/genetics
Humans
Mitochondria/metabolism/genetics
*Adenosine/analogs & derivatives/metabolism
*Alzheimer Disease/metabolism/pathology/genetics/immunology
*RNA Stability
Microglia/metabolism

@article {pmid42320199,
year = {2026},
author = {Dong, L and Yang, J and Meng, Y and Yang, S and Pan, C and Luo, F and Long, H and Lv, S and Gong, Y and Xu, J and Xiong, Y and Dong, Y},
title = {Single molecule, dual actions: GSK-3β/AChE dual inhibition for Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {316},
number = {},
pages = {119075},
doi = {10.1016/j.ejmech.2026.119075},
pmid = {42320199},
issn = {1768-3254},
abstract = {The pathogenesis of Alzheimer's disease (AD) is closely related with glycogen synthase kinase 3β (GSK-3β) and acetylcholinesterase (AChE). Our previous work verified that GL10a displayed superior GSK-3β inhibitory and neuroprotective activities relative to Tideglusib. Accordingly, a molecular hybridization strategy was applied to design and synthesize a series of dual target inhibitors against GSK-3β and AChE by conjugating GL10a and carbamate fragment of Rivastigmine's pharmacophore. After in vitro evaluations, the compound AJ-4 was screened as the most remarkable compound with potent inhibitory activities against GSK-3β (IC50: 4.7 nM) and AChE (IC50: 2.97 μM). Meanwhile, in vitro and in vivo data revealed that the optimal compound AJ-4 with excellent enzyme selectivity could decrease amyloid precursor protein (APP) and phosphorylated Tau expressions and increase phosphorylated GSK-3β levels. With favorable pharmacokinetic characteristics and tissue distribution, AJ-4 obviously ameliorated scopolamine-induced learning and memory impairments and alleviated hippocampal neuronal injury in AD mice. In conclusion, GSK-3β/AChE dual inhibitors represent a promising strategy for developing multi-target anti-AD drugs.},
}

@article {pmid42320286,
year = {2026},
author = {Li, J and Chen, T},
title = {Cytomegalovirus-related immune activation and major neuropsychiatric disorders: Mendelian randomization and bulk transcriptomic validation.},
journal = {Psychiatry research},
volume = {364},
number = {},
pages = {117279},
doi = {10.1016/j.psychres.2026.117279},
pmid = {42320286},
issn = {1872-7123},
abstract = {BACKGROUND: Cytomegalovirus (CMV) establishes lifelong latency and induces persistent changes in peripheral immunity. Observational links to neuropsychiatric disorders are difficult to interpret because of confounding and reverse causation.

METHODS: We performed two-sample, multivariable, and bidirectional Mendelian randomization (MR) on genetically predicted CMV seropositivity and antigen-specific antibody levels for Parkinson's disease (PD), bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder (MDD), and Alzheimer's disease (AD). Instruments were selected at P < 5 × 10[-6] (secondary at P < 5 × 10[-7]). Multivariable MR (MVMR) sensitivity analysis accounting for age-related genetic structure, pleiotropy/heterogeneity tests, and reverse MR evaluated robustness. Bulk transcriptomic validation tested whether CMV CD14+ late-response and HCMV reactivation-related host signatures were enriched in public PD and BD whole-blood datasets.

RESULTS: Genetically predicted anti-CMV IgG seropositivity was associated with PD (MVMR sensitivity aOR: 1.12, P = 0.020), with directional consistency in a single-instrument secondary analysis (OR: 1.25, P = 0.003). Anti-CMV pp28 antibody levels were associated with BD (aOR: 1.12, P = 0.043). The SCZ signal attenuated after adjustment, and no robust evidence was observed for MDD or AD. Both CMV-related host signatures were significantly enriched among PD-upregulated genes (CMV CD14+ NES = 1.85, FDR = 2.73 × 10[-6]; HCMV reactivation NES = 2.03, FDR = 9.11 × 10[-9]); BD showed no robust positive enrichment after covariate adjustment.

CONCLUSIONS: Integrated genetic and transcriptomic evidence prioritizes CMV-related peripheral immune activation as a plausible contributor to PD risk. The pp28-BD signal is hypothesis-generating and requires validation in datasets with direct CMV serostatus.},
}

@article {pmid42320774,
year = {2026},
author = {Ren, L and Liu, S and Sun, X and Zhang, Y and Wang, P and Liu, L and Chen, LL},
title = {Ditan Decoction alleviates glutamate excitotoxicity in an Aβ-induced Alzheimer's disease-like model through the regulation of ERBB2/PI3K/AKT signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122084},
doi = {10.1016/j.jep.2026.122084},
pmid = {42320774},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD), as the most prevalent form of dementia among the elders, poses a major global health challenge. Ditan Decoction (DTD), a classic prescription from traditional Chinese medicine, demonstrates potent capacity against neurological disorders. Nevertheless, the specific components of DTD and its mechanisms in treating AD remain unclear.

AIM OF THE STUDY: The study was designed to investigate the underlying substance basis and molecular mechanisms of DTD in treating Aβ1-42-induced cognitive decline in rats.

MATERIALS AND METHODS: The AD model rats established by Aβ1-42 injection were subjected to cognitive function assessment through Y-maze, Morris water maze and novel object recognition tests. Neuronal damage and dendritic spine integrity were evaluated by Nissl and Golgi staining. The constituent assignment of DTD in vitro and in vivo were accomplished by LC-MS, and potential targets for AD treatment were predicted through network pharmacology, broad-target metabolomics, molecular docking and molecular dynamics simulations. Immunofluorescence and neurotransmitter assay served to analyze neuronal activation levels and glutamate content. Protein expressions of signal pathway were detected in hippocampus and validated by serum pharmacology in HT22 cells using Western blot analysis.

RESULTS: DTD treatment significantly alleviated the cognitive dysfunction in AD model rats. LC-MS analysis identified 268 compounds in DTD, with 23 active ingredients absorbed in vivo. Integrated analyses combining network pharmacology, metabolomic profiling, molecular docking, and molecular dynamics simulations indicated that DTD may exert therapeutic effects against AD by lowering glutamate levels in hippocampus via the regulation of ERBB2/PI3K/AKT signaling pathways. DTD upregulated the expression of ERBB2 and p-AKT, reduced glutamate-induced neuronal activation levels and hippocampal glutamate content, and elevated the level of synaptic proteins PSD95, Syn1 and NR2A/B, thereby improving the structural and functional integrity of synapses. Cell tests confirmed that DTD alleviated glutamate-induced excitotoxicity and synaptic dysfunction in HT22 cells via ERBB2/PI3K/AKT pathway, which was abolished by ERBB2 inhibitor AG-825 and PI3K inhibitor LY294002.

CONCLUSIONS: This study elucidates the neuroprotective mechanism of DTD within AD model rats. DTD improves synaptic dysfunction by reducing hippocampal glutamate concentrations and counteracting glutamate-mediated excitotoxicity via the ERBB2/PI3K/AKT signaling pathway.},
}

@article {pmid42320775,
year = {2026},
author = {Sharma, A and Raut, SS and Shukla, A and Parul, N and Singh, A and Mishra, A},
title = {Ethnopharmacological Landscape of Azadirachta indica (Neem): Phytochemical Diversity Bridging Traditional Heritage and Modern Medicine.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122088},
doi = {10.1016/j.jep.2026.122088},
pmid = {42320775},
issn = {1872-7573},
abstract = {Azadirachta indica A. Juss. (neem) is a cornerstone of traditional medicine across tropical regions, recognized for its broad-spectrum therapeutic applications. However, the translation of its extensive ethnopharmacological legacy into evidence-based therapy is hindered by fragmented reports and a lack of systematic integration.

AIM OF THE REVIEW: This narrative review aims to provide a quantitative and mechanistic synthesis of neem's phytochemical diversity and pharmacological landscape, explicitly distinguishing itself from prior work by mapping over 140 bioactive compounds to specific molecular pathways and clinical potential, while critically evaluating translational barriers.

METHODS: A literature search of Web of Science, PubMed, and Scopus was conducted for peer-reviewed articles published between January 2001 and November 2025, using keywords related to Azadirachta indica, neem phytochemistry, pharmacology, and toxicology.

RESULTS: Phytochemical investigations have identified over 140 distinct compounds, including limonoids (e.g., azadirachtin, nimbolide, gedunin), flavonoids, and phenolic acids, distributed across all plant parts. These compounds modulate core signaling hubs-NF-κB, PI3K/Akt/mTOR, Nrf2, and MAPK-underpinning a broad pharmacological spectrum. Preclinical studies suggest that neem-derived compounds exhibit antiproliferative activity against breast, cervical, colon, and prostate cancer cell lines, although in vitro IC50 values alone are not predictive of clinical efficacy. Neem extracts and phytochemicals have also demonstrated neuroprotective effects in experimental models of Alzheimer's and Parkinson's diseases and antidiabetic activity in streptozotocin-induced diabetic rodents; however, the translational relevance of these findings to human disease remains to be established through rigorous clinical investigation. Beyond human health, neem's insecticidal and antifeedant properties support eco-friendly agricultural applications. However, clinical validation remains strikingly limited: only fifteen interventional trials are registered, most for oro-dental conditions, with no published phase II/III results for systemic diseases. Toxicological reports confirm dose- and route-dependent risks, including pediatric encephalopathy from neem oil ingestion and embryotoxicity, necessitating explicit safety guidelines.

CONCLUSIONS: Neem possesses validated, multi-target therapeutic potential, yet its clinical translation is currently impeded by poor bioavailability, extract standardization gaps, and a paucity of rigorous human trials. Future research must prioritize pharmacokinetic optimization (e.g., nanoformulations), establishment of certified reference materials, and well-designed phase trials in oncology and metabolic disease, rather than further preclinical cataloging.},
}

@article {pmid42320781,
year = {2026},
author = {Bashaw, AG and Roman-Ortiz, C and Gao, SX and Schier, LA and Borner, T and Kanoski, SE},
title = {Glucagon-like peptide-1 signaling in learning and memory: evidence, mechanisms, and therapeutic implications.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2026.06.006},
pmid = {42320781},
issn = {1873-2402},
abstract = {Glucagon-like peptide-1 (GLP-1) is primarily known for its role in glucose homeostasis and food intake control, and GLP-1 analogs (either as monotherapy or dual agonists) are commonly used for Type 2 Diabetes and obesity treatment in humans. Beyond these functions, the receptor for GLP-1 (GLP-1R) is widely expressed throughout the brain, including in the hippocampus and interconnected regions that contribute to learning and memory processes. Here we review emerging evidence supporting a role for GLP-1 signaling in promoting learning and memory function, particularly in dementia and other conditions that present hippocampal dysfunction. Evidence is synthesized from preclinical rodent models revealing that GLP-1 analog treatment improves deficits in memory function and hippocampal neuronal signaling processes in various models of dementia, aging, and metabolic disruption. While findings from human clinical trials and meta-analyses also show promise for GLP-1 analog-based treatment for memory disorders, results thus far are mixed, with many studies underpowered and/or lacking comprehensive memory evaluation. We describe several distinct yet non-mutually exclusive neurobiological mechanisms via which GLP-1R signaling can enhance memory, including blood-brain barrier penetration and direct action on hippocampal GLP-1Rs, improved peripheral and central insulin sensitivity, vagus nerve GLP-1R activation, and peripheral metabolic and inflammatory improvements. We conclude by emphasizing important considerations for future clinical trials for GLP-1 analogs in the treatment of Alzheimer's and other memory disorders, including focusing on metabolically vulnerable individuals, stratifying results by cardiovascular and metabolic status, and leveraging existing GLP-1 analogs and drug delivery approaches towards maximizing bioavailability and brain penetrance.},
}

@article {pmid42320785,
year = {2026},
author = {Toyokawa, M and Yasuda, K and Kikuya, A and Asada-Utsugi, M and Hida, M and Nakamura, Y and Yanagida, N and Toda, S and Kaji, S and Kinoshita, Y and Ono, Y and Takahashi, R and Matsumoto, R and Kinosita, A and Maki, T},
title = {Amyloid-β1-42 oligomers compromise oligodendrocyte precursor cells and disrupt blood-brain barrier integrity in vitro.},
journal = {Brain research},
volume = {},
number = {},
pages = {150436},
doi = {10.1016/j.brainres.2026.150436},
pmid = {42320785},
issn = {1872-6240},
abstract = {Amyloid-β (Aβ), particularly the aggregation-prone Aβ1-42, plays a central role in Alzheimer's disease (AD). While its neuronal toxicity is well known, effects on glial and vascular cells remain unclear. To investigate how Aβ1-42 oligomers affect oligodendrocyte precursor cells (OPCs), pericytes (PCs), and endothelial cells (ECs), and how these effects contribute to blood-brain barrier (BBB) dysfunction. In vitro assays were used to assess cell viability and BBB integrity following Aβ exposure. Transcriptomic profiling was performed on Aβ1-42-treated OPCs. Transendothelial electrical resistance (TEER) was used to measure barrier function. Aβ1-42, but not Aβ1-40, induced cytotoxicity in OPCs and PCs. ECs showed impaired barrier function without cell death. Aβ1-42-treated OPCs upregulated pro-inflammatory genes (Mmp9, Il1b) and downregulated genes related to cell cycle and growth signaling. Conditioned media from Aβ-exposed OPCs and PCs reduced TEER in ECs, indicating paracrine-mediated BBB disruption. These findings demonstrate that Aβ1-42 oligomers impair BBB integrity under in vitro conditions through both direct and non-cell autonomous mechanisms. Further in vivo studies are warranted to validate the relevance of these mechanisms in AD pathogenesis.},
}

@article {pmid42321014,
year = {2026},
author = {Kehmeier, MN and Famiano, A and Cullen, AE and Leonhardt, T and Ferguson, SJ and Snyder, M and McCurdy, CE and Tyrrell, DJ and Alkayed, NJ and Walker, AE},
title = {APOE4 negates the effects of ovarian hormones on cerebrovascular endothelial and mitochondrial function.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP290852},
pmid = {42321014},
issn = {1469-7793},
support = {//John L. Luvaas Family Fund/ ; 23PRE1023169//AHA/ ; //Endocrine Technologies Core/ ; R01AG064106//HHS, National Institutes of Health/ ; P51OD011092//HHS, National Institutes of Health/ ; S10OD026701//HHS, National Institutes of Health/ ; },
abstract = {The APOEε4 allele and oestrogen deficiency independently predispose females to an increased risk of vascular and metabolic impairments, but their cerebrovascular effects are less understood. The purpose of this study was to determine the interaction between APOE genotype and oestrogen on cerebrovascular endothelial and mitochondrial function. We studied young female homozygous APOEε3 and APOEε4 mice (n = 19-20/group; ∼6 months old) that were fed a high-fat diet and were ovariectomized (OVX), OVX and supplemented with 17β-oestradiol, or left intact. In APOEε3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilatation, which was rescued by 17β-oestradiol. However, in APOEε4 mice, there was no effect of OVX or 17β-oestradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17β-oestradiol treatment in APOEε3 mice, but there was no impact of OVX or 17β-oestradiol in the APOEε4 mice. In cerebral arteries and arterioles, 17β-oestradiol led to higher mitochondrial complex I respiration in APOEε3 but not APOEε4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes and pro-inflammatory factors. Overall these results indicate that the APOE genotype modulates the impact of OVX and oestradiol on the cerebral vasculature. We found that 17β-oestradiol enhances cerebrovascular endothelial and mitochondrial function in OVX APOEε3 mice but not in APOEε4 mice. This suggests that 17β-oestradiol supplementation may have more cerebrovascular benefits for APOEε4 non-carriers. KEY POINTS: Females have twice the risk of Alzheimer's disease than males, and the APOEε4 genetic variant has a greater risk for Alzheimer's disease than the APOEε3 variant. The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. There are highly inconsistent results among past studies examining the interaction between APOE genotype and oestrogens on brain outcomes, and their impact on the vasculature has not been studied. We aimed to determine the impact of APOEε4 genotype on the cerebrovascular response to ovariectomy and oestradiol. We found that oestradiol improved cerebral artery endothelial function and mitochondrial respiration in ovariectomized APOEε3 mice following ovariectomy. In contrast APOEε4 mice were resistant to the beneficial effects of ovarian hormones on cerebrovascular and mitochondrial function. This research suggests that APOE genotype may be a consideration when weighing the risks and benefits of prescribing hormone replacement therapy to postmenopausal females.},
}

@article {pmid42321169,
year = {2026},
author = {Croese, T and Abellanas, MA and Polonsky, H and Arad, M and Peralta Ramos, JM and Androsova, Y and Riccitelli, S and Medina, S and Palmas, F and Strobel, R and Castellani, G and Kviatcovsky, D and Phoebeluc-Colaiuta, S and Adam, M and Murad, S and Partney, H and Kitsberg, D and Dieter, A and Salame, TM and Brandis, A and Mehlman, T and Singer, O and Rivlin-Etzion, M and Wiegert, S and Shaul, Y and Kobiler, O and Yizhar, O and Habib, N and Schwartz, M},
title = {Disruption of the brain-spleen axis impairs monocyte-microglia communication and accelerates disease progression in a mouse model of amyloidosis.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-74253-z},
pmid = {42321169},
issn = {2041-1723},
abstract = {Alzheimer's disease (AD) is characterized by a prolonged asymptomatic phase before cognitive decline emerges, yet the mechanisms driving symptom onset remain unclear. Here, we hypothesized that the transition from asymptomatic to symptomatic disease is linked to dysfunction of brain-immune communication. Retrograde neuronal tracing in the 5xFAD mouse model of amyloidosis reveals reduced brain-spleen connectivity at advanced disease stages. To probe the functional role of the brain-spleen axis in coping with disease, we denervated the splenic nerve at an early presymptomatic stage. This intervention accelerated cognitive decline, impaired splenic hematopoiesis, diminished monocyte recruitment to the brain, disrupted monocyte-microglia signaling networks, and reduced the transition of microglia from a homeostatic to a disease-associated (DAM) state. Conversely, enhancing splenic noradrenergic input increased hematopoiesis, restored monocyte homing to the brain, and delayed cognitive impairment. The protective role of splenic monocytes was independently validated in a retinal cytotoxic injury model, in which splenic denervation impairs post-insult survival of retinal ganglion cells. Together, these findings identify an active brain-spleen circuit in regulating monocyte recruitment, and establish peripheral monocytes as important drivers of microglial state transitions and disease progression.},
}

@article {pmid42321246,
year = {2026},
author = {Marquina, VMS and Del Carmen Pardo, M and Franco-Pereira, AM},
title = {Extension of overlap measures for Multi-Class Biomarker Evaluation in Alzheimer's Disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-55865-3},
pmid = {42321246},
issn = {2045-2322},
support = {PID2022-137050NB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; },
abstract = {In a progressive disease such as the Alzheimer's disease (AD), the availability of suitable biomarkers tracking the stages of its progression could markedly accelerate drug development by providing an earlier indication of drug efficacy. Investigators use diagnostic tests to classify disease stages into probable Alzheimer's disease, mild cognitive impairment (MCI), and normal cognitive aging. In this paper, we focus on developing a proper statistical overlap measure-based method to evaluate the diagnostic accuracy of tests with three diagnostic categories. Parametric and non-parametric approaches for the estimation of the overlap measure (OVL) are presented as well as their bootstrap confidence intervals (CIs). The performance of these estimations and its CIs are evaluated through simulations. Furthermore, it is compared with the Volume Under the ROC Surface (VUS), the most common measure to assess the accuracy of tests with three ordinal diagnostic categories. A neuropsychological data set from a longitudinal cohort study for the detection of biomarkers for identifying stages of Alzheimer's disease is discussed.},
}