@article {pmid41896988,
year = {2026},
author = {Ma, Y and Xie, M and Ibáñez, CF},
title = {Palmitoylation of death receptor p75[NTR] contributes to Alzheimer's disease progression by regulating APP trafficking and degradation.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41896988},
issn = {1758-9193},
abstract = {UNLABELLED: Although protein palmitoylation has been associated with Alzheimer’s Disease (AD), it remains unclear whether or how palmitoylation of specific proteins contributes to any of the pathological features of AD. The p75 neurotrophin receptor (p75[NTR]) contributes to AD progression by regulating the intracellular trafficking and amyloidogenic processing of amyloid precursor protein (APP). p75[NTR] is palmitoylated at a juxtamembrane cysteine but it is currently unknown whether this has any effect on its role in AD. Here, we report that 5xFAD mice, an animal model of AD, expressing a palmitoylation-deficient mutant of p75[NTR] (p75[C281A]) display significantly attenuated neuropathology and cognitive deficits. Mechanistically, p75[C281A] showed enhanced internalization, trafficking to Rab5/Rab7 endosomes and lysosomal-mediated degradation. In mutant p75[C281A] neurons, APP displayed accelerated co-internalization with p75[NTR], increased trafficking to late endosomes and lysosome, and enhanced degradation, thereby limiting neuronal Aβ production. Interestingly, the brain of 5xFAD mice shows increased levels of p75[NTR] palmitoylation. These results indicate that palmitoylation of p75[NTR] enhances its stability and, indirectly, that of APP by reducing their trafficking to the lysosome, resulting in increased Aβ accumulation and neuropathology in the AD brain. Selective inhibitors of p75[NTR] palmitoylation may find applications in the treatment of AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02032-5.},
}

@article {pmid41896998,
year = {2026},
author = {van der Schaar, J and van der Flier, WM and Visser, LNC and van de Giessen, E and van Harten, AC and Sikkes, SAM and van Leeuwenstijn-Koopman, MSSA and Hendriksen, HMA and Trieu, C and Bredenoord, AL and van den Hoven, MA and Asscher, ECA},
title = {Long-term impact of disclosing amyloid PET results to individuals with subjective cognitive decline.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41896998},
issn = {1758-9193},
support = {LSHM20106//Health∼Holland, Topsector Life Sciences & Health/ ; LSHM20106//∼Holland, Topsector Life Sciences & Health/ ; 73305095007/ZONMW_/ZonMw/Netherlands ; 73305095007/ZONMW_/ZonMw/Netherlands ; 73305095007/ZONMW_/ZonMw/Netherlands ; },
abstract = {BACKGROUND: Biomarker assessments increasingly inform the diagnostic evaluation and treatment decisions in Alzheimer disease (AD). However, evidence on the impact of amyloid positron emission tomography (PET) disclosure is primarily derived from studies of cognitively unimpaired trial participants with follow-up limited to 18 months. In contrast, long-term implications for individuals with cognitive concerns who seek medical evaluation in memory clinics remain unknown. We aimed to examine the psychosocial and behavioral impact three years after amyloid PET disclosure in individuals presenting with subjective cognitive decline (SCD) at a memory clinic.

METHODS: In-depth semi-structured interviews were conducted with 17 participants from the Subjective Cognitive Impairment Cohort (SCIENCe) (67 ± 7 years; 5 female; 10 amyloid positive) 35 ± 4 months post-disclosure. All had SCD at imaging; one had progressed to mild cognitive impairment (MCI) at interview. Verbatim transcripts were analyzed inductively.

RESULTS: Participants’ motivations for testing and long-term adaptation to the results were strongly shaped by cognitive concerns and personal experiences of dementia in relatives. All demonstrated accurate comprehension of their amyloid status. Those with negative scans described immediate relief and reattributed memory lapses to normal aging, while recognizing that the reassurance was provisional. Although positive scans provoked initial shock and fear of deterioration, participants valued information over uncertainty, and over time, fear attenuated as they perceived no rapid decline. Both groups regarded results as meaningful and personally actionable, informing health behavior, life priorities, and preparations for future decline. Fourteen of 17 participants spontaneously mentioned considering options for self-determined end-of-life. Regardless of amyloid status, most participants shared their result with close relatives and friends, some also informed colleagues or acquaintances, while others limited communication to avoid stigma, protect loved ones, or reduce the burden of repeated explanations. Participants valued testing, expressed no regret, and would choose disclosure again.

CONCLUSIONS: Three years after disclosure, participants generally had adjusted to living with their imaging result, finding personal meaning and practical engagement without reporting ongoing psychological harm. Some reported residual concerns and uncertainty, irrespective of amyloid status. These findings offer timely guidance for clinicians and patients as biomarker disclosure is more widely incorporated into routine practice.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02026-3.},
}

@article {pmid42089987,
year = {2026},
author = {Chen, S and Zhao, K and Shi, Z and Zhang, C and Wu, H and Tian, M and Sun, Y and He, L},
title = {Study on the improvement effect and mechanism of resveratrol on cognitive impairment in tau mutant adenovirus-induced alzheimer's disease model mice.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42089987},
issn = {1432-2072},
abstract = {RATIONALE: Tau protein hyperphosphorylation and neuroinflammation playimportant roles in the onset and progression of Alzheimer's disease (AD). SIRT1has been implicated in the regulation of synaptic plasticity, cognitive function, andmemory, and is associated with the modulation of autophagy-and inflammation-related signaling pathways, including AMPK/mTOR/ULK1 and NF-κB. Resveratrol(RSV) has been reported to ameliorate cognitive impairment in AD models,primarily in the context of Aβ-related pathology; however, its potential effects andunderlying mechanisms in Tau-driven pathology remain incompletely understood.

OBJECTIVES: To investigate the effect of RSV on cognitive impairment in mice withTau mutation-induced Alzheimer's disease, and to explore its effects on autophagyand neuroinflammation.

METHODS: Tauopathy models were established using AAV-P301L-Tau. Cognitivefunction was assessed via behavioral tests; Hippocampal injury was evaluatedAccepted manuscriptACCEPTED MANUSCRIPTusing HE and Nissl staining, while autophagy was assessed byimmunofluorescence staining. Mechanisms were examined using Western blot,qRT-PCR, and CCK-8 assays.

RESULTS: RSV treatment was associated with attenuation of neuronal damage,reduction of p-Tau accumulation, and improvement of cognitive impairment in ADmice. Consistent trends were observed in vitro, where RSV treatment wasassociated with increased cell viability and modulation of autophagy-relatedmarkers in AAV-P301L-Tau-induced BV2 cells. In addition, RSV administration wasaccompanied by coordinated changes in signaling components related to SIRT1,AMPK/mTOR/ULK1, and NF-κB pathways, along with reduced expression ofinflammatory mediators.

CONCLUSIONS: RSV treatment was associated with coordinated modulation ofsignaling components related to the AMPK/mTOR/ULK1 and NF-κB pathways,together with improvements in cognitive performance in AD mice. These findingssupport the potential therapeutic relevance of RSV in Tau-drivenneurodegenerative pathology, while further studies are required to clarify theunderlying mechanisms.},
}

@article {pmid42090736,
year = {2026},
author = {Malotaux, V and Ku, V and Ospina Lopera, P and Su, Y and Chen, Y and Singh, A and Ruiz-Triviño, J and Hidalgo, MJ and Osorio, L and Serna, L and Giraldo, D and Alzate, D and He, B and Tristão-Pereira, C and Ramirez Gomez, L and Do Carmo, S and Cuello, AC and Ashton, NJ and Reiman, EM and Aguillón, D and Quiroz, YT},
title = {Associations of plasma biomarkers with age in the presenilin-1 E280A autosomal dominant Alzheimer's disease kindred.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100578},
doi = {10.1016/j.tjpad.2026.100578},
pmid = {42090736},
issn = {2426-0266},
abstract = {BACKGROUND: Autosomal-dominant Alzheimer's disease (ADAD) offers a model to define early biological changes in Alzheimer's disease due to its predictable age at symptom onset. Although ultrasensitive plasma assays are available, their associations with age in ADAD remain incompletely characterized.

OBJECTIVES: To characterize age-related changes in plasma biomarkers and examine associations with cognition in PSEN1 E280A ADAD.

DESIGN AND SETTING: Cross-sectional observational study in members of the Colombian PSEN1 E280A kindred.

PARTICIPANTS: A total of 164 individuals were included, comprising 83 mutation carriers (mean age 34.36±9.82 years; 54% female) and 81 non-carriers (mean age 33.75±9.84 years; 52% female).

MEASUREMENTS: Plasma Aβ42/Aβ40, phospho-tau217 (p-tau217), brain-derived tau (BD-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were quantified. Sex-adjusted associations with age, divergence ages between groups, classification performance (ROC curves), and associations with cognition (MMSE and CERAD delayed recall) were assessed.

RESULTS: All plasma biomarkers were associated with age (p < .01). Divergence between carriers and non-carriers began with Aβ42/Aβ40 before age 18, followed by p-tau217 (26.0 years), GFAP (26.1 years), BD-tau (27.9 years), and NfL (38.7 years). Aβ42/Aβ40 showed the highest discrimination of mutation status (AUC=0.99), followed by p-tau217 (AUC=0.87) and GFAP (AUC=0.84). Among carriers, p-tau217, GFAP, BD-tau, and NfL were associated with MMSE, while p-tau217, GFAP, and NfL predicted CERAD delayed recall.

CONCLUSION: Plasma biomarkers exhibit a temporal cascade in PSEN1 E280A ADAD. P-tau217 and GFAP show the strongest associations with early cognitive decline, suggesting their potential utility for tracking disease progression and monitoring treatment effects in E280A carriers.},
}

@article {pmid42090785,
year = {2026},
author = {Sánchez Valle, R and Lleó Bisa, A and Villarejo Galende, A and Cuartero Rodríguez, E and Escudero-Torrella, J and Bargallo Alabart, N},
title = {Adapting the spanish healthcare system for disease-modifying treatments in early-stage alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100586},
doi = {10.1016/j.tjpad.2026.100586},
pmid = {42090785},
issn = {2426-0266},
abstract = {BACKGROUND: The emergence of disease-modifying therapies targeting amyloid pathology represents a major paradigm shift in the management of Alzheimer disease (AD). However, their implementation poses substantial organizational, infrastructural, and clinical challenges for health systems.

OBJECTIVES: To identify the key challenges and establish priority recommendations for the effective incorporation of amyloid-targeting therapies into the Spanish National Health System.

This multiphase consensus study was conducted within the Spanish National Health System between September 2024 and July 2025. The study comprised a narrative literature review, qualitative research, regional workshops, and a modified RAND/UCLA Delphi process. A total of 56 experts participated, including a scientific committee of 6 Alzheimer disease specialists and an expert panel of 50 multidisciplinary professionals involved in AD care.

MEASUREMENTS: Identification of key challenges across the AD care pathway; development, evaluation, and prioritization of consensus-based recommendations; and estimation of patient demand, including projected increases in day hospital activity and magnetic resonance imaging utilization.

RESULTS: Ten key challenge areas were identified, encompassing early detection and referral, diagnostic confirmation, assessment of patient eligibility, treatment administration in day hospitals, monitoring of amyloid-related imaging abnormalities, evaluation of treatment effectiveness, infrastructure and capacity, professional training, patient information and support, and health care planning. Of the 43 recommendations assessed, 38 were rated as appropriate and necessary, with 14 prioritized for immediate implementation. Demand estimation models indicated that 11 to 26 patients per 100,000 inhabitants could be treated under current care patterns, increasing to 17 to 115 per 100,000 inhabitants under alternative eligibility scenarios.

CONCLUSIONS: This consensus defines the clinical, organizational, and infrastructural requirements necessary to integrate amyloid-targeting therapies into routine care within the Spanish National Health System. The prioritized recommendations define immediate actions to address the challenges identified and may serve as a reference for other health systems facing similar implementation processes.},
}

@article {pmid42091766,
year = {2026},
author = {Kumar, V and Kakoty, V and Wadhwa, P},
title = {Advancements in Gene Delivery using Nucleic Acid Loaded Nanoparticles for Region Specific Delivery in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42091766},
issn = {1559-1182},
mesh = {*Alzheimer Disease/therapy/genetics ; *Nanoparticles/chemistry/administration & dosage ; Humans ; *Gene Transfer Techniques ; Animals ; *Nucleic Acids/administration & dosage ; *Genetic Therapy/methods ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive and the most common neurodegenerative condition, having a deleterious effect on memory, eventually leading to death. In the recent past, gene therapy has emerged as a promising and revolutionary treatment for AD. This study demonstrated that nucleic acid-loaded nanoparticles which deliver small interfering RNA through lipid nanoparticles successfully reduced Alzheimer's disease-related symptoms in preclinical models by decreasing amyloid-β levels and enhancing cognitive abilities. However, every rose has its thorn, as the output of gene therapy is considerably hampered by the physiological barriers of the brain, which include the blood-brain barrier and the brain's extracellular matrix (ECM). For this reason, many researchers have modified the gene delivery technique by developing 'brain penetrating' NPs coated with components that can prevent sticking to the ECM. Moreover, to overcome the challenge of low transgene expression and reduced accumulation in the brain, even when delivered at high doses, scientists have proposed that injection/delivery of gene vectors directly into a specific area in the brain can achieve maximum therapeutic efficacy. Hence, this review focuses on the advancements and advantages of region-specific delivery of nucleic acid-loaded NPs for the effective therapeutic management of AD.},
}

*Alzheimer Disease/therapy/genetics
*Nanoparticles/chemistry/administration & dosage
Humans
*Gene Transfer Techniques
Animals
*Nucleic Acids/administration & dosage
*Genetic Therapy/methods
Brain/metabolism

@article {pmid42091792,
year = {2026},
author = {Otaegui, L and Lehoux, J and Begu, S and Moujellil-Legagneur, T and Zussy, C and Vitalis, M and Mathias, M and Beau, A and Durand, T and Givalois, L and Bernoud-Hubac, N and Crauste, C and Desrumaux, C},
title = {Intranasal lipid nanocapsule administration of the new lipophenol quercetin-3-O-DHA-7-O-iPr reduces carbonyl stress and improves behavior in a mouse model of Alzheimer's disease.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {42091792},
issn = {2190-3948},
support = {CBS2 PhD grant//Université Montpellier/ ; MUSE-AAP20REC-FRS09-GAiA//Université Montpellier/ ; PhD grant//Association France Alzheimer/ ; ANR-AAP2022-R22102FF-EpiNeurAge//Agence Nationale de la Recherche/ ; ANR-18-CE18-0017//Agence Nationale de la Recherche/ ; ANR-11-LABEX-0021-LipSTIC//Agence Nationale de la Recherche/ ; MND202003011477-OPA//Fondation pour la Recherche Médicale/ ; },
abstract = {Oxidative and carbonyl stresses (COS), which damage brain cells through the accumulation of toxic reactive carbonyl species (RCS), are key players in the etiology of Alzheimer's disease (AD). Our group developed lipophenols, i.e. COS-targeting hybrid molecules combining polyunsaturated fatty acids (PUFAs) and alkyl-(poly)phenols. Among them, quercetin-3-O-docosahexaenoate-7-O-isopropyl (Quercetin-3-O-DHA-7-O-iPr or "Q-iP-DHA") afforded neuroprotection against acrolein-induced toxicity, reduced carbonyl stress, and lowered amyloid-beta secretion in neuroblastoma cells. To evaluate Q-iP-DHA in vivo, it was formulated into lipid nanocapsules (to allow solubilization) then administered intranasally to J20 transgenic mice, a model of AD. This approach was chosen to optimize blood-brain barrier (BBB) penetration. This delivery led to improvements in well-being, organizational skills and spatial memory. In addition, Q-iP-DHA treatment reduced hippocampal amyloid plaque numbers, normalized expression of the Receptor for Advanced Glycation End-products (RAGE), and decreased microglial activation, indicating anti-inflammatory effects. Overall, our preclinical findings suggest that intranasal administration of nanoformulated Q-iP-DHA may represent a promising multitarget therapeutic approach against AD.},
}

@article {pmid42093461,
year = {2026},
author = {Andreão, FF and da Silva, RO and Negreli, MFLA and Aguiar-Barros, ABP and Santos, DH},
title = {Baseline epidemiological differences between donanemab and lecanemab users in real-world settings: a retrospective cohort study.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/17582024.2026.2667432},
pmid = {42093461},
issn = {1758-2032},
abstract = {AIMS: Donanemab and Lecanemab are anti-amyloid monoclonal antibodies recently approved for the treatment of Alzheimer's disease. Although their efficacy and safety have been investigated in randomized trials, real-world epidemiological data on treated populations remain limited. This study aimed to compare baseline clinical and laboratory characteristics of patients treated with donanemab versus lecanemab in routine practice.

PATIENTS AND METHODS: We conducted a retrospective analysis using the TriNetX US Collaborative Network, including patients with Alzheimer's disease treated with donanemab or lecanemab between January 2024 and September 2025. Demographics, laboratory values, comorbidities, and concomitant medications were compared using standardized mean differences (SMD) and p-values. Variables with SMD ≥0.1 or p < 0.05 were considered meaningfully different.

RESULTS: A total of 1,799 patients were included (donanemab n = 360; lecanemab n = 1,439). Demographic characteristics were well balanced (mean age 73.1 vs 72.5 years; SMD 0.028). Lecanemab users were more likely to be prescribed antidepressants (52% vs 41%; p < 0.0001; SMD = 0.23) and donepezil (61% vs 52%; p = 0.0145; SMD = 0.14). Donanemab users had higher prothrombin time (12.2 ± 2.17 vs 11.8 ± 1.66 s; p = 0.0158; SMD = 0.20) and INR (1.06 ± 0.19 vs 1.03 ± 0.13; p = 0.0369; SMD = 0.17), and a higher prevalence of vascular dementia (81% vs 76%; p = 0.0272; SMD = 0.12).

CONCLUSION: While demographic variables were similar. These findings likely reflect real-world clinical selection patterns and should be accounted for in comparative effectiveness and safety analyses of anti-amyloid therapies.},
}

@article {pmid42094385,
year = {2026},
author = {Sanders, B and Korthauer, M and Singh Parihar, K and Ifergan, I},
title = {Poly(lactic-co-glycolic acid) immunomodulatory nanoparticles attenuate neuroinflammation and Alzheimer's disease-related pathology in 5xFAD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.27.720934},
pmid = {42094385},
issn = {2692-8205},
abstract = {Alzheimer's disease is characterized by progressive cognitive decline, amyloid-β deposition, neuroinflammation, and neurodegeneration, yet effective and well-tolerated therapies remain limited. Because dysregulated myeloid responses are increasingly recognized as important drivers of disease progression, we investigated the therapeutic potential of poly(lactic-co-glycolic acid) immunomodulatory nanoparticles in the 5xFAD mouse model of amyloid-driven neurodegeneration. Poly(lactic-co-glycolic acid) immunomodulatory nanoparticles and fluorescently labeled particles displayed the expected size range and negative surface charge. After intraperitoneal administration, fluorescent particles were preferentially associated with myeloid cells in the blood, spleen, and brain, with greater uptake by brain myeloid populations in 5xFAD mice than in wild-type controls. Therapeutic treatment of 6.5-month-old 5xFAD mice, a stage at which behavioral abnormalities are already established, resulted in significant improvement in elevated plus maze behavior and a more modest improvement in Barnes maze performance. Flow cytometric analysis performed 9 weeks after the final treatment demonstrated persistent changes in brain immune composition, with the most prominent effects observed in P2RY12 [+] microglial populations, particularly the CD11c [+] subset, and comparatively limited sustained effects in CD11b [+] P2RY12 [-] myeloid cells. These changes were accompanied by reduced expression of activation- and disease-associated markers and lower pro-inflammatory cytokine production within microglial populations. Histological analysis further showed reduced cortical amyloid plaque burden, decreased CD68 immunoreactivity, and reduced neurodegeneration in treated 5xFAD mice. Together, these findings show that systemically administered poly(lactic-co-glycolic acid) immunomodulatory nanoparticles produce durable behavioral, immunological, and pathological benefits in 5xFAD mice and support further investigation of this biodegradable myeloid-targeted platform as a therapeutic strategy for Alzheimer's disease.},
}

@article {pmid42094534,
year = {2026},
author = {Moore, SJ and Murphy, GG},
title = {Acarbose improves cognitive function in a mouse model of normal aging but not Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.28.721469},
pmid = {42094534},
issn = {2692-8205},
abstract = {INTRODUCTION: Declines in function occur in both normal aging (in the absence of disease) and age-related pathological contexts, like Alzheimers disease (AD). Whether anti-aging interventions (that extend lifespan) also promote cognitive function in aging and AD remains unexplored.

METHODS: We assessed the effect of acarbose (1000 ppm from 4 months of age) on spatial learning and memory using the Morris water maze in young adult (6 mo), mid-aged (12 mo), or aged (24 mo) cohorts of normal aging (Ntg-HET3) and AD-relevant (5xFAD-HET3) genetically heterogeneous mice.

RESULTS: In mid-aged and aged Ntg-HET3 mice, acarbose treatment resulted in performance equivalent to young adults. Conversely, acarbose failed to ameliorate age-related deficits in 5xFAD-HET3 mice.

DISCUSSION: This work demonstrates that anti-aging interventions can also promote cognitive longevity in normal aging. Further, it reinforces that AD is not simply accelerated aging and requires therapies beyond anti-aging interventions that target its unique molecular and cellular drivers.},
}

@article {pmid42094538,
year = {2026},
author = {Woodham, TA and Kelsey, MMG and Sedivy, JM},
title = {Characterization of Cellular Senescence in Primary Human Astrocytes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.29.721581},
pmid = {42094538},
issn = {2692-8205},
abstract = {Senescent astrocytes have been identified in the brains of patients with neurodegenerative disorders, including Alzheimer's disease, yet the molecular characteristics of replicative senescence in human astrocytes remain largely unexplored. Prior work has been hampered by the low proliferative capacity and limited telomere shortening of primary human astrocytes in culture. Here, we describe a culture system in which primary human astrocytes propagated under physiological (3%) oxygen reach canonical telomeric replicative senescence after extensive expansion (up to ~76 population doublings). Senescence was confirmed through multiple biomarkers, including reduced EdU incorporation, elevated senescence-associated beta-galactosidase (SA-β-gal) activity, persistent DNA damage foci (γH2AX and 53BP1) predominantly localized to telomeres, and nuclear accumulation of p53. RNA sequencing across a 12-week time course revealed early upregulation of young LINE-1 (L1HS) retrotransposon transcripts, type-I interferon (IFN-I) and senescence-associated secretory phenotype (SASP) pathway genes, alongside downregulation of cell-cycle and DNA repair programs. To resolve L1HS expression at individual locus resolution, we performed Nanopore DNA sequencing to generate a custom reference genome incorporating non-reference LINE-1 insertions. Applying our TE-Seq pipeline, we identified two full-length intergenic L1HS elements consistently upregulated across the replicative senescence time course, one of which, L1HS_9q22.32_2, retained intact ORF1 and ORF2 open reading frames, indicating potential retrotransposition competence. To contextualize the astrocyte replicative senescence program, we compared it to three additional conditions. First, parallel astrocyte cultures maintained under normoxic (20%) oxygen entered senescence earlier and showed stronger SASP upregulation. Second, DNA damage-induced senescence (DDIS) triggered by etoposide treatment produced a stronger pro-inflammatory transcriptional signature than replicative senescence, including elevated IL6, IL1A, and IL1B expression. DDIS also upregulated L1HS_9q22.32_2 as well as a second intact element, L1HS_14q23.2_3, which we have previously identified among the small number of intact L1HS loci activated during replicative senescence in fibroblasts. The convergent activation of these intact elements across cell types and senescence modalities reinforces L1HS-driven IFN-I signaling as a conserved feature of the senescent program. Third, comparison with replicatively senescent fibroblasts revealed cell-type-specific SASP regulation: the pro-inflammatory cytokines IL6 and CCL2 were downregulated in senescent astrocytes relative to proliferating cells, opposite to their behavior in fibroblasts. Together, these data establish the first comprehensive transcriptomic profile of replicative senescence in human astrocytes, offering a resource for understanding brain aging and senescence-associated neurodegeneration.},
}

@article {pmid42095064,
year = {2026},
author = {Cummings, JL and Zhou, Y and Yang, Y and Zhong, K and Fonseca, J and Osse, AL and Cheng, F},
title = {Alzheimer's disease drug development pipeline: 2026.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70251},
pmid = {42095064},
issn = {2352-8737},
abstract = {INTRODUCTION: Discovery and development of new therapies for Alzheimer's disease (AD) are urgently needed to address the world's growing population of individuals on the AD pathophysiological continuum. Clinicaltrials.gov is a resource for studying drugs in development for treatment of AD.

RESULTS: There are currently 158 drugs in 192 AD trials. Of the agents in trials, 39% are small molecule disease targeting therapies (DTTs); 34% are biologic DTTs; 18% are cognition enhancing symptom targeted therapies (STTs); and 10% are STTs being developed to treat neuropsychiatric symptoms of AD. Currently active trials require 54,728 participants of which 38,417 are in Phase 3. The biopharmaceutical industry sponsors 59% of AD trials including 72% of Phase 3 trials. Repurposed drugs represent 35% of the drugs in trials.

DISCUSSION: The AD drug development pipeline has a growing number of trials and drugs in trials. A diverse array of AD pathophysiological processes is being addressed by drugs in trials.},
}

@article {pmid42095076,
year = {2026},
author = {Sajan, MP and Aggarwal, G and Hwang, JJ and Smith, DM and Cooper, DR and Duncan, MA and Hansen, BC and Nguyen, AD and Farese, RV},
title = {Progranulin deficiency in the brain activates an insulin signaling pathway that may promote neurodegeneration.},
journal = {iScience},
volume = {29},
number = {5},
pages = {115720},
pmid = {42095076},
issn = {2589-0042},
abstract = {Molecular mechanisms in frontotemporal dementia (FTD) and Alzheimer's disease (AD) are obscure. FTD can result from loss-of-function progranulin mutations, although pathogenetic consequences are uncertain. Progranulin insufficiency also increases human AD risk, and progranulin treatment improves mouse AD. Furthermore, AD and FTD risks are abetted by obesity/diabetes-induced hyperinsulinemia and hyperactivation of brain insulin signaling, and progranulin deficiency activates insulin signaling in fat and liver. Here, we found progranulin deletion in mouse brain increased activation of IRS-1 and activities of downstream PKC-λ/ι, NF-κB and mTOR, but diminished IRS-2 and Akt. Similarly, in microglial cells, progranulin deletion increased, and progranulin treatment diminished, activation of IRS-1, PKC-λ/ι, NF-κB, and mTOR. These progranulin-related changes in IRS-1 activation were due to JNK-mediated phosphorylation of inhibitory serine-302/307 residues in IRS-1. Progranulin deficiency in brain selectively activates an IRS-1-dependent insulin signaling pathway, and the resultant increases in inflammation and impaired autophagy/lysosomal function may augment progranulin deficiency-related neuropathology.},
}

@article {pmid42095886,
year = {2026},
author = {Maiese, K},
title = {Osteoarthritis and dementia: contrasting disorders driven by mutual pathways of autophagy, mTOR, GLP-1, AMPK, wnt, and WISP1.},
journal = {Expert review of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17512433.2026.2671269},
pmid = {42095886},
issn = {1751-2441},
abstract = {INTRODUCTION: Increased global lifespan is paralleled by a rise in non-communicable diseases with osteoarthritis and dementia, including Alzheimer's disease, impacting all nations with severe disability, death, and financial burden.

AREAS COVERED: Given that osteoarthritis and dementia are worsened with advancing age, progressive in nature, and presently remain only with symptomatic treatments, development of advanced comprehensive therapies is critical for these disorders. New innovative work offers insight into the underlying clinical bond between degenerative joint disease and cognitive loss. Data sources using systematic literature search employed PubMed, Scopus, Web of Science, and ScienceDirect from January 2021 through February 2026.

EXPERT OPINION: Although affecting diverse organ systems, degenerative joint disease and dementia are intimately connected by shared cellular pathways responsible for disease onset and progression. Pioneering avenues of investigation of oxidative stress, autophagy, the mechanistic target of rapamycin (mTOR), cellular metabolism mechanisms with glucagon-like peptide-1 (GLP-1) receptors and AMP activated protein kinase (AMPK), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) offer exciting treatment opportunities for osteoarthritis and Alzheimer's disease. Ultimately, these complex pathways will necessitate focus upon their intricate dependence that may benefit from several targeted approaches including artificial intelligence applications for fruitful clinical translation.},
}

@article {pmid42096531,
year = {2026},
author = {Uchida, H and Gobbi, G and Zohar, J and Young, AH and Rujescu, D and Huang, MC and Sundram, S and Atwoli, L and Vukovic, J and Ikeda, K},
title = {Global Perspectives on CNS Drug Innovation: Achievements, Barriers, and Priorities for the Next Decade.},
journal = {The international journal of neuropsychopharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1093/ijnp/pyag023},
pmid = {42096531},
issn = {1469-5111},
abstract = {BACKGROUND: Over the past decade, neuropsychopharmacology has shifted from stagnation to momentum, with first-in-class mechanisms and biomarker-enabled trials spanning psychiatry and neurology.

METHODS: We narratively synthesized advances from 2013 to 2026 across central nervous system (CNS) discovery and development, including pivotal trials, regulatory actions, digital/real-world evidence, genetics, artificial intelligence (AI), and implementation/global-access themes that are endorsed by international societies.

RESULTS: Therapeutic gains include rapid-acting drugs for treatment-resistant depression (intranasal esketamine); psychedelic-assisted therapy for posttraumatic stress disorder and depression; neuroactive steroid γ-aminobutyric acid-A receptor positive allosteric modulators (brexanolone, zuranolone) for postpartum depression; non-dopaminergic muscarinic agonists (xanomeline-trospium) for schizophrenia; orexin receptor antagonists for insomnia; and anti-amyloid monoclonal antibodies (lecanemab, donanemab) for early Alzheimer's disease. Persistent barriers include high mid-/late-stage attrition that is driven by placebo effects, subjective endpoints, and preclinical-to-clinical gaps; regulatory and economic headwinds; and limited generalizability from tightly run trials. Emerging enablers include adaptive/platform designs, digital health technologies, patient-reported outcomes, and clinical outcome assessments, real-world evidence (RWE), AI/machine learning (ML), genetics for target de-risking and biomarker-guided stratification, and publicly accessible large CNS relevant biological datasets.

CONCLUSIONS: To convert momentum into durable progress, we recommend: (i) deeper academia-industry/stakeholder collaboration and sustained funding for high-risk/high-reward science from industry, governments and non-for profit foundations; (ii) modernized regulation (flexible evidentiary paths, novel endpoints, and clear guidance on adaptive/platform trials); (iii) data-driven development integrating RWE, AI/ML, and precision medicine; (iv) the adoption of Neuroscience-based Nomenclature (NbN); and (v) a global-access mandate with essential-medicine inclusion, equitable pricing/licensing, capacity building, tele-enabled mental health, and geographically diverse research. Aligning scientific innovation with implementation and equity can accelerate translation and ensure new treatments benefit patients worldwide.},
}

@article {pmid42097044,
year = {2026},
author = {Shu, Y and Ding, ZH and Chen, XQ and Liu, F},
title = {40 Hz light flicker stimulation for neurodegenerative diseases: Mechanisms and clinical perspectives.},
journal = {Biochemical and biophysical research communications},
volume = {821},
number = {},
pages = {153858},
doi = {10.1016/j.bbrc.2026.153858},
pmid = {42097044},
issn = {1090-2104},
abstract = {Neurodegenerative diseases are a class of disorders characterized by the progressive degeneration and dysfunction of neurons, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Due to their high incidence rate, irreversible pathological processes and huge social and economic burdens, these diseases have become a major challenge in global public health. Light Flicker Stimulation (LFS), as a non-invasive form of physical therapy, shows significant neuroprotective potential by modulating electrical brain oscillations and particular signaling pathways. We critically examine the role of stimulation parameters (frequency, wavelength, multisensory combination) and discuss the state of clinical translation, including completed and ongoing trials, safety considerations, and technological innovations such as alternating bilateral stimulation and organic light-emitting diode (OLED) devices. By integrating mechanistic insights with clinical perspectives, this review aims to identify key gaps and future directions for harnessing 40 Hz LFS as a viable treatment for neurodegenerative diseases.},
}

@article {pmid42097270,
year = {2026},
author = {Cho, E and Lee, S and Lee, H and Kim, J and Kwon, YW and Hoe, HS and Kim, D and Yoon, JH},
title = {An integrative proteomic approach to reveal altered signaling modules during Alzheimer's disease progression in PS19 tauopathy mice.},
journal = {Molecular & cellular proteomics : MCP},
volume = {},
number = {},
pages = {101580},
doi = {10.1016/j.mcpro.2026.101580},
pmid = {42097270},
issn = {1535-9484},
abstract = {Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease that is characterized by cognitive, functional, and behavioral impairments. These changes occur owing to the progressive accumulation of extracellular amyloid-beta plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is associated with the dysfunction of several essential neurotransmitter systems, such as dopamine, and impaired neurotransmission. Despite the association of neurotransmitter changes within the brain and AD pathology, in-depth profiling studies on neurotransmitters and their related proteomic changes are limited. This study was conducted to profile and integrate the proteomes and neurotransmitters in seven brain regions of PS19 (Tau P301S) mice according to AD progression between 4 and 7 months. Proteomic analysis revealed significantly altered canonical pathways in various brain regions, including metabolic abnormalities. In the neurotransmitter profile, we found significant alterations in the levels of six neurotransmitters-dopamine, serotonin, homovanillic acid, norepinephrine, 3-methoxytyramine, and 3,4-dihydroxyphenylacetic acid-during AD progression. Using an integrative approach between proteome and neurotransmitter profiles, we found that AD progression-dependent dopamine- and serotonin-related signaling modules are closely related to neurotransmitter changes, especially in the hippocampus and cerebellum. This integrative approach could provide new signaling modules to help understand AD progression and thereby enable improved treatment and clinical outcomes.},
}

@article {pmid42097395,
year = {2026},
author = {Shahsavari, F and Rajizadeh, MA and Pirmoradi, Z and Sabzalizadeh, M and Kohlmeier, KA and Soti, M and Shabani, M},
title = {Abscisic acid ameliorates cognitive deficits in an amyloid-β-induced mouse model of Alzheimer's disease associated with alterations in markers of neuroplasticity and neuroinflammation.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138619},
doi = {10.1016/j.neulet.2026.138619},
pmid = {42097395},
issn = {1872-7972},
abstract = {Abscisic acid (ABA, C15H20O4), a mammalian hormone, exhibits neuroprotective and anti-inflammatory properties. This study aimed to investigate the effects of ABA on the hippocampal-dependent processes: anxiety-, depression-like behaviors and cognitive impairments as well as levels of factors involved in neuroplasticity and neuroinflammation in an amyloid-β (Aβ)-induced mouse model of Alzheimer's disease (AD). One week following intracerebroventricular (i.c.v.) injection of Aβ1-42 in male mice, ABA was administered i.c.v. at doses of 10 or 15 µg/µl for 7 consecutive days. Behavioral assessments were conducted using the novel object recognition, open field, elevated plus maze, tail suspension, Morris water maze, and passive avoidance tests. Hippocampal gene expression levels of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate receptor (NMDAR), and nuclear factor-κB (NF-κB) were evaluated using real-time PCR. ABA treatment significantly attenuated anxiety-like behaviors and improved spatial, avoidance and recognition memory deficits induced by Aβ1-42 administration with more behavioral domains affected at the 15 µg/µl dose. ABA induced significant upregulation in the hippocampus of NMDAR and BDNF expression and marked suppression of NF-κB in the ABA (15 µg/µl)-treated Aβ group, which could have played a mechanistic role in improvements in behaviors controlled by this structure. Histological analysis demonstrated attenuation of neuronal degeneration and pyknosis in the hippocampal CA1 region following ABA intervention. Collectively, these findings suggest that ABA ameliorates anxiety-related behaviors and cognitive impairments in an experimental mouse model of AD, potentially through modulation of neuroinflammatory and neuroplasticity-related pathways.},
}

@article {pmid42083975,
year = {2026},
author = {Saffold, K and Tall, A and Lowery, AT and Pryor, T and Jones-Muhammad, M and Shao, Q and Warrington, JP},
title = {Mouse Offspring Exposed to Preeclampsia/Eclampsia-like Symptoms Exhibit Cerebral Hypoperfusion & Mild Cognitive Impairment at 2 months of age.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpheart.00711.2025},
pmid = {42083975},
issn = {1522-1539},
support = {5R25HL145817//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 1 R56 HL159447//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; P30GM103328//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; Startup/Bridge Funds from the Department of Neurology//University of Mississippi (UM)/ ; },
abstract = {Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of organ damage, after the 20[th] week of pregnancy. Children born to mothers with preeclampsia or eclampsia (new-onset seizures during pregnancy) are more likely to develop learning and memory deficits and are more susceptible to neurovascular diseases compared to those born from normal pregnancies. The contributing mechanisms are unknown. In this study, we assessed whether exposure to reduced uteroplacental perfusion (RUPP), modeling placental hypoperfusion and preeclampsia, with or without pentylenetetrazol (PTZ) injection (to induce seizures and model eclampsia), results in cognitive impairment, Alzheimer's disease markers, and regional cerebral perfusion changes in adult offspring. On gestational day (GD)13.5, pregnant C57BL/6 mice (n=22) underwent Sham or RUPP surgery followed by injection or no treatment with PTZ (40 mg/kg) on GD18.5. At 2 months of age, spatial learning and cerebral perfusion were measured in randomly selected offspring or averaged to obtain mean data per sex, per litter (n=4-6 data points per group/treatment). RUPP-exposed offspring took a longer distance and made more errors navigating the Barnes maze. Cerebral perfusion was reduced in offspring exposed to RUPP, specifically in the prefrontal cortex, superior sagittal sinus, and whole brain. There was a significant reduction in perfusion in seizure-exposed offspring in the superior sagittal and transverse sinuses, whole brain, and cerebellum. Our results support the hypothesis that exposure to preeclampsia/eclampsia-like symptoms leads to mild learning impairment through reduced cerebral perfusion to cortical regions and decreased drainage of waste from the brain via the cerebral sinuses.},
}

@article {pmid42083983,
year = {2026},
author = {Au, R and Gifford, KA and Paschalidis, IC and Wighton, P and Levin, M and Imam, F and Bose, N and Pratap, A},
title = {The myth of digital biomarkers in Alzheimer's disease: how to make them a reality.},
journal = {Current opinion in psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42083983},
issn = {1473-6578},
abstract = {PURPOSE OF REVIEW: With an estimated 41.1B digital devices, the term "digital biomarkers" has been increasingly bandied about in the research literature. There is, however, a significant disconnect between the presumption of digital biomarkers and the reality of digital biomarkers.

RECENT FINDINGS: The research literature embraces the concept of digital biomarkers without concomitant evidence for validation of digital measures as biomarkers. Unlike imaging or blood-based biomarkers, there is a woeful lack of research dedicated to validating digital measures as biomarkers. This gap also presents an opportunity. Regulatory agencies worldwide have long-standing protocols used by pharmaceutical and biotech companies to stand up quality management systems (QMS) that track research from inception to regulatory approved submissions. The recent United States (US) Food and Drug Administration (FDA) approval of Alzheimer's disease (AD) plasma biomarkers is another example where successful QMS implementation provided the processes and transparency necessary to obtain approval. Regulatory guidelines for digital technology validation are more circumspect on validation pathways of AD digital biomarkers, but FDA provides a framework for building a QMS that could potentially do so.

SUMMARY: Building an open source QMS for AD digital biomarker validation will be a critical breakthrough for harnessing the potential of digital technologies for detection, monitoring and treatment of AD and related disorders.},
}

@article {pmid42084750,
year = {2026},
author = {Hafez, MM and Abbas, HA and Shoman, NA and Soubh, AA and Aly, O and Sallam, MF and Seliem, M and Malaak, FA},
title = {A new era in neuropharmacology: assessing the efficacy and safety of novel anti-amyloid and non-amyloid drug targets for Alzheimer's disease.},
journal = {Journal of neurology},
volume = {273},
number = {5},
pages = {},
pmid = {42084750},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Neuropharmacology/trends/methods ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; Animals ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia in the world with the prevalence expected to increase threefold to 152.8 million people by 2050. The current medications provide a short-term ameliorative effect, and this requires development of disease-modifying treatments, which address the biological pathogenesis.

METHODS: This review assesses the changing neuropharmacological environment offering a critical analysis of anti-amyloid monoclonal antibodies and investigates the so-called expanding frontier of non-amyloid targets. It also examines the approaches of clinical trials and the trend of biomarker-based patient selection and precision medicine.

RESULTS: Although β-site APP-cleaving enzyme 1 (BACE1) and secretase inhibitors did not achieve success in clinical trials because of mechanism-based toxicity and cognitive impairment, new monoclonal antibodies such as lecanemab and donanemab have shown high amyloid plaque clearance and reduced cognitive deterioration. Nevertheless, the treatments are associated with amyloid-related imaging abnormalities (ARIA). In addition to amyloid, studies are focusing on tau hyperphosphorylation, neuroinflammation through triggering receptor on myeloid cells 2 (TREM2) and NLR family pyrin domain containing 3 (NLRP3) and growth factor-mediated synaptic plasticity through brain-derived neurotrophic factor (BDNF).

CONCLUSIONS: AD treatment has entered the new era that demands a paradigm shift from monotherapies to multi-target cocktails. The future lies in precision neuropharmacology, where genetic stratification and individual biomarker analysis are used to provide the correct treatment at the most appropriate biological stage.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Neuropharmacology/trends/methods
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Antibodies, Monoclonal/therapeutic use/pharmacology
Animals

@article {pmid42084972,
year = {2026},
author = {Kumar, D and Singh, SB and Sagar, V and Prasad, MK and Kapoor, N and Mukul, A and Nishant, A},
title = {Breakthrough Vaccines and Transformative Therapies on the Horizon of Progress toward Diabetes Management.},
journal = {Indian journal of public health},
volume = {},
number = {},
pages = {},
doi = {10.4103/ijph.ijph_102_25},
pmid = {42084972},
issn = {0019-557X},
abstract = {Diabetes mellitus (DM) affects millions of people globally. Over the years, diabetes has emerged as a significant global health concern, with steadily increasing prevalence. This review explores the various aspects of DM and delves into the evolving field of new emerging treatments and diabetes vaccines, highlighting the potential they hold in revolutionizing diabetes management in the future. Therefore, it is imperative to know about the potential vaccines and novel emerging treatment options for DM and to understand the challenges faced in making novel therapies. It is also needed to recognise the intricate relationship between diabetes and Alzheimer's disease, an emerging entity known as type 3 diabetes. Literature search was done in PubMed database, and relevant articles were selected for the narrative review. The review reveals that currently, most vaccines that have been developed are in animal studies and early phases of trials. Only few human trials have been conducted, but, with positive outcome. There are also some novel therapeutics emerging as potential management options for diabetes. There are evidences to support that Alzheimer's disease can rightly be called type 3 diabetes. In conclusion, there is a growing interest in the development of vaccines as a revolutionary approach to diabetes management. As our understanding of diabetes deepens and vaccine technology advances, the prospect of a diabetes vaccine becoming a reality offers hope for millions living with this condition and in reducing the burden of diabetes-related complications.},
}

@article {pmid42086977,
year = {2026},
author = {Khan, TTS and Wong, CYJ and Sheikh, Z and Fathi, A and Maleknia, S and Oveissi, F and Abrams, T and Knox, W and van der Hoven, J and Antonito, A and Murray, M and Svolos, M and Suman, J and Tietz, O and Ong, HX and Traini, D},
title = {Repurposing insulin for Alzheimer's disease treatment: intranasal delivery of a thermoresponsive nanocarrier-based insulin formulation to the brain.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {42086977},
issn = {2190-3948},
abstract = {The Intranasal route provides an effective pathway for insulin delivery to the brain compared to oral/subcutaneous routes as it provides direct access to the brain, bypassing the restrictive blood-brain barrier (BBB), while minimizing systemic exposure. The present study investigated the potential of a thermoresponsive polymer, PNPHO, as a nanocarrier for brain-targeted insulin delivery through the intranasal route, with the aim of repurposing insulin for Alzheimer's disease treatment. Insulin-loaded nanoparticles (NP) were formulated using an advanced crossflow mixing technology with lower (F1) and higher (F2) PNPHO concentrations and characterised in vitro for size, zeta potential, encapsulation efficiencies, stability, drug deposition, and transport and in vivo for biodistribution. Both F1 and F2 NP demonstrated particle sizes ranging from 35.9 to 49.8 nm with low polydispersity index (< 0.3), negative surface charges, high encapsulation efficiencies (> 99%), and conserved structural integrity post 4 weeks of stability study. NP demonstrated significantly greater in vitro nasal deposition compared to insulin alone. Notably, the PNPHO nanocarrier protected insulin from enzymatic degradation, overcoming a key barrier associated with protein/peptide delivery. In vitro drug transport studies showed an initial delay in NP transport across nasal cells due to PNPHO-mucoadhesive properties, followed by increased transport. Significantly enhanced time-dependent NP transport across the BBB cells compared to insulin alone (p < 0.0001) confirmed NP's ability to cross the BBB. In vivo, NP demonstrated prolonged nasal retention and higher brain: serum ratio in mice, suggesting sustained drug release and improved brain delivery compared to insulin alone. Collectively, the study highlight the potential of PNPHO as a promising nanocarrier for achieving targeted and efficient intranasal delivery of insulin to the brain.},
}

@article {pmid42087592,
year = {2026},
author = {Liu, X and Xu, H and Zhao, Y and Yang, J and Zhang, L and Wang, Z and Lim, K and Zhang, C and Lu, L},
title = {Roles of POU3F2 in Brain Development and Neuropsychiatric Disorders.},
journal = {Developmental neurobiology},
volume = {86},
number = {3},
pages = {e70034},
doi = {10.1002/dneu.70034},
pmid = {42087592},
issn = {1932-846X},
support = {202200331//Cooperative Research Project/ ; //Shanxi Province Higher Education/ ; 82571379//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Humans ; *Brain/growth & development/metabolism ; *Mental Disorders/metabolism/genetics ; *POU Domain Factors/metabolism/genetics ; *Homeodomain Proteins/metabolism ; *Nerve Tissue Proteins/metabolism ; },
abstract = {POU3F2, a member of the Pit-Oct-Unc (POU) domain transcription factor family, is widely expressed in the central nervous system and essential for the development and maturation of brain. POU3F2 deletion results in impaired hypothalamus and neocortex development, and most mice die between postnatal days 0 and 10. Recently, emerging evidences have demonstrated that POU3F2 is involved in neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, bipolar disorder, schizophrenia, and autism spectrum disorder, albeit still with some limitations in current studies. Besides, POU3F2 also plays a vital role in the reprogramming of somatic cells into neuronal lineages, which provides new ideas and directions for the treatment of neuropsychiatric disorders. This review aims to systematically summarize and analyze the diverse roles of POU3F2 in brain development, neuropsychiatric disorders, and neuronal reprogramming. Furthermore, the potential of POU3F2-targeted therapies for neuropsychiatric disorders and proposed key questions for future research are also emphasized. POU3F2 plays a pivotal role in brain development, the pathogenesis of neurological and psychiatric disorders, and the reprogramming of neural cells. A more comprehensive and systematic understanding of its molecular mechanism might provide novel therapeutic approaches for neuropsychiatric disorders.},
}

Animals
Humans
*Brain/growth & development/metabolism
*Mental Disorders/metabolism/genetics
*POU Domain Factors/metabolism/genetics
*Homeodomain Proteins/metabolism
*Nerve Tissue Proteins/metabolism

@article {pmid42088060,
year = {2026},
author = {Hou, DL and Ho, J and Guan, T and Dong, XX and Zeng, L and Sanders, LH and Wu, YC and Tan, EK and Zhou, ZD},
title = {E3 ubiquitin ligases in neurodegenerative diseases.},
journal = {Military Medical Research},
volume = {13},
number = {1},
pages = {100032},
pmid = {42088060},
issn = {2054-9369},
mesh = {Humans ; *Ubiquitin-Protein Ligases/therapeutic use ; *Neurodegenerative Diseases/physiopathology ; },
abstract = {Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss and proteostatic failure, driven by impaired clearance of misfolded proteins via the ubiquitin-proteasome system (UPS) and autophagy. In UPS, E3 ubiquitin ligases are crucial for regulating protein ubiquitination and degradation. Mutations in E3 ligases, along with dysfunctions of specific ligases such as Parkin, the C-terminus of HSC70-interacting protein (CHIP), and tripartite motif-containing proteins, have been identified as key factors in the buildup of amyloid-β, α-synuclein, tau, trans-active response DNA-binding protein 43, and mutant huntingtin. These accumulations are associated with NDs like Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Therapeutic strategies targeting E3 ligases, particularly proteolysis-targeting chimeras (PROTACs), are being developed for ND treatment and are currently in clinical trials. These approaches aim to enhance E3 ligase activity and promote selective protein degradation. Here, we examine how individual E3 ligases influence cell-fate decisions in NDs, showing that their substrate selection determines whether neurons survive or die. Building on this knowledge, we present an innovative therapeutic pipeline that includes ligase activators, PROTAC degraders, and miRNA switches, which are molecules designed to transition from research to clinical application.},
}

Humans
*Ubiquitin-Protein Ligases/therapeutic use
*Neurodegenerative Diseases/physiopathology

@article {pmid42089471,
year = {2026},
author = {Shu, D and Fu, C and Liu, Z and Li, C},
title = {The role of Annexin A2 in Alzheimer's disease: From cellular functions to therapeutic potential.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70574},
pmid = {42089471},
issn = {1742-4658},
support = {31900692//National Natural Science Foundation of China/ ; 32070961//National Natural Science Foundation of China/ ; 2024AFB558//Natural Science Foundation of Hubei Province/ ; },
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder with a rising global prevalence, is pathologically characterised by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). These lesions lead to synaptic damage, neuronal loss, and cognitive impairment. Despite the recent approval of immunotherapies for AD treatment, their limited efficacy highlights the urgent need for exploring novel disease mechanisms and developing targeted therapeutic strategies. Annexin A2 (ANXA2), a calcium-dependent phospholipid-binding protein, participates in diverse physiological processes (e.g. membrane organisation, cytoskeleton linkage) and contributes to the pathogenesis of diseases such as cancer and Parkinson's disease. Emerging evidence indicates that ANXA2 interacts with AD-related pathological components (Aβ, tau) and regulates AD-associated inflammatory pathways, suggesting its potential role in AD. However, current evidence regarding ANXA2 in AD remains limited, and the molecular mechanisms underlying its contribution to AD pathogenesis remain unclear. This review comprehensively summarises the current knowledge on ANXA2's cellular and physiological functions in the central nervous system (CNS), as well as its involvement in AD pathology, aiming to provide guidance for research into ANXA2's therapeutic potential for AD prevention and treatment.},
}

@article {pmid42089534,
year = {2026},
author = {Liang, S and Lapane, KL and Ott, BR and Tjia, J and Baek, J and Yuan, Y and Alcusky, M},
title = {Antidepressant Use Among US Nursing Home Residents With Dementia.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70492},
pmid = {42089534},
issn = {1532-5415},
support = {5R01AG068450-03/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: In 2024, 6.9 million Americans lived with Alzheimer's disease and related dementias (ADRD), with nursing homes serving as a major site of care. Antidepressants are the most prescribed psychotropic medications among nursing home residents with ADRD, yet detailed information on prescribing patterns, potential indications, and associated resident and facility characteristics remain limited.

METHODS: Using 2018 minimum data set 3.0 assessments linked to Medicare claims, we conducted a cross-sectional study of long-stay nursing home residents aged ≥ 65 years with ADRD who were continuously enrolled in Medicare fee-for-service for 120 days before their annual assessment. We described usage by drug class and type and compared characteristics of users versus non-users overall and by potential indications: depression, anxiety, pain, and insomnia.

RESULTS: Among 232,543 residents with ADRD, 51.6% used antidepressants. Fewer than 5% had moderate or severe depressive symptoms (PHQ-9 ≥ 10). Use was highest among residents with depression or anxiety (69.5%), pain (61.9%), and insomnia (60.0%). Among those without these conditions, 14.1% were prescribed antidepressants. SSRIs were the most prescribed class (60.7%) overall. Citalopram, mirtazapine, sertraline, and trazodone were the most common medications. Residents with any current level of depression severity were more likely to use antidepressants compared to those without symptoms, whereas all levels of cognitive impairment were associated with lower use compared with cognitively intact residents with ADRD. Polypharmacy was strongly associated with increased use, while diabetes, heart failure, and stroke were associated with reduced use.

CONCLUSIONS: Antidepressants were frequently prescribed to residents with ADRD despite limited documentation of active depressive symptoms. Limitations in accurately capturing depressive symptoms in nursing home records, including underreporting by residents due to cognitive impairment and reliance on staff observation rather than self-report, may contribute to apparent discordance between symptoms and prescribing. Further research should evaluate treatment appropriateness, deprescribing opportunities, and risk-benefit balance of chronic treatment in this population.},
}

@article {pmid42082519,
year = {2026},
author = {Wang, J and Mao, Y and Liu, X and Hao, W and , },
title = {Learning patient-specific spatial biomarker dynamics via operator learning for Alzheimer's disease progression.},
journal = {NPJ systems biology and applications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41540-026-00719-x},
pmid = {42082519},
issn = {2056-7189},
support = {1R35GM146894/GM/NIGMS NIH HHS/United States ; 1R35GM146894/GM/NIGMS NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with substantial heterogeneity in progression and treatment response. Despite recent therapeutic advances, predictive models capable of accurately forecasting individualized future biomarker states remain limited. Here, we present a machine learning-based operator learning framework for personalized modeling of AD progression, integrating longitudinal multimodal imaging, biomarker, and clinical data. Unlike conventional models with prespecified dynamics, our approach directly learns patient-specific disease operators governing the spatiotemporal evolution of amyloid, tau, and neurodegeneration biomarkers. Using Laplacian eigenfunction bases, we construct geometry-aware neural operators capable of capturing complex brain dynamics. Embedded within a digital twin paradigm, the framework enables individualized predictions, simulation of therapeutic interventions, and in silico clinical trials. Applied to AD clinical data, our method achieves high prediction accuracy exceeding 90% across multiple biomarkers, substantially outperforming existing approaches. This work offers a scalable, interpretable platform for precision modeling and personalized therapeutic optimization in neurodegenerative diseases.},
}

@article {pmid42082800,
year = {2026},
author = {Nazli, D and Poyraz, YK and Can, K and Ipekgil, D and Cakmak, N and Turhanlar-Sahin, E and Hacoglu, S and Erdost, HA and Iyilikci, L and Ozhan, G},
title = {Dexmedetomidine Exerts Multi-level Effects to Ameliorate Alzheimer's Disease Pathology in the Adult Zebrafish Brain.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42082800},
issn = {1559-1182},
mesh = {Animals ; Zebrafish ; *Dexmedetomidine/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/genetics ; *Brain/pathology/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *Aging/pathology/drug effects ; Behavior, Animal/drug effects ; Peptide Fragments ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition involving β-amyloid (Aβ) deposition, tau abnormalities, neuroinflammation, neuronal degeneration, and progressive impairment of cognitive functions. Despite extensive research, effective disease-modifying therapies remain limited, highlighting the need for translationally relevant models and repurposable therapeutic candidates. Dexmedetomidine (DEX), an α2-adrenergic receptor agonist with known neuroprotective properties, was investigated in an adult zebrafish model of AD established through cerebroventricular administration of Aβ42. DEX treatment significantly reduced Aβ accumulation and was associated with reduced amyloidogenic gene expression, indicating transcriptional changes in amyloidogenic pathway-related genes. DEX attenuated neuroinflammation by reducing glial activation, lowering pro-inflammatory cytokine gene expression, and increasing expression of the anti-inflammatory gene il10. Immunofluorescence assessment further demonstrated reduced astrogliosis and preserved neuronal marker integrity, as indicated by increased HuC/D levels. Interestingly, DEX attenuated Aβ-induced proliferative responses, characterized by decreased PCNA expression, while enhancing cleaved caspase-3 levels, suggesting changes in proliferation and apoptotic signaling under Aβ stress conditions. Behavioral assessments further demonstrated that DEX alleviated Aβ42-induced anxiety- and aggression-like behaviors, improving behavioral phenotypes in this model. Overall, these findings underscore the multi-level effects of DEX in modulating AD-related pathological features. As a clinically available agent, DEX represents a promising candidate for repurposing in neurodegenerative disease contexts. Further preclinical studies in mammalian models are warranted to validate its translational relevance and therapeutic potential.},
}

Animals
Zebrafish
*Dexmedetomidine/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/pathology/genetics
*Brain/pathology/drug effects/metabolism
Amyloid beta-Peptides/metabolism
Disease Models, Animal
*Aging/pathology/drug effects
Behavior, Animal/drug effects
Peptide Fragments

@article {pmid42082802,
year = {2026},
author = {Motieiyan, E and Motahari, R and Aliabadi, A and Khaksar, S and Abdolmaleki, S},
title = {Cobalt complexes in biology and medicine: enzymatic functions, pharmacological applications, and health challenges.},
journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry},
volume = {},
number = {},
pages = {},
pmid = {42082802},
issn = {1432-1327},
abstract = {Cobalt is an essential trace element in biochemistry that plays a crucial role in the structure and function of several important biomolecules. In this review, vitamin B12 is discussed as one of the best-known examples in this area. Various forms of this vitamin, including methylcobalamin and adenosylcobalamin, play a crucial role in metabolic reactions in mammals and prokaryotes. It also discusses cobalt-containing enzymes that are essential for various biological processes. These enzymes are B12-dependent enzymes, which are well studied, and cobalt-containing enzymes, which are less well known, such as methionine aminopeptidase, nitrile hydratase, glucose isomerase, and prolidase. In addition to the significant role of cobalt complexes in biochemistry, these complexes are considered potent anticancer agents that can exert their antiproliferative effects through the production of ROS, cell cycle arrest, MMP breakdown, and induction of apoptosis in cancer cells. Cobalt complexes are also being explained here for their antimicrobial properties against a variety of pathogens, including bacteria, fungi, and viruses. Furthermore, examples of these complexes are presented as promising agents for the suppression of AD, which could be effective by binding to Aβ-peptides and preventing their aggregation, which is a central feature of the pathogenesis of AD, or by combating the oxidative damage associated with the disease, or even by interfering with the enzyme activities associated with this disease. Finally, the challenges related to the toxicity of cobalt and its compounds in medicine are discussed, and chelation therapy is considered an effective treatment for cobalt poisoning.},
}

@article {pmid42082835,
year = {2026},
author = {Zheng, X and Chen, P and Li, D and Li, W and Liao, J and Zhang, M},
title = {Lamotrigine Improves Spatial Learning and Attenuates AD-Related Pathology in APP/PS1 Mice, with Possible Involvement of the cAMP/PKA/CREB Pathway.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42082835},
issn = {1573-6903},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Lamotrigine/pharmacology/therapeutic use ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; *Spatial Learning/drug effects ; Mice, Transgenic ; Mice ; Presenilin-1/genetics ; Cyclic AMP Response Element-Binding Protein/metabolism ; Signal Transduction/drug effects ; Cyclic AMP/metabolism ; Male ; Brain/drug effects/metabolism/pathology ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) is characterized by impaired spatial learning functions, amyloid-β accumulation, tau hyperphosphorylation, and neuroinflammation. Antiepileptic drugs such as lamotrigine have shown promise in improving brain functions in AD, but the underlying mechanisms remain unclear. This study aimed to evaluate the therapeutic effects of lamotrigine in amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and elucidate the underlying molecular mechanisms using integrated transcriptomic and metabolomic analyses. APP/PS1 mice were treated with lamotrigine from 3 months of age, and spatial learning performance was assessed using the Morris water maze test. Histological and molecular changes were evaluated through hematoxylin and eosin staining, Western blotting, ELISA, and immunohistochemistry. High-throughput RNA sequencing and untargeted metabolomics were performed to explore differentially expressed genes, metabolites, and enriched signaling pathways. Western blot validation and pharmacological inhibition were used to verify pathway involvement. Lamotrigine treatment significantly improved spatial learning performance, ameliorated neuronal degeneration, and decreased Aβ1 levels and tau phosphorylation in the brains of APP/PS1 mice. Inflammatory markers and glial activation were also markedly suppressed. Multi-omics analysis revealed alterations in key pathways related to synaptic plasticity, lipid metabolism, and autophagy. Notably, both omics data and protein validation highlighted the cAMP/PKA/CREB pathway as a potentially relevant pathway. Co-administration of the PKA inhibitor H89 abolished lamotrigine-induced upregulation of p-CREB and BDNF, supporting the involvement of this pathway. Lamotrigine improves spatial learning and attenuates AD-related pathology in APP/PS1 mice, possibly through modulation of the cAMP/PKA/CREB signaling pathway, highlighting its potential as a candidate for further investigation.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
*Lamotrigine/pharmacology/therapeutic use
Cyclic AMP-Dependent Protein Kinases/metabolism
Amyloid beta-Protein Precursor/genetics/metabolism
*Spatial Learning/drug effects
Mice, Transgenic
Mice
Presenilin-1/genetics
Cyclic AMP Response Element-Binding Protein/metabolism
Signal Transduction/drug effects
Cyclic AMP/metabolism
Male
Brain/drug effects/metabolism/pathology
Maze Learning/drug effects

@article {pmid42082960,
year = {2026},
author = {Liu, S and Zhu, J and Zhong, H and Zhou, D and Long, Q and Zhang, Z and Yang, X and Wu, Q and Cheng, C and Wu, J and Luu, HN and Wang, J and Zhao, B and Wu, C and Deng, Y and Wu, L},
title = {Investigating causal associations among inflammatory proteins, blood metabolites, and Alzheimer's disease risk.},
journal = {BMC psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12888-026-08136-4},
pmid = {42082960},
issn = {1471-244X},
abstract = {Alzheimer's disease (AD) is a prevalent degenerative neurological disorder with limited treatment options. Prior studies reported specific metabolites and inflammatory proteins to be related to AD risk. However, the intricate relationship between inflammatory proteins, blood metabolites, and AD risk in European population remains unclear. Genetic instruments for 1,091 metabolites and 736 inflammatory proteins were derived from two recent comprehensive genome-wide association studies. Univariable Mendelian Randomization was employed to assess potential causal effects of metabolites on AD risk, potential effects of inflammatory proteins on metabolites, and effects of inflammatory proteins on AD risk. Multivariable MR (MVMR) was further applied to disentangle direct effects of proteins and metabolites on AD. Twelve metabolites were identified to be associated with AD risk, and 226 inflammatory proteins demonstrated likely to be causal effects on these 12 metabolites. Further examining the associations between such inflammatory proteins and AD risk revealed 22 associations for which the effect directions from inflammatory proteins to metabolites, from metabolites to AD risk, and from inflammatory proteins to AD risk were aligned, suggesting inflammatory protein - metabolite - AD risk pathway. MVMR further highlighted four trios in which the effect directions were consistent with the UVMR results, supporting a metabolite‑mediated pattern. This large‑scale genetic analysis highlights specific metabolites as direct contributors to AD risk and suggests that certain inflammatory proteins may influence AD primarily through downstream metabolic pathways. Our findings offer potential novel therapeutic targets for AD intervention.},
}

@article {pmid42083360,
year = {2026},
author = {Pandey, H and Kaur, A and Khan, J and Sharma, A},
title = {Nanomedicine for Alzheimer's Disease: Diagnostic and Therapeutic Progress.},
journal = {MicroRNA (Shariqah, United Arab Emirates)},
volume = {},
number = {},
pages = {},
doi = {10.2174/0122115366427696260203074113},
pmid = {42083360},
issn = {2211-5374},
abstract = {The complex nature of the pathophysiology and limited treatment options of AD make it a huge challenge in healthcare. The recent developments in nanotechnology have given fresh hope for diagnosing and treating AD, which could serve as a way out of the existing problems. This review dwells on the role of nanotechnology in AD and its applications at its early stages through the development of nanosensors and boost imaging methods. Additionally, nanotechnology-driven therapeutic strategies are being investigated with nanoparticle-based drug delivery systems that aim to target the blood-brain barrier, among others. Current research innovations, clinical trials, and prospects highlight the transformative potential of nanotechnology in reshaping AD management. Ethical issues related to applying nanomedicine in neurodegenerative diseases, as well as fears about nanoparticles, are carefully analyzed herein. Finally, this review concludes with a synthesis of how nanotechnology has affected Alzheimer's Disease (AD) while emphasizing emerging trends and future directions toward advancing research on Alzheimer's Disease (AD). This comprehensive overview underscores the pivotal role of nanotechnology in revolutionizing AD prognosis and therapy, paving the way for personalized and effective treatment strategies.},
}

@article {pmid42083572,
year = {2026},
author = {Minhas, AM and Khan, AU and Gul Qazi, N and Nadeem, H and Ali, F},
title = {Pharmacological investigation of oxadiazole derivatives in Alzheimer's disease: Modulation of oxidative stress, neuroinflammation, and iNOS signaling.},
journal = {Iranian journal of basic medical sciences},
volume = {29},
number = {3},
pages = {423-437},
pmid = {42083572},
issn = {2008-3866},
abstract = {OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by deposition of amyloid-beta (Aβ) aggregates. Aβ peptides alter synaptic function and produce neuroinflammation. The neurotoxic mechanisms are also related to increases in the expression of iNOS (inducible nitric oxide synthase), resulting in further neuronal degeneration and memory impairment.

MATERIALS AND METHODS: In the current study, we assessed the in vivo effect of the 1,3,4-oxadiazole derivative 2-{[5-(2-aminophenyl)-1,3,4-oxadiazol-2-yl] sulfanyl}-
N-(1,3-benzothiazol-2-yl) acetamide (MA) on spatial memory and inflammatory responses induced by AlCl3 administration in animals.

RESULTS: A notable improvement in memory function was observed in the AlCl3-induced group at 29[th] post-injection, following MA treatment (5, 10, and 20 mg/kg), as indicated by the behavioral analysis. This effect is correlated with decreases in inflammatory markers such as NFKƁ, IL-6/ß1, IFN-γ, TNϜ-α, and NO levels, as well as a reduction in expression of neurodegenerative markers: β-amyloid and p-tau (*P<0.05, **P<0.01, ***P<0.001 vs disease control). The results from our study suggested that MA significantly enhances the levels of glutathione, catalase, and glutathione S-transferase while decreasing the lipid peroxidation (LPO) in comparison to the disease control group, and also improves mitochondrial dysfunction. The effects are further enhanced when MA was used in combination with aminoguanidine (AG), an iNOS inhibitor. Molecular dynamics (MD) simulations, along with protein mRNA expression and iNOS western blotting, further supported the results of in vivo experiments.

CONCLUSION: Our study proposed that MA attenuated the cytokine release, decreased oxidative stress, and iNOS expression, leading to a decrease in neurodegeneration.},
}

@article {pmid42083945,
year = {2026},
author = {Kumar, D and Walhekar, V and Kasaragod, MS and Kini, S},
title = {Discovery of Novel Quinazoline Thiazole Uredio Analogs as Dual Inhibitors of GSK-3β and CK-1δ as Anti-Alzheimer's Agents: Catching Two Fish with One Net.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266378266251017045841},
pmid = {42083945},
issn = {1873-4294},
abstract = {INTRODUCTION: AD is a widespread and debilitating neurodegenerative disorder, and existing treatments have demonstrated limited efficacy, emphasizing the need for novel therapeutic strategies. This study focused on the design of drug-like molecules with enhanced efficacy and minimized side effects through the application of structure-based scaffold hopping and molecular hybridization strategies.

METHODS: Molecular docking was carried out on the Glide module, Molecular dynamics simulation of 500 ns was executed employing Desmond, and ADMET prediction was achieved by the QikProp modules of Schrodinger.

RESULTS: Through molecular docking studies targeting the GSK-3β and CK-1δ enzymes, the compounds VDK12 and VDK14 were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of -9.9 kcal/mol and -10.1 kcal/mol, respectively. Molecular dynamics simulations further revealed that the VDK12 and VDK14 complexes exhibited stable interactions within the active sites of GSK-3β and CK-1δ throughout a 500 ns simulation. Additionally, in silico ADMET analysis demonstrated that VDK1 exhibited an excellent human oral absorption rate of 91.349%, outperforming other compounds in the series.

DISCUSSION: Molecules as dual inhibitors were designed successfully by the application of scaffold hopping and molecular hybridization. Designed molecules demonstrated excellent molecular docking and dynamics simulation results with an appropriate ADMET profile.

CONCLUSION: These findings strongly suggest the potential of VDK12 and VDK14 as dual inhibitors of GSK-3β and CK-1δ, offering a promising foundation for the development of new lead compounds for AD treatment.},
}

@article {pmid42083963,
year = {2026},
author = {Kanojia, N and Deswal, G and Grewal, AS and Kumar, J and Thapa, K and Sharma, A and Sharma, A and Dheer, D and Puri, V and Rani, L and Saini, V},
title = {Advances in Microneedle Technology for Targeted Therapy in Alzheimer's and Parkinson's Disease.},
journal = {Current drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672018425956260117232402},
pmid = {42083963},
issn = {1875-5704},
abstract = {INTRODUCTION: The fourth major cause of death worldwide is Neurodegenerative Diseases (NDs), including Alzheimer's and Parkinson's disease. The existing therapies have only a small effect on alleviating symptoms, mainly because the therapeutic agents are difficult to cross the bloodbrain barrier. The purpose of the review is to discuss the potential of microneedle-based transdermal delivery systems to improve the delivery of drugs to the central nervous system and thereby manage neurodegenerative diseases effectively.

METHODS: The article summarizes and synthesizes the available literature that targets the strategies of microneedle-mediated drug delivery. The literature on the design, composition, pharmacokinetics, and mechanistic benefits of different microneedle platforms for surmounting central nervous system barriers was identified and thematically synthesized.

RESULTS: Microneedle systems have emerged as non-invasive delivery systems with the potential for localized and sustained drug delivery, overcoming the stratum corneum and the blood-brain barrier. Micro-needles can be used to deliver small molecules, peptides, and nanoparticles to the brain, thereby avoiding systemic side effects and enhancing drug bioavailability. Some of those designs include dissolving, coated, hollow, hydrogel-forming, and stimuli-responsive microneedles, which have been shown to target the brain and exhibit higher therapeutic efficiency in preclinical models.

DISCUSSION: Although technological advances have improved, the clinical translation of microneedlebased strategies remains limited. The future directions could include using microneedles with stem cell-based therapies, CRISPR/Cas9 gene editing, artificial intelligence-based delivery systems, and responsive release technology to facilitate customized treatment.

CONCLUSION: The Microneedle-based drug delivery systems are promising in overcoming the current limitations in the treatment of neurodegenerative diseases. Nonetheless, a large-scale clinical validation is necessary to guarantee safety, efficacy, and scalability to be applied to real-life scenarios.},
}

@article {pmid42068226,
year = {2026},
author = {Stites, SD and Kuz, C and Largent, EA and Harkins, K and Krieger, A and Sankar, P and Barber, SJ},
title = {Four Common Beliefs About Patient Memory Evaluations: Who Has Them and What Modifies Them?.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261447038},
doi = {10.1177/15333175261447038},
pmid = {42068226},
issn = {1938-2731},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnosis/psychology ; Aged ; Middle Aged ; Adult ; *Health Knowledge, Attitudes, Practice/ethnology ; *Aging/psychology ; Aged, 80 and over ; },
abstract = {Understanding public beliefs about patients at memory centers may inform efforts to promote early diagnosis and guide clinical discussions of Alzheimer's disease (AD). Adults (N=3,527) read a vignette describing a fictional person at a memory center and rated the person's condition as a mental illness, part of typical aging, and psychological or biological origins. Vignettes varied by AD biomarker result, symptom stage, and treatment availability. Participants most strongly believed that the condition was part of typical aging and biological in origin, though beliefs varied across subgroups. Black and Asian participants reported stronger beliefs than White participants that the condition was a mental illness (β=0.39, P<0.001) and psychological (β=0.46, P<0.001). Men reported stronger beliefs that the condition was a mental illness (β=0.19, P<0.001), psychological (β=0.14, P<0.001), and part of typical aging (β=-0.08, P=0.04). Biomarker positivity heightened biological and lowered psychological attributions (all P<0.05). The findings offer specific insights to guide intervention.},
}

Humans
Male
Female
*Alzheimer Disease/diagnosis/psychology
Aged
Middle Aged
Adult
*Health Knowledge, Attitudes, Practice/ethnology
*Aging/psychology
Aged, 80 and over

@article {pmid42068460,
year = {2026},
author = {Chen, JH and Tsai, TF},
title = {A Narrative Review: Do Systemic Drugs Used in the Treatment of Psoriatic Disease Affect Alzheimer's Disease?.},
journal = {Dermatology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42068460},
issn = {2193-8210},
abstract = {Various comorbidities have been associated with psoriasis. Most clinical studies support the hypothesis that psoriasis may be a risk factor for dementia. Meanwhile, some evidence indicates that certain immunomodulatory agents, many of which are widely used in psoriatic disease management, exert neuroprotective effects and may attenuate dementia progression. In view of the lack of existing studies that specifically investigate the effects of systemic treatments for psoriatic disease on dementia or cognitive impairment, in this narrative review, we focus on Alzheimer's disease, as a model to explore whether systemic psoriasis treatments influence dementia risk and severity. Our findings suggest that some systemic treatments for psoriasis may also provide potential neuroprotective benefits.},
}

@article {pmid42071065,
year = {2026},
author = {Fikry, H and Sadek, DR and Saleh, LA and Hasanin, MTM and Alkhalek, HAA},
title = {Dual protective role of curcumin- encapsulated chitosan nanoparticles against gastric and neural injury in a rat model of gut-brain axis dysfunction: a histological and biochemical study.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42071065},
issn = {1432-1912},
abstract = {Gastric ulcer (GU) and Alzheimer's disease (AD) are prevalent age-associated disorders frequently accompanied by systemic oxidative stress and inflammation. Emerging evidence suggests that gastrointestinal dysfunction and inflammatory signaling may aggravate neurodegenerative processes. Curcumin (Cur) exhibits well-established antioxidant, anti-inflammatory, neuroprotective, and gastroprotective properties; however, its therapeutic utility is limited by poor bioavailability. The present study aimed to formulate and characterize Curcumin- encapsulated chitosan nanoparticles (Cur-CSNPs) and evaluate their dual protective effects in a clinically relevant comorbid rat model combining scopolamine-induced AD-like pathology and ethanol-induced GU. Male Wistar rats were divided into six groups: control, Cur-CS-NPs alone, GU, AD, GU + AD, and GU + AD treated with Cur-CSNPs. Behavioral assessments, biochemical analyses, histopathological evaluation, and immunohistochemical investigations were performed on brain and gastric tissues. GU + AD rats exhibited cognitive deficits, neuronal degeneration, amyloid-β accumulation, astrocyte activation, gastric mucosal injury, increased oxidative stress, NF-κB activation, elevated inflammatory cytokines, and enhanced apoptotic signaling. Cur-CSNP treatment significantly improved cognitive performance, reduced oxidative stress and inflammation, suppressed NF-κB signaling, decreased amyloid-β deposition, inhibited apoptosis, and restored gastric mucosal integrity. In conclusion, Cur-CSNPs exert concurrent neuroprotective and gastroprotective effects in a comorbid AD and GU model through coordinated modulation of oxidative stress, inflammation, amyloidogenic activity, and apoptotic pathways. These findings demonstrate that Cur-CSNPs exert dual neuroprotective and gastroprotective effects by modulating oxidative stress, inflammation, amyloidogenic pathways, and apoptosis, highlighting nano-curcumin as a promising therapeutic strategy for gut-brain axis-related disorders. Further investigations are warranted to elucidate the detailed molecular mechanisms and to explore the clinical applicability of nano-formulated curcumin as a therapeutic strategy for disorders involving concurrent gastrointestinal and neurodegenerative pathology.},
}

@article {pmid42071257,
year = {2026},
author = {Richard, JE and Mohammad, A and Lieblich, SE and Go, KA and Wang, S and Rechlin, RK and Splinter, TFL and Barreto, GE and Galea, LAM},
title = {Reproductive history differentially shapes the neural response of middle-aged hAPOEɛ4 female rats to estradiol therapy after a metabolic challenge.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-026-00911-y},
pmid = {42071257},
issn = {2042-6410},
support = {PJT173554/CAPMC/CIHR/Canada ; },
abstract = {BACKGROUND: Advancing age, the APOEɛ4 allele, and female sex are the top nonmodifiable risk factors for Alzheimer's disease (AD). Female-specific experiences, such as parity and hormone therapy (HT) affect aging biomarkers such as metabolism and immune signaling, and may affect AD risk. Estradiol (E2), a component of many HTs, affects cognition and brain health in aging females although studies suggest the effects can vary depending on parity, genotype, and metabolic status which may account for some of the inconsistencies in the literature. We hypothesized that prior parity influences brain and metabolic health, including response to E2, depending on APOE genotype.

METHODS: Middle-aged female (10 month) wildtype (WT) or humanized (h) APOEɛ4 expressing rats, with different reproductive experience (nulliparous or primiparous) were fed a Western (WD) or standard diet (SD) for 2 months. In the second month, rats were given E2 or vehicle (oil) injections daily. Fear associative learning, plasma metabolic hormones, hippocampal inflammatory cytokine expression, and neuroplasticity (neurogenesis, synaptic protein) were assessed.

RESULTS: Females fed a WD gained weight and displayed metabolic dysregulation, regardless of genotype. E2 treatment reduced WD-induced weight gain and reduced metabolic hormones, with stronger effects in WT rats. E2 treatment increased dorsal hippocampal inflammatory cytokine expression selectively in primiparous hAPOEɛ4 females fed a WD. Previous parity increased neurogenesis and reduced certain cytokine expression in the hippocampus of middle-aged WT rats under a SD. Both E2 treatment and previous parity decreased dorsal neurogenesis in hippocampus of hAPOEɛ4 rats. In hAPOEɛ4 females, higher weight was associated with reduced contextual fear memory, an effect driven by primiparous females. In the cued fear conditioning task, hAPOEɛ4 females displayed better cued fear memory than WT, however, WD exposure reduced cued fear memory only in this group. Together, this indicates that diet and weight gain may be more detrimental to associative memory in hAPOEɛ4 females and that E2 treatment has more favourable outcomes in WT rats.

CONCLUSIONS: Previous parity alters how females respond to E2 and metabolic stress in midlife. Primiparous hAPOEɛ4 females were especially vulnerable to the effects of WD and E2, exhibiting more inflammation, impaired memory, and reduced weight-loss. These findings highlight the importance of considering parity and genotype when evaluating midlife metabolic and cognitive risk.},
}

@article {pmid42071824,
year = {2026},
author = {Li, Q and Jing, S and Li, N and Yuan, X and Wang, T},
title = {Causality relationship between 91 inflammatory factors and Alzheimer disease: A bidirectional Mendelian randomization study.},
journal = {Medicine},
volume = {105},
number = {17},
pages = {e48136},
doi = {10.1097/MD.0000000000048136},
pmid = {42071824},
issn = {1536-5964},
support = {2024439//Chengdu Medical Research Project/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/blood ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Inflammation/genetics/blood ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; },
abstract = {Alzheimer disease (AD) is a neurodegenerative disorder characterized by amyloid plaque deposition, neurofibrillary tangles, and chronic neuroinflammation. Due to its complexity and difficult-to-treat nature, it has cast a huge shadow over global health. In addition to genetic susceptibility, the development of AD is closely related to systemic inflammation. This study aims to evaluate the association between systemic inflammatory factors and AD through a bidirectional Mendelian randomization (MR) design. Our MR design incorporated aggregated data from extensive genome-wide association studies to investigate the causal relationship between genetically determined systemic inflammatory factors and AD. The MR analysis results identified 9 potential systemic inflammatory regulatory factors: C-X-C motif chemokine 5, interleukin-18 receptor 1, interleukin-6, and tumor necrosis factor, which were associated with an increased risk. Conversely, AD is significantly correlated with 5 circulating inflammatory regulatory factors, namely, tumor necrosis factor-related apoptosis-inducing ligand, stem cell factor, monocyte chemoattractant protein-4, interleukin-5, and cystatin D, which are considered downstream consequences of AD. It is worth noting that our results have, for the first time, clarified the significant roles of inflammatory factors such as cystatin D and monocyte chemoattractant protein-4 in AD, providing new markers and key targets for further exploration of the molecular mechanism and clinical diagnosis and treatment of AD.},
}

Humans
*Alzheimer Disease/genetics/blood
Mendelian Randomization Analysis
Genome-Wide Association Study
*Inflammation/genetics/blood
Genetic Predisposition to Disease
Polymorphism, Single Nucleotide

@article {pmid42072160,
year = {2026},
author = {Tng, TJW and Cheah, IK and Halliwell, B and Lim, KL},
title = {Potential Protection Against Parkinson's Disease by Ergothioneine-Nature's Multifactorial Neuroprotectant.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {4},
pages = {},
doi = {10.3390/antiox15040519},
pmid = {42072160},
issn = {2076-3921},
support = {#023643-00001//Ministry of Education/ ; },
abstract = {The use of neuroprotective nutraceuticals as a strategy against neurodegenerative diseases such as Parkinson's disease (PD) has gained considerable traction in recent years. In this review, we highlight ergothioneine (ET)-a naturally occurring thiol/thione derivative abundant in mushrooms-as a promising candidate, given its long half-life, blood-brain barrier penetration, and high bioavailability. Numerous population studies have linked low blood ET levels with increased risk and progression of neurological and other age-related disorders in humans, suggesting that dietary ET may confer neuroprotective benefits. Supporting this, several studies have demonstrated the efficacy of ET treatment in reducing PD-associated molecular damage across various pre-clinical models such as C. elegans, Drosophila, rodent models and human neuronal cultures, leading to marked improvements in disease phenotypes. Here, we summarize some of the proposed mechanisms by which ET may exert neuroprotection in PD, including the reduction of protein aggregation, enhancement of mitochondrial function, mitigation of oxidative stress, and attenuation of apoptosis and neuroinflammation. We also highlight recent clinical trials demonstrating the safety and potential efficacy of ET and propose future research to facilitate the translation of ET into the clinic.},
}

@article {pmid42072570,
year = {2026},
author = {Dong, L},
title = {A Unified Information Bottleneck Framework for Multimodal Biomedical Machine Learning.},
journal = {Entropy (Basel, Switzerland)},
volume = {28},
number = {4},
pages = {},
doi = {10.3390/e28040445},
pmid = {42072570},
issn = {1099-4300},
support = {R01CA309499/CA/NCI NIH HHS/United States ; },
abstract = {Multimodal biomedical machine learning increasingly integrates heterogeneous data sources (including medical imaging, multi-omics profiles, electronic health records, and wearable sensor signals) to support clinical diagnosis, prognosis, and treatment response prediction. Despite strong empirical performance, most existing multimodal systems lack a principled theoretical foundation for understanding why fusion improves prediction, how information is distributed across modalities, and when models can be trusted under incomplete or shifting data. This paper develops a unified information-theoretic framework that formalizes multimodal biomedical learning as an information optimization problem. We formulate multimodal representation learning through the information bottleneck principle, deriving a variational objective that balances predictive sufficiency against informational compression in an architecture-agnostic manner. Building on this foundation, we introduce information-theoretic tools for decomposing modality contributions via conditional mutual information, quantifying redundancy and synergy, and diagnosing fusion collapse. We further show that robustness to missing modalities can be cast as an information consistency problem and extend the framework to longitudinal disease modeling through transfer entropy and sequential information bottleneck objectives. Applications to multimodal foundation models, uncertainty quantification, calibration, and out-of-distribution detection are developed. Empirical case studies across three biomedical datasets (TCGA breast cancer multi-omics, TCGA glioma clinical-plus-molecular data, and OASIS-2 longitudinal Alzheimer's data) show that the framework's key quantities are computable and interpretable on real data: MI decomposition identifies modality dominance and redundancy; the VMIB traces a compression-prediction tradeoff in the information plane; entropy-based selective prediction raises accuracy from 0.787 to 0.939 at 50% coverage; transfer entropy reveals stage-dependent modality influence in disease progression; and pretraining/adaptation diagnostics distinguish efficient from wasteful fine-tuning strategies. Together, these results develop entropy and mutual information as organizing principles for the design, analysis, and evaluation of multimodal biomedical AI systems.},
}

@article {pmid42072691,
year = {2026},
author = {Fu, T and Shi, Y and Yang, Z and Zhou, J and Huang, L and Fu, Y and Xiong, W},
title = {Variecolactone, a Natural PDE4 Inhibitor from Marine-Derived Talaromyces sp. ZSD-1, Alleviates Amyloid-β Accumulation and mtDNA Dyshomeostasis via cAMP-PKA-CREB Signaling Pathway.},
journal = {Biomolecules},
volume = {16},
number = {4},
pages = {},
doi = {10.3390/biom16040570},
pmid = {42072691},
issn = {2218-273X},
support = {825QN283//Hainan Provincial Natural Science Foundation of China/ ; 82404601//National Natural Science Foundation of China/ ; 22577021//Natural Science Foundation of China/ ; },
mesh = {*Amyloid beta-Peptides/metabolism ; *Phosphodiesterase 4 Inhibitors/pharmacology/chemistry ; Signal Transduction/drug effects ; Cyclic AMP/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism ; Humans ; *DNA, Mitochondrial/metabolism/genetics ; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Animals ; Mitochondria/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β deposition, neuroinflammation, and mitochondrial dysfunction. Phosphodiesterase 4 (PDE4), a key regulator of cyclic nucleotides in neurons, represents a promising therapeutic target for AD. In this study, we performed a PDE4 inhibition-guided screen of an in-house marine natural product library derived from marine fungi, leading to the identification of a sesterterpenoid variecolactone (VLT) as a potent PDE4 inhibitor. VLT exhibited selective PDE4D inhibition (IC50 = 2.302 μM) with minimal activity against other PDE subtypes. Further mechanical investigation revealed that VLT treatment elevated cAMP and p-CREB levels, reduced amyloid-β (Aβ) accumulation, promoted synaptic function, and ameliorated mitochondrial fragmentation, along with mtDNA homeostasis in the AD cell model. Moreover, under conditions of mtDNA depletion or Drp1 overexpression, VLT exerted neuroprotective effects and maintained mtDNA homeostasis via the cAMP-PKA-CREB signaling pathway. These results demonstrate that PDE4 inhibition by VLT represents a promising therapeutic strategy for AD and related neurodegenerative disorders.},
}

*Amyloid beta-Peptides/metabolism
*Phosphodiesterase 4 Inhibitors/pharmacology/chemistry
Signal Transduction/drug effects
Cyclic AMP/metabolism
Cyclic AMP-Dependent Protein Kinases/metabolism
Cyclic AMP Response Element-Binding Protein/metabolism
Humans
*DNA, Mitochondrial/metabolism/genetics
Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism
Alzheimer Disease/drug therapy/metabolism
Animals
Mitochondria/drug effects/metabolism

@article {pmid42072789,
year = {2026},
author = {Chung, WK and Kim, HM and Lee, MB and Kim, K and Kwon, OI and Yoo, YJ and Rhee, HY and Jahng, GH},
title = {Evaluation of Low-Dose Radiation Treatment Effects Using Conductivity, Diffusivity, and Brain Tissue Volumes Treated in Patients with Mild Alzheimer's Disease: Exploratory Investigation.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {8},
pages = {},
doi = {10.3390/diagnostics16081163},
pmid = {42072789},
issn = {2075-4418},
support = {RS-2024-00335770//National Research Foundation of Korea (NRF) grants funded by the Ministry of Science and ICT/ ; A21IP11//Korea Hydro & Nuclear Power Co. Ltd/ ; },
abstract = {Purpose: No prior clinical studies have quantitatively evaluated the effect of low-dose radiation therapy (LDRT) on Alzheimer's disease (AD) brain changes using multi-modal MRI. This study examined the feasibility of using conductivity, diffusion, and brain tissue volume measures to detect treatment effects in patients with AD receiving LDRT. Methods: Nine patients with mild AD were enrolled in three groups. Three patients in each group were assigned to the control group (0 cGy) and the treated groups [24 cGy/6 fractions (4 cGy for each fraction) and 300 cGy/6 fractions (50 cGy for each fraction)]. Conductivity, diffusivity, and brain tissue volume were acquired at baseline and 6 months post-treatment and were evaluated to assess within-group MRI changes and evaluate associations between MRI measures and Mini-Mental State Examination (MMSE) scores. Results: Region-of-interest (ROI) analyses identified substantial changes in high-frequency conductivity (HFC) (e.g., left insula), cerebrospinal fluid (CSF) volumes (e.g., anterior cingulate, limbic regions), and diffusion tensor imaging (DTI) metrics, such as axial diffusivity (AxD) and fractional anisotropy (FA), in fusiform, thalamic, hippocampal, and occipital areas. Correlation analysis showed strong associations between MRI measures and cognition, most notably HFC in the left fusiform gyrus (r = 0.843, p = 0.0043) after treatment. Diffusion indices across multiple regions also showed significant positive or negative correlations with MMSE. Conclusions: This exploratory clinical study demonstrates that LDRT induces measurable physiological and microstructural alterations in the brain detectable via conductivity and diffusion MRI. Conductivity emerged as the sensitive biomarker, showing strong cognitive correlations. These exploratory findings suggest that multi-modal quantitative MRI can serve as an effective tool for evaluating treatment response in clinical LDRT for AD.},
}

@article {pmid42074010,
year = {2026},
author = {Goloborshcheva, VV and Kostikova, YS and Kucheryanu, VG and Morozov, SG and Kokhan, VS},
title = {Insights into the Impact of Low-Dose Ionizing Radiation on Neurodegenerative Disease Progression in In Vivo Models.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083368},
pmid = {42074010},
issn = {1422-0067},
support = {FGFU-2025-0004//Russian state contract/ ; },
mesh = {Animals ; Humans ; *Radiation, Ionizing ; *Neurodegenerative Diseases/radiotherapy/pathology/metabolism ; Disease Models, Animal ; Disease Progression ; Autophagy/radiation effects ; DNA Repair/radiation effects ; },
abstract = {The effective treatment of neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, remains a critical challenge in modern medicine. Given the limitations of current therapies, alternative strategies to slow neurodegeneration are urgently needed. This study presents a critical review of the current evidence regarding low-dose ionizing radiation (IR) as a promising modality for modulating neurodegenerative processes. This study examines current experimental data on the effects of low-dose IR (LDIR) on cellular protective and compensatory mechanisms, including evidence from in vivo models of NDDs. Our analysis demonstrates that LDIR enhances antioxidant activity and DNA repair, stimulates autophagy and neuroplasticity, and modulates neuroinflammatory signaling. Collectively, these findings support the hypothesis of the neuroprotective potential of LDIR, underscoring its translational viability provided that strict dosimetric guidelines are followed and individual biological responses are rigorously monitored.},
}

Animals
Humans
*Radiation, Ionizing
*Neurodegenerative Diseases/radiotherapy/pathology/metabolism
Disease Models, Animal
Disease Progression
Autophagy/radiation effects
DNA Repair/radiation effects

@article {pmid42074152,
year = {2026},
author = {Wang, W and Zhao, Y and Li, Z and Lv, Y and Xu, Z and Qi, B and Yin, J and Wang, C},
title = {Astragaloside IV Improves Cognitive Impairment in Alzheimer's Mice by Alleviating Neuron PANoptosis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {8},
pages = {},
doi = {10.3390/ijms27083508},
pmid = {42074152},
issn = {1422-0067},
support = {ZD2023C004//Heilongjiang Natural Science Foundation/ ; 32371840 and 82001113//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Saponins/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Triterpenes/pharmacology/therapeutic use ; Mice ; *Neurons/drug effects/metabolism/pathology ; *Cognitive Dysfunction/drug therapy/metabolism ; Hippocampus/drug effects/metabolism/pathology ; Male ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Neuroprotective Agents/pharmacology ; Pyroptosis/drug effects ; Apoptosis/drug effects ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder for which no effective treatments are currently available. PANoptosis is a coordinated cell death pathway involving pyroptosis, apoptosis, and necroptosis. Astragaloside IV (AS-IV) is a bioactive saponin derived from Astragalus membranaceus. Behavioral performance was evaluated using the Morris water maze and open field tests, while neuronal damage was assessed by Nissl staining. The expression levels of Aβ, IL-18, and PANoptosis-related proteins were analyzed by Western blot. Immunofluorescence was performed to assess the co-localization of PANoptosis-associated proteins with neurons in the hippocampal region. In addition, the effects of AS-IV on the expression of PANoptosis-related proteins were examined in Aβ-induced HT22 cells. AS-IV improved spatial memory performance and alleviated anxiety-like behaviors in AD mice. Furthermore, AS-IV treatment significantly reduced Aβ protein levels and attenuated neuronal loss in the hippocampus. Key markers of PANoptosis were downregulated following AS-IV treatment. Immunofluorescence revealed strong co-localization between PANoptosis-associated proteins and neurons. In vitro, AS-IV also inhibited the Aβ-induced upregulation of PANoptosis-related proteins in HT22 cells. Collectively, these results indicate that AS-IV exerts neuroprotective effects in AD models, which may be associated with reduced Aβ protein deposition, attenuated neuronal loss, and the regulation of PANoptosis-related proteins in the hippocampus.},
}

Animals
*Saponins/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology
*Triterpenes/pharmacology/therapeutic use
Mice
*Neurons/drug effects/metabolism/pathology
*Cognitive Dysfunction/drug therapy/metabolism
Hippocampus/drug effects/metabolism/pathology
Male
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Neuroprotective Agents/pharmacology
Pyroptosis/drug effects
Apoptosis/drug effects

@article {pmid42074388,
year = {2026},
author = {Manias, M and Vieira, JVR and Cremonesi, AS},
title = {In Silico Analyses Suggest That Exercise-Induced Irisin-Mediated Neuroprotection Supports Non-Pharmacological Preventive Strategies for Alzheimer's Disease in Public Health.},
journal = {International journal of environmental research and public health},
volume = {23},
number = {4},
pages = {},
doi = {10.3390/ijerph23040449},
pmid = {42074388},
issn = {1660-4601},
mesh = {*Fibronectins/metabolism/chemistry/genetics ; *Alzheimer Disease/prevention & control/epidemiology ; Humans ; Brazil/epidemiology ; *Exercise ; Molecular Docking Simulation ; *Neuroprotection ; Public Health ; Male ; Computer Simulation ; Female ; Aged ; Molecular Dynamics Simulation ; Hospitalization/statistics & numerical data ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and imposes a high economic and social burden on healthcare systems. In Brazil, the consistent increase in costs associated with AD hospitalizations, coupled with the absence of curative therapies and population aging, reinforces the need for low-cost, broadly applicable preventive strategies. This study investigated the role of irisin, a myokine induced by physical activity, in the prevention of AD, integrating epidemiological and bioinformatic analyses. Public data on the nutritional status of the Brazilian population in the early 2000s and on AD hospitalizations approximately 20 years later were analyzed, assessing the temporal association using a lagged Spearman correlation. Additionally, genes associated with AD were analyzed through protein-protein interaction networks and functional enrichment. Structural models of irisin and the integrin αV/β5 receptor were employed in molecular docking and molecular dynamics analyses. Historical data indicated a high prevalence of excess weight in the early 2000s (46.7% ± 4.2% of the adult population) and a strong positive correlation with AD hospitalizations two decades later (ρ = 0.88; p = 0.033). Functional analyses revealed enrichment of pathways related to neurodegeneration, neurotrophins, and neuronal plasticity, involving proteins such as BDNF, AKT, ERK1/2, and CREB. Docking and molecular dynamics indicated a stable interaction of irisin with the αV/β5 receptor, suggesting activation of neuroprotective pathways. The findings reinforce physical exercise as a strategic public health tool for the prevention of AD, providing an epidemiological and molecular basis to reduce the future burden of the disease, thereby shifting the focus of public health policy from treatment to prevention.},
}

*Fibronectins/metabolism/chemistry/genetics
*Alzheimer Disease/prevention & control/epidemiology
Humans
Brazil/epidemiology
*Exercise
Molecular Docking Simulation
*Neuroprotection
Public Health
Male
Computer Simulation
Female
Aged
Molecular Dynamics Simulation
Hospitalization/statistics & numerical data

@article {pmid42076103,
year = {2026},
author = {Vasilica, PDF and Dorin, PI and Vladulescu, C and Popescu, C and Trasca, DM and Radivojevic, K and Varut, RM and Vintilescu, ȘB and Stepan, MD and Stoica, GA},
title = {Cyclodextrin-Based Strategies for Brain Drug Delivery: Mechanistic Insights into Blood-Brain Barrier Transport and Therapeutic Applications.},
journal = {Pharmaceutics},
volume = {18},
number = {4},
pages = {},
doi = {10.3390/pharmaceutics18040451},
pmid = {42076103},
issn = {1999-4923},
abstract = {Cyclodextrins (CDs) have gained increasing attention as versatile platforms for enhancing drug delivery to the central nervous system, particularly in overcoming the restrictive properties of the blood-brain barrier (BBB). Owing to their unique cyclic oligosaccharide structure, CDs are capable of forming inclusion complexes with a wide range of therapeutic agents, thereby improving their solubility, stability, and bioavailability. In addition to their role as excipients, growing evidence indicates that CDs can actively modulate biological processes, including membrane fluidity and cholesterol homeostasis, which are critical factors in neurological disorders. This review explores the application of CDs in facilitating drug transport across the BBB through multiple mechanisms, including carrier-mediated transport, receptor-mediated transcytosis, and nanoparticle-based delivery systems. Special emphasis is placed on their use in the treatment of neurodegenerative and neurological diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, Niemann-Pick type C disease, and other central nervous system disorders. In these contexts, CD-based formulations have demonstrated the ability to enhance brain targeting, reduce pathological protein aggregation, and improve therapeutic outcomes in preclinical models. This review uniquely integrates cyclodextrin's physicochemical properties with specific blood-brain barrier transport mechanisms, proposing a structure-transport-therapy framework that enables a more predictive understanding of brain-targeted drug delivery.},
}

@article {pmid42077232,
year = {2026},
author = {Ding, T and Chen, J and Xiang, Y and Zhou, X and Zheng, H and Bai, Y and Wang, W and Fu, Q and Chen, Y and Fu, Y},
title = {The Gut-Brain Axis in Alzheimer's: From Microbiota Genetics to Stigmasterol's Neuroprotection Mechanism.},
journal = {Degenerative neurological and neuromuscular disease},
volume = {16},
number = {},
pages = {580890},
pmid = {42077232},
issn = {1179-9900},
abstract = {OBJECTIVE: This study aimed to identify novel therapeutic targets for Alzheimer's disease (AD) by investigating the role of the intestinal flora (IF) via the gut-brain axis, and to predict a potential natural compound for AD treatment and elucidate its underlying mechanism.

METHODS: Following a primary analytical axis, we first employed Mendelian randomization (MR) to infer causal relationships between gut microbiota and AD. To pinpoint molecular targets, we integrated Summary-data-based MR (SMR) with single-cell and spatial transcriptomics. Subsequently, network pharmacology and molecular docking were used to identify stigmasterol as a candidate compound targeting the causal pathway. Finally, the neuroprotective effects and the STIM1/Orai1-mediated mechanism were experimentally validated in vitro using Aβ1-42 exposed SH-SY5Y cells.

RESULTS: MR-based causal inference identified Desulfovibrio as a risk factor for AD, while Slackia and the Lachnospiraceae NK4A136 group were protective factors. Seven key AD-related genes were identified by combining MR results with databases, which were highly druggable. SMR analysis and multi-omics integration pinpointed STIM1-mediated calcium signaling as the core causal pathway. Following the identification of stigmasterol via network pharmacology and molecular docking, in vitro experimental validation confirmed that stigmasterol significantly inhibited Aβ1-42 induced neuronal apoptosis and calcium overload by specifically modulating the STIM1/Orai1 pathway and the Bcl-2/Bax ratio.

CONCLUSION: This study decodes the gut-brain axis by establishing the specific causal pathway. We demonstrate that Stigmasterol exerts neuroprotective effects by inhibiting apoptosis through a IF-associated mechanism involving the STIM1/Orai1 pathway, provideing novel insights into AD pathogenesis and offering a promising therapeutic strategy based on natural compounds.},
}

@article {pmid42078936,
year = {2026},
author = {Wu, W and Wang, H and Zhang, L and Li, D and Chen, Y and Lin, B and Jiang, H and Meng, T and Zhu, Z and He, L and Zhang, H and Liu, H and Zhang, R},
title = {Dexmedetomidine attenuates Alzheimer's pathogenesis by targeting the ROS-mediated XIAP-MDM2-p53 signaling axis.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1811373},
pmid = {42078936},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a complex pathological process, in which oxidative stress serves as a key pathogenic mechanism. Studies have shown that the anesthetic adjuvant dexmedetomidine (Dex) can improve postoperative cognitive function in AD patients. This study aimed to explore whether dexmedetomidine alleviates AD-associated neuronal apoptosis and cognitive impairment via reducing overproduction of ROS and regulating the XIAP signaling pathway.

METHODS: In vitro experiments were conducted using Aβ1-42-exposed SH-SY5Y cells and primary neurons, employing interventions such as the ROS scavenger NAC, yohimbine pre-treatment, and siRNA-mediated XIAP knockdown. In vivo cognitive deficits and brain pathology were evaluated in AD model mice using Morris water maze tests and immunofluorescence staining.

RESULTS: Experimental results demonstrated that Aβ1-42 induced apoptosis in neuronal cells, while dexmedetomidine incubation significantly reduced Aβ1-42 elicited ROS generation, activated XIAP, suppressed MDM2 and ameliorated P53 overactivation, thereby effectively preventing neuronal death. Combined administration of NAC and dexmedetomidine reversed Aβ1-42-induced XIAP inhibition, ROS accumulation, and cell apoptosis. Furthermore, both yohimbine pre-treatment and XIAP knockdown effectively abrogated the ability of Dex to reduce ROS accumulation and mitigate apoptosis. In vivo results indicated that dexmedetomidine improved cognitive deficits and intervened in AD pathology in the hippocampal region of AD model mice.

CONCLUSION: This study reveals that dexmedetomidine inhibits ROS release and activates the XIAP-MDM2-p53 signaling pathway, thereby delaying apoptosis and ameliorating cognitive impairment in AD progression.},
}

@article {pmid42079210,
year = {2026},
author = {Caohuy, H and Ognoon, M and Chen, T and Yang, Q and Dib, T and Pollard, BS and Fatima, N and Flagg, T and Soni, DK and Biswas, R and Rittase, W and L'Esperance, OJ and Juliano, S and Pollard, HB},
title = {PM2.5 toxin benzo[a]pyrene induces life-limiting inflammation and oxidative stress in the airway by up-regulation of TRPC6 and inactivation of β2AR/CFTR signaling.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.21.719931},
pmid = {42079210},
issn = {2692-8205},
abstract = {BACKGROUND: Sustained exposures to high atmospheric levels of PM2.5 at population scale are associated with increased risks for pulmonary inflammatory diseases. These are marked by activation of the TRPC6 (Transient Receptor Potential Canonical type 6) calcium channel, increased reactive oxygen species (ROS) and oxidative stress. Long term exposures are associated with reduced life span, and increased incidences of cardiovascular diseases, dementia, Parkinson's and Alzheimer disease, and increased risk of autism and autism spectrum disorders. It has been proposed that the PM2.5 toxin is benzo[a]pyrene (B[a]P) that is adsorbed to the surface of the PM2.5 particle.. But the mechanism by which B[a]P might drive pulmonary inflammatory diseases, or any other of the indications above, are not known.

HYPOTHESIS: B[a]P was recently reported to bind irreversibly and destructively to the β2 Adrenergic Receptor (β2AR) in the lung. We have therefore hypothesized that B[a]P is the adsorbed PM2.5 toxin, and that β2AR is the B[a]P receptor responsible for TRPC6 activation in lung epithelial cells.

RESULTS: To test this hypothesis, we exposed a polarized organoid model of normal human lung epithelia, polarized lung epithelial 16HBE14o-cells, and tracheobronchial slice cultures from ferret lung to either PM2.5 or B[a]P. We found that both PM2.5 and B[a]P: (i) irreversibly activated of β2AR signaling via G i to PI3K/AKT; (ii) increased NFκB-activated release of proinflammatory cytokines through IKKαβ activation by PI3K/AKT, which was suppressed by the PI3K inhibitor LY 294002 (iii) desensitized and destroyed the activated β2AR receptor by endocytic recycling; (iv) also destroyed β2AR's signalplex partner CFTR by the same process; (v) activated the CFTR-bound calcium channel protein TRPC6 due to loss of inhibitory CFTR; leading to (vi) increased cytosolic [Ca [2+] ] concentration; (vii) increased ROS due to mitochondrial uncoupling; and (viii) increased expression of oxidative stress. Treatment with the TRPC6 inhibitor BI 749327 blocked steps (vi-viii), and preserved CFTR from endocytic loss. Treatment of tracheobronchial slice cultures of ferret lung with either PM2.5 or B[a]P resulted in increased secretion of IL-6, increased expression of TRPC6, and reduced expression of β2AR and CFTR. Finally, we found that exposure of lung organoids to B[a]P significantly reduced expression of the same five microRNAs (miR-126a-3p, miR-30b-5p, miR-103a-3p, miR-26a-5p, and miR-766-3p) previously identified in sera from service members exposed to PM2.5 from burn pit emissions during deployment to Iraq and Afghanistan.

CONCLUSION: PM2.5 and the PM2.5 toxin benzo[a]pyrene (B[a]P) induce inflammation and oxidative stress in the airway by increased expression of TRPC6 and inactivation of β2AR/CFTR signaling. These discoveries mark the first identification of a mechanism by which exposure to PM2.5 or the PM2.5 toxin B[a]P itself can induce inflammation and TRPC6-dependent oxidative stress in lung epithelia.},
}

@article {pmid42080000,
year = {2026},
author = {Darwish, M and Lin, N and Dirks, B and Jaworowicz, D and Maxwell, K and Pathak, S},
title = {Population pharmacokinetics of remlifanserin (ACP-204), a serotonin 2A receptor inverse agonist.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70254},
pmid = {42080000},
issn = {2352-8737},
abstract = {INTRODUCTION: Remlifanserin, or ACP-204, is a potent serotonin 2A receptor inverse agonist under investigation for treatment of Alzheimer's disease psychosis and Lewy body dementia psychosis. A population pharmacokinetics (popPK) model for remlifanserin was developed to evaluate the impact of covariates affecting pharmacokinetic variability and assess the clinical relevance of these factors in a virtual population.

METHODS: A popPK model was developed using remlifanserin plasma concentrations (n = 3935) from 209 participants across seven Phase 1 trials (10 to 180 mg, oral). Data were pooled and analyzed using non-linear mixed-effects modeling. Intrinsic (demographics, hepatic/renal function) and extrinsic (food effect) factors were assessed. Model evaluation included goodness-of-fit plots and prediction-corrected visual predictive checks (pcVPCs). Interindividual variability was estimated for key parameters; residual variability was modeled using proportional error. Simulated steady-state exposures (maximum plasma concentration at steady state [Cmax,ss] and area under the plasma concentration-time curve over the 24-h dosing interval at steady state [AUC0-24,ss]) in a virtual population (n = 1000; 60 mg/day) were derived using PK parameters sampled from the final model. The clinical relevance of significant covariates was evaluated using geometric mean ratios and 90% confidence intervals (CIs) of exposures using a 0.8 to 1.25 boundary presented in a forest plot.

RESULTS: The final popPK model was a one-compartment model with first-order absorption with lag time and linear elimination. Typical parameter estimates included apparent oral clearance (35.4 L/h), apparentoral volume of distribution (V/F) (male, 930 L; female, 799 L), absorption lag time (ALAG1) (fasted, 0.720 h; fed, 0.929 h)and absorption rate constant (Ka) (0.692/h). Goodness-of-fit plots and pcVPCs demonstrated that the model adequately captured the central tendency and magnitude of variability in remlifanserin concentrations. Statistically significant relationships were found between food and ALAG1 and between sex and V/F (P < 0.001); however, neither factor had a clinically relevant impact on Cmax,ss or AUC0-24,ss.

DISCUSSION: The pharmacokinetics of oral remlifanserin (10 to 180 mg) are well described by dose-proportional linear kinetics. No intrinsic or extrinsic factors exhibited a clinically relevant effect on steady-state remlifanserin exposures.},
}

@article {pmid42081122,
year = {2026},
author = {Dieguez Ferreira, Y and Braga Moura, C and Carneiro Rodrigues, A and Pereira Da Silva, AM and Haddad Santos, D and Fernanda Mendes, M},
title = {Causes of death in patients with dementia: A study in a geriatric hospital in São Paulo, Brazil.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261445578},
doi = {10.1177/13872877261445578},
pmid = {42081122},
issn = {1875-8908},
abstract = {BackgroundDementia contributes to morbidity and mortality in aging populations, with infectious diseases as frequent terminal events. In Brazil, data on causes of death in dementia and hospital-based end-of-life care are limited.ObjectiveTo describe causes of death, clinical characteristics, and pharmacological treatment patterns during the last month of life among patients with dementia hospitalized in a geriatric hospital in São Paulo, Brazil.MethodsThis retrospective observational study included all patients with clinically diagnosed dementia who died between 2015 and 2023 in a specialized geriatric hospital. Demographic, clinical, and pharmacological data were extracted from electronic medical records. Causes of death were classified using ICD-10 codes. Associations between dementia subtypes and infection-related deaths were evaluated using logistic regression adjusted for age, sex, and comorbidities. Statistical analyses were performed using R, with p < 0.05 considered significant.ResultsA total of 122 patients were included (mean age 83.6 ± 7.4 years; 61.5% female). Alzheimer's disease was the most frequent subtype (52.5%), followed by vascular (26.2%) and mixed dementia (21.3%). Infectious diseases accounted for 67.2% of deaths, mainly pneumonia (48.3%) and sepsis (18.9%). Antibiotics were prescribed in 76.2% of cases, and antipsychotics in 58.1%. Palliative care measures were documented in 41.0% of cases.ConclusionsInfectious diseases were the most frequent causes of death among hospitalized patients with dementia, with high antibiotic use and limited palliative care documentation. These findings indicate the need for integrated end-of-life protocols and improved recognition of palliative needs.},
}

@article {pmid42081190,
year = {2026},
author = {Liu, F and Wang, J and Kang, Y and Su, G and Wang, X},
title = {Effects of high-frequency repetitive transcranial magnetic stimulation on memory of post-stroke cognitive impairment patients: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261447431},
doi = {10.1177/13872877261447431},
pmid = {42081190},
issn = {1875-8908},
abstract = {BackgroundThere is an evident interrelationship between stroke and Alzheimer's disease (AD). Post-stroke cognitive impairment (PSCI) is a frequently encountered and potentially disabling outcome of stroke. Memory impairment is an important component of the post-stroke cognitive syndrome, and high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has been widely used for memory in patients with PSCI.ObjectiveIn this study, we systematically evaluated the therapeutic effects of HF-rTMS on memory function in patients with PSCI, offering insights that may also inform the treatment of AD.MethodsAll relevant publications in Chinese and English were systematically searched from ten databases up to March 20, 2025. Retrieved articles were carefully screened. The quality of the included studies was assessed using the Cochrane Collaboration's risk of bias tool. The Review Manager 5.4 software was adopted for meta-analysis.ResultsTwenty-one studies of 1746 participants with PSCI were included. Meta-analysis revealed that HF-rTMS ameliorated memory of PSCI patients according to several outcome indicators: Rivermead Behavioural Memory Test [mean difference (MD) = 2.59, 95% confidence interval (CI) (2.08, 3.11), p < 0.00001], forward digit span [MD = 1.79, 95% CI (1.36, 2.22), p < 0.00001] and backward digit span [MD = 1.18, 95% CI (0.77, 1.59), p < 0.00001] of digit span test, Delayed Recall of the Montreal Cognitive Assessment [MD = 0.53, 95% CI (0.47, 0.59), p < 0.00001]; all p < 0.05.ConclusionsThe HF-rTMS might enhance memory in patients with PSCI, with the left dorsolateral prefrontal cortex being the most common stimulation site.},
}

@article {pmid42081371,
year = {2026},
author = {Gawor, K and Statz, K and Schaeverbeke, J and Thal, DR},
title = {Alzheimer's disease subtyping approaches and the role of co-pathologies.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag157},
pmid = {42081371},
issn = {1460-2156},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β plaques and abnormal phosphorylated tau protein-containing neurofibrillary tangles, yet it shows marked heterogeneity in clinical presentation, neuroanatomical involvement, and progression rate. This variability challenges the traditional view of AD as a single disease entity and has prompted efforts to define patient subgroups with shared characteristics who might benefit from targeted treatment strategies. Here, we provide a cross-disciplinary overview of current subtyping strategies. We describe both traditional stratification approaches, including those based on clinical AD syndromes, neuropathological staging, and age of onset, as well as emerging data-driven methods that utilize clinical information, neuroimaging, omics data, and multimodal data integration. Subtypes derived using these data-driven methods overlap to some extent with hypothesis-driven classifications but also uncover additional axes of heterogeneity, including distinct anatomical patterns and molecular signatures. Furthermore, we highlight that most AD patients exhibit co-pathologies such as transactive response DNA-binding protein 43, α-synuclein, or cerebrovascular changes, which are often overlooked in existing stratification systems, despite their potential to affect atrophy patterns and progression rate and, hence, influence subtype interpretation. Finally, we outline future directions for developing unified stratification frameworks that link clinical features with underlying biology, including co-pathologies, aiming to enhance diagnostic precision and enable future personalized therapeutic interventions.},
}

@article {pmid42082123,
year = {2026},
author = {Fan, YH and Fan, KS and Lin, TL},
title = {Reduced dementia risk in middle-aged and older atopic dermatitis patients treated with dupilumab: A target trial emulation.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106796},
doi = {10.1016/j.bbi.2026.106796},
pmid = {42082123},
issn = {1090-2139},
abstract = {BACKGROUND: Middle-aged and older adults with atopic dermatitis (AD) are at increased risk of dementia, possibly driven by chronic inflammation and involving IL-4 and IL-13 pathways. Whether treatment with dupilumab, an IL-4/IL-13 inhibitor, influences subsequent dementia risk in this population remains unclear.

METHODS: This target trial emulation study utilized the TriNetX database. Patients aged ≥ 50 years with AD were identified and divided into two groups: those newly prescribed dupilumab and those newly prescribed conventional systemic agents without dupilumab exposure. Propensity score matching (1:1) was performed based on age, sex, race, and comorbidities. Dementia risk was assessed using Cox regression.

RESULTS: After matching, each group included 10,039 patients (∼52% female; mean age, 63 years; 63% White). The 5-year cumulative incidence of dementia was lower among dupilumab users than controls (2.37% vs 3.33%; P = 0.001). Dupilumab use was associated with a reduced risk of all-cause dementia (HR 0.68; 95% CI, 0.54-0.86), with similar reductions observed across dementia subtypes, including secondary (HR 0.69; 95% CI, 0.48-0.99), unspecified (HR 0.70; 95% CI, 0.53-0.93), and Alzheimer's dementia (HR 0.61; 95% CI, 0.40-0.93). Subgroup and sensitivity analyses showed consistent results, with control outcome analyses supporting the robustness of the findings. In a validation analysis of middle-aged and older asthma patients, dupilumab users likewise had a lower dementia risk than omalizumab users (HR 0.68; 95% CI, 0.47-0.98).

CONCLUSIONS: Dupilumab use was associated with a reduced risk of dementia in middle-aged and older adults with AD compared with conventional systemic agents.},
}

@article {pmid42067018,
year = {2026},
author = {Belavadi, S and Kadiri, SK},
title = {From Pathology to Precision Therapy: Contemporary and Emerging Strategies in Alzheimer's Disease Treatment.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178913},
doi = {10.1016/j.ejphar.2026.178913},
pmid = {42067018},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by dementia, confusion, irritability, a lack of cognition, and mood swings. Since its discovery in 1906, many small molecules have been designed to block disease progression by targeting the primary targets β-amyloid and tau proteins. Subsequent research focused on small-molecule inhibitors targeting secondary targets, such as β-secretases and γ-secretases. However, the clinically approved conventional therapies include acetylcholinesterase inhibitors and N-methyl-D-aspartate inhibitors that relieve only disease symptoms, and their efficacy remains limited. Recently, approved novel approaches, such as monoclonal antibodies and vaccines, aim to slow disease progression by targeting the molecular mechanisms underlying amyloid and tau proteins. In addition, these drugs have controversial side effects, which call into question their therapeutic efficacy. A newer strategy involving small peptides is gaining traction because of their lower toxicity, improved permeability, and target specificity. Various homogenous and heterogeneous peptidomimetic inhibitors have been designed to target traditional protein targets. Although various peptidomimetic inhibitors have demonstrated therapeutic efficacy, none have entered clinical trials. Upon conducting an extensive literature survey, we identified several regions, targets, and technologies that could be leveraged to ameliorate Alzheimer's disease progression. In this review, we address the progression of AD, its historical context, and the development of therapeutic approaches that target this disease. We focus on the evolution of subsequent therapies aimed at alleviating the disease and highlight recent developments in drug delivery and formulation techniques that enhance therapeutic efficacy and address the shortcomings of traditional treatments.},
}

@article {pmid42067052,
year = {2026},
author = {Darzi, M and Golchoobian, R and Varzi, HN and Shanehbandpour Tabari, F},
title = {Metformin attenuates neurodegeneration in ICV-STZ-induced Alzheimer's model via antioxidant and anti-inflammatory mechanisms: implications for disease-modifying therapy.},
journal = {Neuroscience letters},
volume = {880},
number = {},
pages = {138617},
doi = {10.1016/j.neulet.2026.138617},
pmid = {42067052},
issn = {1872-7972},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, accounting for over 60% of cases in older adults. Growing evidence suggests that metformin, a first-line antidiabetic drug, may have neuroprotective properties. This study evaluated metformin's effects in a streptozotocin (STZ)-induced rat model of sporadic AD. Thirty-two male rats were divided into four groups (n = 8/group): Sham, STZ, Metformin, and Metformin + STZ. The AD model was established via bilateral intracerebroventricular STZ injections (3 mg/kg) on days 61 and 63, with metformin administered in drinking water (2 mg/mL) for 82 days. Metformin treatment significantly enhanced hippocampal catalase activity while reducing malondialdehyde (MDA) and total oxidative status (TOS) levels in both brain and serum. Notably, it selectively decreased hippocampal IL-1β without affecting serum levels, suggesting central-specific anti-inflammatory effects. These findings demonstrate metformin's dual antioxidant and anti-inflammatory actions in an AD model, supporting its potential as a disease-modifying therapy. The dissociation between central and peripheral IL-1β responses highlights the importance of blood-brain barrier considerations in AD treatment strategies.},
}

@article {pmid42067300,
year = {2026},
author = {Wu, H and Chai, C and Islam, MS and Sheng, S and Xie, G and Chen, T},
title = {An aptamer-mediated EXPAR fluorescence biosensor for early and sensitive detection of Aβ42 and Aβ40.},
journal = {Analytica chimica acta},
volume = {1406},
number = {},
pages = {345513},
doi = {10.1016/j.aca.2026.345513},
pmid = {42067300},
issn = {1873-4324},
mesh = {*Amyloid beta-Peptides/blood/analysis ; *Biosensing Techniques/methods ; *Aptamers, Nucleotide/chemistry ; Humans ; *Peptide Fragments/blood/analysis ; Limit of Detection ; Alzheimer Disease/blood/diagnosis ; Fluorescence ; Fluorescent Dyes/chemistry ; SELEX Aptamer Technique ; Spectrometry, Fluorescence ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder with increasing cases worldwide. Early screening is important for AD prevention and treatment, but current methods still face many challenges.

RESULTS: To address these challenges, we developed a simple and novel molecular beacon (MB) fluorescent biosensor. This sensor combines aptamers with exponential amplification reaction (EXPAR). Through special design of the EXPAR templates, the sensor achieves triple signal amplification. It showed a limit of detection (LOD) of 110 fM for Aβ42 and 300 fM for Aβ40, exhibits high sensitivity. The coefficient of variation (CV) for detecting different target concentrations ranged from 4.42% to 8.85%, showing good repeatability. We also applied this sensor to detect these biomarkers in plasma samples from AD patients. The spike recovery rates were 104.67%-109.3% for Aβ42 and 104.2%-106.93% for Aβ40, demonstrating strong resistance to plasma matrix interference. Due to the specificity of aptamers and nucleic acid design, this method allows simultaneous detection of multiple targets (e.g., Aβ42, Aβ40) in the same system, improving detection efficiency and reliability in complex samples.

SIGNIFICANCE: Compared with traditional Aβ detection methods such as ELISA and colorimetry, our method shows 10-10[4] times higher sensitivity. Compared with emerging techniques like electrochemical detection and single-molecule array, our sensor has the advantages of stronger resistance to plasma matrix interference, more stable results, lower cost and biotoxicity, simpler operation and better biocompatibility and potential of multiple-target detection. These features make it a promising tool for high-throughput early screening of AD, with potential to advance early diagnosis.},
}

*Amyloid beta-Peptides/blood/analysis
*Biosensing Techniques/methods
*Aptamers, Nucleotide/chemistry
Humans
*Peptide Fragments/blood/analysis
Limit of Detection
Alzheimer Disease/blood/diagnosis
Fluorescence
Fluorescent Dyes/chemistry
SELEX Aptamer Technique
Spectrometry, Fluorescence

@article {pmid42067950,
year = {2026},
author = {Allouche, A and Colin, J and Birck, C and Schroeder, H and Tallandier, V and Baldoni, M and Muller, C and Afrassi, M and Violle, N},
title = {Aging alters the vulnerability pattern to amyloid-beta oligomers in wild-type mice: a behavioral and neurobiological study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02051-2},
pmid = {42067950},
issn = {1758-9193},
abstract = {BACKGROUND: Aging is the primary risk factor for sporadic Alzheimer's disease (AD). While amyloid-beta oligomers (AβOs) accumulation is a key neuropathological process in AD, their specific effects in aged brains and how aging modulates brain response to AβOs remains poorly understood. We investigated how aging contributes to AβO-induced neurotoxicity and cognitive deficits in mice.

METHODS: After biochemical and in vitro characterizations on primary cultures of cortical neurons, AβOs or their vehicle were intracerebrally injected into both 3- and 18-month-old wild-type mice. A broad spectrum of assays including synaptic markers, neuroinflammation, apoptosis and cognitive functions was used to establish a preliminary characterization of the interplay between age and AβOs. In vivo data were analyzed using a multifactorial design (Treatment × Age), with two-way ANOVA or other appropriate statistical models.

RESULTS: Old mice had significantly reduced synaptic proteins SNAP-25 and PSD-95, elevated neuroinflammatory markers, and increased neuronal apoptosis in hippocampus and cortex, despite showing cognitive performances similar to young mice. All brain biomarkers were worsened after AβO injection in both young and old mice. Age and AβO effects either accumulated or interacted to promote neuroinflammation and apoptosis, depending on brain areas, whereas their effects on synaptic proteins were strictly additive. Moreover, AβO injection induced only mild spatial memory deficits in young mice, in contrast with those observed in old mice in both episodic and spatial memory tests.

DISCUSSION: Whereas the young brain showed resilience to maintain memory performances after AβO injection, the coping capacities of the aging brain were exceeded by AβO effects. At the neurobiological level, age and AβO effects were mainly additive, but also acted synergistically in a brain region-dependent vulnerability pattern. This study highlights the value of incorporating aging into preclinical models to improve their translational validity and enhance their relevance for drug testing targeting early stages of sporadic AD.},
}

@article {pmid41872793,
year = {2026},
author = {Yang, A and Hu, B and Ye, M and Zhang, X and Yu, W and Yin, J},
title = {A mobile app (mWITH ME) for family caregivers of persons living with Alzheimer's disease: development and initial evaluation.},
journal = {BMC medical informatics and decision making},
volume = {26},
number = {1},
pages = {},
pmid = {41872793},
issn = {1472-6947},
support = {No.20AC003//the National Social Science Foundation of China/ ; },
abstract = {BACKGROUND: The rising global aging population has increased the prevalence of Alzheimer’s disease (AD), a condition with limited treatment options, making non-pharmacological interventions essential. While mobile health apps are increasingly common, there is currently a lack of theory-based, user-centered research to support the development of mobile health apps for family caregivers of persons living with AD.

OBJECTIVE: This study aimed to design a theory-based and user-centered mobile application that supports family caregivers by leveraging non-pharmacological interventions to aid in the management and potential slowing of AD progression, with the ultimate goals of improving care quality and reducing their burden.

METHODS: The study employed a three-phase methodology: (1) Establishing a theoretical framework based on Narrative Evidence-Based Medicine and Maslow’s hierarchy of needs; (2) Conducting semi-structured interviews with target users (n = 18), with transcripts analyzed thematically to inform the app’s development by an interdisciplinary team; (3) Performing a preliminary evaluation with participants (n = 20) who used the app for three weeks, after which a questionnaire assessed its short-term impact and user-friendliness.

RESULTS: Thematic analysis yielded five key themes: Content, Platform, Functionality, Interactivity, and Interface. The mWITH ME app consists of four modules: educational support, professional support, peer support, and health monitoring. In the preliminary evaluation, 75% (n = 15) of participants reported that using the app reduced their daily caregiving burden, 80% (n = 16) expressed satisfaction with the application, and 70% (n = 14) acknowledged its role in improving care quality. The modules for Educational, Professional, and Peer Support received particularly positive feedback, which aligns with the app’s underlying theoretical framework of Narrative Evidence-Based Medicine and Maslow’s hierarchy of needs. Nonetheless, the Health Monitoring module was identified as requiring further enhancements to better meet user expectations.

CONCLUSIONS: The mWITH ME app demonstrates feasibility in supporting family caregivers by addressing their professional, educational, and emotional needs. Future work should focus on developing features for mood and fatigue monitoring, while long-term studies are needed to evaluate its integration into standard care pathways and its potential to improve the quality of life for both the caregivers and persons living with AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12911-026-03456-7.},
}

@article {pmid42066770,
year = {2026},
author = {Xie, J and Dai, XJ and Li, Q and Zhang, W and Nie, X and Ji, H and Chen, X and Wang, Y and Feng, J and Li, Z and Liu, Q and Ye, J and Zhang, G and Nie, S},
title = {Escherichia coli Nissle 1917 alleviates Alzheimer's disease in mice through OmpA-containing outer membrane vesicles.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102781},
doi = {10.1016/j.xcrm.2026.102781},
pmid = {42066770},
issn = {2666-3791},
abstract = {Gut microbiota dysbiosis is a driving factor in Alzheimer's disease (AD), yet the mechanisms behind remain elusive. Emerging evidence highlights that outer membrane vesicles (OMVs) are critical mediators of microbiota-host communication. Here, we observed a reduction in a gut probiotic Escherichia coli Nissle 1917 (EcN)-like strain in AD patients, and its levels are positively associated with cognitive ability. The EcN OMVs containing outer membrane protein A (OmpA) translocate to the brain, reshaping the dysregulated immune network. Specifically, EcN OMVs are internalized by glia and neurons, suppressing glial hyperactivation and restoring synaptic function, thereby reducing Aβ deposition and cognitive deficits. The results further show that OmpA plays an important role in vesicle trafficking and inflammatory pathways and may be the key regulator of inflammatory mediators in EcN OMVs, modulating astrocyte-microglia-neuron interactions and functionality. This work discloses the substantial therapeutic potential of the probiotic and its secreted OMVs in intervention and treatment of neurological disorders.},
}

@article {pmid42059045,
year = {2026},
author = {Xie, K and Jiang, Y and Chen, T and Liu, S and Fang, Y and Chen, F and Shen, J and Zeng, X and Li, P and Qiu, T and Wang, J and Yu, L and Zang, X and Wang, N and Yuan, J and Pang, H and Zhang, W and Ni, Z and Gu, L and Guo, Y and Lu, R},
title = {A prospective, randomized, double-blind, placebo-controlled, multicenter study of thiamin plus folic acid in the treatment of cognitive impairment in patients undergoing maintenance hemodialysis.},
journal = {Renal failure},
volume = {48},
number = {1},
pages = {2658981},
doi = {10.1080/0886022X.2026.2658981},
pmid = {42059045},
issn = {1525-6049},
mesh = {Humans ; *Thiamine/administration & dosage/therapeutic use/blood/adverse effects ; *Folic Acid/administration & dosage/therapeutic use/blood/adverse effects ; Female ; Male ; Double-Blind Method ; *Renal Dialysis/adverse effects ; Middle Aged ; *Cognitive Dysfunction/drug therapy/etiology/blood ; Prospective Studies ; Adult ; Aged ; Treatment Outcome ; *Kidney Failure, Chronic/therapy/complications ; Vitamin B Complex ; Young Adult ; Homocysteine/blood ; Adolescent ; },
abstract = {This prospective, randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of thiamin and folic acid for cognitive impairment in maintenance hemodialysis (MHD) patients. A total of 215 MHD patients aged 18-75 with cognitive impairment were randomized to receive either oral thiamin (90 mg/day) plus folic acid (30 mg/day) or a placebo for 96 weeks. The primary endpoint was the change in the Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-Cog) score. After 96 weeks, the treatment group showed a significant improvement in ADAS-Cog scores (from 21.25 ± 9.2 to 15.07 ± 8.38, p < 0.001), whereas the placebo group showed a non‑significant improvement (from 24.53 ± 11.01 to 26.53 ± 14.43, p = 0.077). The treatment group also demonstrated significantly increased blood levels of thiamin (from 5.59 ± 0.95 to 18.21 ± 3.91 ng/mL) and folate (from 12.37 ± 4.62 to 63.33 ± 16.02 ng/mL), and a reduction in homocysteine levels (from 4709.06 ± 353.15 to 2962.68 ± 158.87 ng/mL, p < 0.001), with no significant changes in the placebo group. While mortality was similar between the two groups (12.1% vs. 12.0%, p = 0.978), the incidence of adverse events was significantly lower in the treatment group (31.8% vs. 62.0%, p = 0.0017), particularly cardiovascular and cerebrovascular events (13.1% vs. 25.9%, p = 0.001). The study concludes that combined thiamin and folic acid supplementation improves cognitive function in MHD patients with a favorable safety profile.},
}

Humans
*Thiamine/administration & dosage/therapeutic use/blood/adverse effects
*Folic Acid/administration & dosage/therapeutic use/blood/adverse effects
Female
Male
Double-Blind Method
*Renal Dialysis/adverse effects
Middle Aged
*Cognitive Dysfunction/drug therapy/etiology/blood
Prospective Studies
Adult
Aged
Treatment Outcome
*Kidney Failure, Chronic/therapy/complications
Vitamin B Complex
Young Adult
Homocysteine/blood
Adolescent

@article {pmid42060857,
year = {2026},
author = {Mitchell, B and Harkess-Murphy, E and Douglas-Smith, N and Cheyne, J},
title = {Touch-Based Therapies in Dementia Care: A Systematic Review and Narrative Synthesis.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261445473},
doi = {10.1177/14713012261445473},
pmid = {42060857},
issn = {1741-2684},
abstract = {Touch-based therapies (massage, acupressure, reflexology/shiatsu, and therapeutic/healing touch) are used in dementia care, but effectiveness remains uncertain. The authors evaluated their impact on behavioural and psychological symptoms of dementia (BPSD) and pain, and extracted pragmatic "dose" and delivery parameters to inform a research blueprint. The authors searched major databases (MEDLINE, CINAHL, PsycINFO, Embase, CENTRAL) for studies from January 2005 to February 2023 involving people with any dementia aetiology/severity in community, residential, or inpatient settings. Eligible designs included randomised, quasi-experimental, and pre-post studies with a comparator (usual care, attention/quiet presence, or sham/light-touch). Data were extracted to a prespecified template; study quality was appraised using CASP tools. Owing to substantial clinical and methodological heterogeneity, the authors conducted a structured narrative synthesis as opposed to meta-analysis. Thirty-three studies met inclusion: 21 massage, 8 acupressure, 3 therapeutic/healing touch, and 2 reflexology/shiatsu. Most were in long-term care or inpatient settings. Interventions typically used brief, repeated sessions (5-20 minutes, several times per week for 2-6 weeks). The most consistent finding was short-term calming, particularly reductions in agitation immediately post-session or over brief treatment courses, with the clearest pattern for massage and acupressure. Effects on broader neuropsychiatric symptoms (e.g., NPI/NPI-NH domains) and pain were mixed. Where monitored, no serious adverse events were reported; minor transient issues (e.g., brief restlessness, skin sensitivity with aromatherapy oils) were infrequent and acceptability generally high. Risk of bias was mixed (≈49% low, 42% moderate, 9% high), and durability beyond 4-8 weeks was rarely assessed. Current evidence provides preliminary indications that brief, touch-based therapies may offer short-term calming effects when used alongside person-centred care, although certainty remains low and findings should be interpreted cautiously. The authors propose a pragmatic research blueprint that predefines session length, frequency, and course duration; uses attention/sham controls; adopts core outcomes (e.g., Cohen Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory/Neuropsychiatric Inventory adapted for Nursing Homes (NPI/NPI-NH); Pain Assessment in Advanced Dementia (PAINAD) where relevant); ensures blinded assessment; and extends follow-up. The authors recommend that future work should prioritise feasibility/pilot studies, followed by adequately powered trials to determine effectiveness, durability, and scalability for practice.},
}

@article {pmid42060990,
year = {2026},
author = {Hsu, YH and Liang, CK and Chou, MY and Davidson, J and Wang, YC and Nalls, MA and Ferrucci, L and Cookson, M and Iwaki, H},
title = {Amyloid pathology and modifiable risk factors in cognitive decline among cognitively unimpaired older adults.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100574},
doi = {10.1016/j.tjpad.2026.100574},
pmid = {42060990},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) pathology, particularly amyloid-β (Aβ) deposition, occurs years before clinical symptoms. Modifiable risk factors may influence cognitive trajectories during this preclinical stage, but whether amyloid status alters their effects remains unclear.

OBJECTIVES: To investigate interactions between amyloid pathology and modifiable risk factors in predicting longitudinal cognitive decline among cognitively unimpaired older adults.

DESIGN AND SETTING: This study was a secondary analysis of data derived from two large multicenter longitudinal cohort studies, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study.

PARTICIPANTS: A total of 1707 cognitively unimpaired adults aged 65-85 years were included, comprising 1169 amyloid-positive participants from the A4 Study (Aβ+) and 538 amyloid-negative participants from the LEARN Study (Aβ-).

MEASUREMENTS: Cognitive function was assessed every six months using the Preclinical Alzheimer's Cognitive Composite (PACC) over a mean follow-up of 4.9 years. Eight established modifiable risk factors-low education, alcohol use, diabetes, high cholesterol, high blood pressure, obesity, depressive symptoms, and physical inactivity-were evaluated. Linear mixed-effects models were applied to examine associations between each risk factor and longitudinal PACC decline, and to test interactions with amyloid status, adjusting for demographic and genetic covariates.

RESULTS: Significant interactions between amyloid status and modifiable risk factors were observed for diabetes (adjusted β = -0.206, p = 0.032), high cholesterol (adjusted β = -0.155, p < 0.001), and physical inactivity (adjusted β = -0.161, p = 0.046), indicating combined effects rather than additive effects on cognitive decline among Aβ+ individuals. In the A4 study (Aβ+), low education, diabetes, high cholesterol, and physical inactivity were independently associated with accelerated cognitive decline, whereas obesity was linked to slower decline. In contrast, in the LEARN study (Aβ-), these associations were not statistically significant.

CONCLUSIONS: In conclusion, the significant interactions with amyloid status were observed for diabetes, high cholesterol, and physical inactivity, indicating that these risk factors were associated with faster cognitive decline specifically in Aβ+ individuals. The results suggest that consideration of amyloid status may be important when evaluating the potential role of metabolic and lifestyle risk factors in preclinical cognitive decline. In Aβ+ individuals, obesity was associated with slower cognitive decline, while low education was linked to lower baseline cognition or a reduced symptom threshold, without a significant interaction with amyloid status. Future studies should incorporate amyloid status and longitudinal biomarkers to assess whether modifying these factors can slow preclinical cognitive decline.},
}

@article {pmid42062795,
year = {2026},
author = {Li, L and Yang, M and Tao, J and Zhao, Y and Zhao, N and Sun, S},
title = {Kaempferol Improves Alzheimer's Disease by Inhibiting Neuronal Ferroptosis via Activating GPX4/AKR1C3 Signaling Pathway.},
journal = {Pharmacology research & perspectives},
volume = {14},
number = {3},
pages = {e70255},
doi = {10.1002/prp2.70255},
pmid = {42062795},
issn = {2052-1707},
support = {2022ZD050//Corps Guiding Science and Technology Projects/ ; 2025DA013//Scientific and technological research projects in key fields of the Corps/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Ferroptosis/drug effects ; *Kaempferols/pharmacology/therapeutic use ; PC12 Cells ; Rats ; Signal Transduction/drug effects ; Amyloid beta-Peptides/metabolism ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Mice ; Male ; Neurons/drug effects/metabolism ; Disease Models, Animal ; NF-E2-Related Factor 2/metabolism ; Peptide Fragments ; Mice, Inbred C57BL ; *Neuroprotective Agents/pharmacology ; Humans ; },
abstract = {Kaempferol has been shown to be beneficial in the treatment of Alzheimer's disease (AD) in animal models. However, the action mechanism remains unclear. AKR1B1 has been identified as a target of kaempferol, initially suggested by the Therapeutic Target Database, DrugBank, and PubChem, and subsequently confirmed through experimental validation. Kaempferol treatment facilitated the expression of AKR1B1 in PC12 cells exposed to Aβ1-42. Kaempferol treatment mitigated the Aβ1-42-induced increases in Fe[2+], MDA, and lipid ROS and Aβ1-42-induced decreases in GSH synthesis and SOD activity. The reduction in ferroptosis-related proteins (GPX4, NQO1, SLC7A11, AKR1C1, and AKR1C3) and the inhibition of Nrf2 nuclear translocation and Nrf2/HO-1 signaling caused by Aβ1-42 were also reversed by kaempferol. Overexpressing AKR1B1 led to decreased levels of Fe[2+], MDA, and lipid ROS, along with increased GSH synthesis and SOD activity in Aβ1-42-treated cells, although these effects were negated by Nrf2 inhibition. The upregulation of GPX4 and AKR1C3 by AKR1B1 overexpression was also reversed when Nrf2 expression was inhibited. Notably, silencing AKR1B1 counteracted the protective effects of kaempferol against Aβ1-42-induced neuronal ferroptosis. In vivo studies revealed that kaempferol improved cognitive impairments, reduced deposition of Aβ and p-Tau, and alleviated neuronal ferroptosis in the hippocampal tissues of an AD mouse model in a dose-dependent manner, effects that were diminished by inhibiting AKR1B1 expression. Following kaempferol treatment, the levels of GPX4 and AKR1C3 in the hippocampus of AD mice were found to be reduced. Overall, our findings indicate that kaempferol treatment enhances cognitive function and mitigates pathological alterations in AD mice by inhibiting neuronal ferroptosis through the activation of the Nrf2/HO-1/GPX4/AKR1C3 signaling via upregulation of AKR1B1. This research supports the need for further investigation and clinical exploration of kaempferol.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
*Ferroptosis/drug effects
*Kaempferols/pharmacology/therapeutic use
PC12 Cells
Rats
Signal Transduction/drug effects
Amyloid beta-Peptides/metabolism
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
Mice
Male
Neurons/drug effects/metabolism
Disease Models, Animal
NF-E2-Related Factor 2/metabolism
Peptide Fragments
Mice, Inbred C57BL
*Neuroprotective Agents/pharmacology
Humans

@article {pmid42063485,
year = {2026},
author = {Huang, Y and Xu, J and Fan, Z and Hu, Y and He, X and Chen, A and Liu, Y and Yin, R and Guo, J and DeKosky, ST and Jaffee, M and Zhou, M and Su, C and Wang, F and Guo, Y and Bian, J},
title = {Identifying Alzheimer's Disease Progression Subphenotypes Via a Graph-based Framework Using Electronic Health Records.},
journal = {Journal of healthcare informatics research},
volume = {},
number = {},
pages = {},
pmid = {42063485},
issn = {2509-4971},
abstract = {Understanding the heterogeneity of neurodegeneration in Alzheimer's disease (AD) and identifying distinct progression pathways is critical for improving diagnosis, treatment, prognosis, and prevention. Motivated by this need, this study aimed to identify disease progression subphenotypes among patients with mild cognitive impairment (MCI) and AD using electronic health records (EHRs). We developed a novel approach that combines a graph neural network (GNN)-based framework with time series clustering to characterize progression subphenotypes from MCI to AD. We applied the proposed framework to a real-world cohort of 2,525 patients (61.66% female; mean age 76 years), of whom 64.83% were Non-Hispanic White, 16.48% Non-Hispanic Black, 2.53% were of other races, and 10.85% were Hispanic. Our model identified four distinct progression subphenotypes, each exhibiting characteristic clinical patterns, with average MCI-to-AD progression times ranging from 805 to 1,236 days. These findings indicate that AD does not follow a uniform progression trajectory but instead manifests heterogeneous pathways, and the proposed framework provides an explainable, data-driven approach for delineating AD progression subphenotypes, offering actionable insights for healthcare informatics research and the clinical management of patients at risk for AD.},
}

@article {pmid42063523,
year = {2025},
author = {Fitri, FI and Rambe, AS and Effendy, E and Kadri, A and Prawiroharjo, P and Lubis, IND and Surbakti, KP and Amin, MM and Rusda, M and Gustianingsih, },
title = {Instrument for Assessment of Neurodegenerative Aphasia in Indonesia or Instrumen Afasia Neurodegeneratif Indonesia (IRFANI): Development and pilot study.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251366640},
pmid = {42063523},
issn = {2542-4823},
abstract = {BACKGROUND: Primary progressive aphasia (PPA) is a neurodegenerative disorder causing progressive language impairment. Early diagnosis is crucial for treatment planning, yet no standardized assessment exists for Indonesian speakers.

OBJECTIVE: This study describes the initial development of the Instrumen Afasia Neurodegeneratif Indonesia (IRFANI), focusing on test construction, content validity, and pilot testing.

METHODS: IRFANI was designed to assess syntax, motor speech, semantics, and phonology, following Gorno-Tempini et al. (2011) diagnostic criteria. The blueprint covered key domains, including confrontation naming (nouns/verbs), sentence production/comprehension, single-word comprehension, semantic association, and repetition tasks. Verbal stimuli were selected based on expert input and Indonesian word frequency lists, while custom black-and-white illustrations ensured linguistic and cultural relevance. Five neurobehavioral neurologists assessed content validity using Aiken's Content Validity Index (CVI). A pilot study was conducted with 30 participants diverse in age, sex, education, and ethnicity.

RESULTS: Expert consultations refined the test blueprint. Qualitative analysis identified ambiguous images, multiple correct answers, and unclear phrasing in naming and sentence tasks. Issues included visually similar images and ambiguous sentence structures. Quantitative validation (CVI = 0.9) confirmed strong expert agreement, with items scoring below 0.8 excluded. The pilot study demonstrated good reliability (0.923) and provided insights for further refinement.

CONCLUSIONS: IRFANI was systematically developed through expert validation, pilot testing, and iterative refinement, ensuring clarity and strong content validity. Further studies are needed to confirm its construct validity, reliability, and diagnostic accuracy.},
}

@article {pmid42065636,
year = {2026},
author = {Behler, C and Fay, M and Ramadan, S and Breakspear, M and Behler, A},
title = {Neurophysiology of brain temperature dysregulation in humans.},
journal = {Journal of neurophysiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/jn.00418.2025},
pmid = {42065636},
issn = {1522-1598},
support = {//Tour de Cure (TDC)/ ; //Mark Hughes Foundation Centre for Brain Cancer Research/ ; },
abstract = {Brain temperature, a fundamental modulator of neural function, remains dramatically understudied despite its critical role in health and disease. This review synthesizes current understanding of brain thermoregulation and its disruption in neurological conditions, addressing a significant knowledge gap in neuroscience. We examined the physiological mechanisms maintaining brain temperature homeostasis, including the interplay between cerebral blood flow, metabolism, and cerebrospinal fluid dynamics. Analysis of publication trends reveals brain temperature research is underrepresented by 7- to 37-fold compared to other brain physiological parameters, despite comparable clinical relevance. We evaluated current non-invasive measurement techniques, particularly magnetic resonance-based thermometry, highlighting advances and limitations for clinical application. The review presents evidence for distinct temperature dysregulation patterns in neurological diseases. In Alzheimer's disease, we propose a theoretical framework of early-stage hyperthermia driven by neuroinflammation and hypermetabolism, transitioning to late-stage hypothermia with metabolic decline. Brain tumors exhibit contrasting thermal profiles: glioblastomas frequently present as hypothermic due to necrotic cores acting as metabolic voids, while melanoma metastases show hyperthermia from sustained metabolic activity. These temperature alterations may influence disease progression through effects on protein aggregation, cellular metabolism, and neuron-glial interactions. Looking forward, brain temperature monitoring could provide biomarkers for disease staging and treatment response. Additionally, understanding thermal limits becomes urgent as climate change exposes vulnerable populations with compromised thermoregulation to extreme heat. This review establishes brain temperature as an overlooked but essential axis in neurophysiology, calling for increased research attention to address fundamental questions about thermal regulation in health and disease.},
}

@article {pmid42066672,
year = {2026},
author = {Mast, N and Bederman, I and El-Darzi, N and Pikuleva, IA},
title = {CYP46A1 activation by low-dose efavirenz uncovers the link between brain cholesterol metabolism, energetics, and vasculature.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {199},
number = {},
pages = {119470},
doi = {10.1016/j.biopha.2026.119470},
pmid = {42066672},
issn = {1950-6007},
abstract = {CYP46A1 converts cholesterol to 24-hydroxycholesterol, the principal mechanism for brain cholesterol removal and turnover. CYP46A1 can be allosterically activated with low-dose anti-HIV drug efavirenz and mitigate the manifestations of various neurologic diseases in mouse models and Niemann-Pick type C disease in humans. Yet the underlying reasons for such a broad range of efavirenz therapeutic effects are currently unknown. Here 5XFAD mice, a model of Alzheimer's disease, were treated with low-dose efavirenz, and assessed for changes in their brain proteome, acetylproteome, and metabolome. Sex-independent increases in brain levels of phosphatidylcholines, sphingomyelins, and certain amino acids were documented, and various functional enrichments were identified. The most notable related to brain energy production, vascularization, and prevention of glutamatergic overactivation. Unexpectedly, these and many other enrichments were mediated by different proteins in female and male 5XFAD mice. Efavirenz treatment of 5XFAD mice was repeated, and energy-related compounds were quantified in the brain after in vivo isotopic labeling. Cerebral vasculature was assessed as well. We found increased glycolysis branching, carbon flux through the tricarboxylic acid cycle, and use of alternative energy sources (fatty acids, ketone bodies, and amino acids). Sex-independent improvements in brain vascularization and integrity of the blood-brain barrier were also documented. Collectively, our data suggested that CYP46A1 activation by efavirenz increases brain metabolic flexibility and thereby brain energetics. This enables the increase in production of the building blocks for cellular and tissue repair and rescue of brain pathology, thus explaining the therapeutic benefits for the broad spectrum of neurologic disorders.},
}

@article {pmid39835867,
year = {2025},
author = {Rongve, A and Årsland, D and Fladby, T and Øksengård, AR and Selbæk, G},
title = {[New era in the treatment and diagnosis of Alzheimer’s disease].},
journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke},
volume = {144},
number = {1},
pages = {},
doi = {10.4045/tidsskr.24.0604},
pmid = {39835867},
issn = {0807-7096},
}

@article {pmid41653394,
year = {2026},
author = {Okuyama, C and Oishi, N and Ishizu, K and Hasegawa, H and Ito, M and Fujita, Y and Kusano, K and Okina, T and Kagawa, S and Watanabe, H and Higashi, T and Yamauchi, H and Ono, M},
title = {A new amyloid PET evaluation method using separated gray-matter histogram based on three-component model.},
journal = {Annals of nuclear medicine},
volume = {40},
number = {5},
pages = {564-574},
pmid = {41653394},
issn = {1864-6433},
support = {KAKENHI (JSPS Grant Number JP21K07635).//Japan Society for the Promotion of Science/ ; },
abstract = {OBJECTIVE: We have constructed a three-component model underlying amyloid PET accumulation and developed a new gray matter histogram evaluation method based on this model. This study aims to validate the utility of the new method compared with conventional visual and SUVR-based quantitative evaluation.

METHODS: A retrospective analysis was performed on amyloid PET/CT data from 63 participants (25 healthy volunteers, 38 patients with dementia or cognitive impairment) of previous study using [18]F-FPYBF-2. Subjects were visually classified into three groups: negative, borderline, and positive, and quantitatively evaluated using composed standardized uptake value (comSUVR) with a reference to cerebellar cortex. Histograms were generated for the whole-brain, gray matter (GM-histogram), and white matter (WM-histogram) based on probability-tissue maps. The GM-histogram was further decomposed into two Gaussian components: G1 and G2　using statistical software. Parameters of whole-brain histogram: skewness, mode-to-mean ratio (MMR), and parameters of GM-histogram: GM-kurtosis, µG2 (mean of G2), and πG2 (proportion of G2), were compared among visual groups and the correlation with comSUVR was evaluated.

RESULTS: The GM-histogram was sharply unimodal in visually negative group but showed a wide shape to bimodal patterns in visually positive cases. Visually border group showed significantly higher πG2 than negative group, and positive group showed significantly higher µG2 than border group. GM-kurtosis and µG2 showed stronger negative (p < 0.0001, R[2] = 0.7539) and positive (p < 0.0001, R[2] = 0.8589) correlations with ComSUVR, respectively than the correlations between whole-brain histogram parameters and ComSUVR.

CONCLUSION: Our proposed GM-histogram provides a visually comprehensive morphology and quantitative indicators that match conventional visual and SUVR-based assessments and may potentially detect even subtle amyloid accumulation. This method is considered promising as a complementary tool for early diagnosis and treatment monitoring of Alzheimer’s disease.},
}

@article {pmid41862963,
year = {2026},
author = {Zhang, YY and Huang, NN and Li, XH and Zuo, J and Fan, YC},
title = {Dysfunctional astrocytes regulate excitatory neurons via cell adhesion and vascular lesions in patients with Alzheimer's disease.},
journal = {Journal of translational medicine},
volume = {24},
number = {1},
pages = {},
pmid = {41862963},
issn = {1479-5876},
support = {2024CXGC010604//Key Technology Research and Development Program of Shandong Province/ ; 2021SDUCRCB006//ECCM Program of Clinical Research Centre of Shandong University/ ; },
abstract = {BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Its complex pathogenesis remains unclear, and no specific drugs are available for treatment. Current treatments focus mainly on delaying progression and managing symptoms, a situation that highlights the urgent need for deeper exploration of the pathogenic mechanisms.

METHODS: We retrieved seven datasets (GSE174367, GSE122063, GSE48350, GSE5281, GSE28146, GSE222494, and GSE221365) from the GEO database and performed multi-omics analyses at the transcriptome, single-cell transcriptome, and spatial transcriptome levels.

RESULTS: We identified significant cellular heterogeneity in the frontal cortex when comparing data from the AD group with data from the control group. The combined results of enrichment analyses at the single-cell and transcriptome levels confirmed that AD pathogenesis involves the dysregulation of multiple pathways. Further studies revealed that dysfunctional regulation of neurogenesis, neuropathic immunity, and neural signal transduction could be attributed primarily to astrocytes (ASCs). Cell communication analysis indicated that ASCs may regulate excitatory neurons (ExNs) through via cell adhesion molecule 1 (CADM1) interactions. Additionally, we identified three signature subpopulations of ASCs and a signature gene module, ADr1, as potential biomarkers. Finally, spatial transcriptome analysis revealed the spatial distributions of different cells and potential vascular lesions from AD patients, consistent with the transcriptome results.

CONCLUSION: Our integrative analysis reveals a strong association between ASC dysfunction and impaired ExNs states, potentially mediated by elevated CADM1-dependent adhesion. This interaction may represent a compensatory mechanism or a contributor to neuronal vulnerability in AD. The findings further support the presence of vascular lesions in AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-08027-y.},
}

@article {pmid41862970,
year = {2026},
author = {Gea-González, A and Valle-Pedroso, R and López-Font, I and Zetterberg, H and Blennow, K and Sáez-Valero, J and García-Ayllón, MS},
title = {Selective reduction of ADAM10 in brain and cerebrospinal fluid of Alzheimer's disease patients.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41862970},
issn = {1758-9193},
support = {CIACIF/2021/426//Conselleria of Education, Culture, Universities and Employment/ ; 2019/20110-1 and #2017/18808-5//São Paulo Research Foundation/ ; #ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C//Swedish Research Council/ ; #2017-00915 and #2022-00732//Swedish Research Council/ ; NEuroBioStand, #22HLT07//European Partnership on Metrology/ ; #FO2022-0270//Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden/ ; 860197 (MIRIADE)//H2020 Marie Skłodowska-Curie Actions/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//National Institute for Health and Care Research University College London/ ; #AF-930351, #AF-939721, #AF-968270, and #AF-994551//Swedish Alzheimer Foundation/ ; #ALZ2022-0006, #FO2024-0048-TK-130 and FO2024-0048-HK-24//Hjärnfonden/ ; #ALFGBG-965240 and #ALFGBG-1006418//ALF-agreement/ ; JPND2019-466-236//European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//Alzheimer's Association 2021 Zenith Award/ ; SG-23-1038904 QC//Alzheimer's Association 2022-2025 Grant/ ; PI22/01329//Fondo de Investigaciones Sanitarias/ ; PI24/01421//Fondo de Investigaciones Sanitarias/ ; CIAICO/2024/313//Direcció General de Ciència i Investigació, Generalitat Valenciana/ ; UGP-21-217//Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana/ ; },
abstract = {BACKGROUND: ADAM10 and ADAM17, members of the membrane-bound disintegrin metalloproteinase (ADAM) family, act as α-secretases in the non-amyloidogenic processing of the amyloid precursor protein. While alterations in ADAM10, the primary α-secretase, have been reported in Alzheimer’s disease (AD), with certain controversy between studies, ADAM17 changes remain less understood. Both enzymes display a complex pattern of expression that includes immature zymogen and mature full-length, assigned as the active form, and soluble cleaved species. We reported for the first time that ADAM10 is present in human cerebrospinal fluid (CSF), and levels of the full-length and soluble fragments decrease in samples from AD patients.

METHODS: ADAM10 and ADAM17 levels were determined in human samples from frontal cortex (Brodmann areas 9/10) from histopathologically-confirmed AD cases (n = 16) and non-dementia controls (n = 13), and in CSF from individuals with cognitive symptoms and an AD-consistent biomarker profile (n = 20) and from controls with normal biomarker parameters (n = 18). Levels were also assessed in SH-SY5Y cells differentiated to neurons, after 48 h of 3 µM Aβ42 treatment. Protein species were resolved by electrophoresis followed by quantitative fluorescent western blotting. Significant differences between AD and control groups were evaluated using Student’s unpaired t-test or the Mann–Whitney U test, as appropriate.

RESULTS: We confirm the significant reduction in levels of mature and soluble ADAM10 species in lumbar CSF of AD patients. We also validate in postmortem AD brain the decrease in mature species of ADAM10 with no change in the levels of its zymogen nor mRNA transcript, suggesting a post-translational dysregulation in the production of active protein. In contrast, ADAM17 levels remained unchanged in both brain and CSF samples, highlighting a differential regulation between these two α-secretases in AD pathology. In SH-SY5Y-differentiated neurons, treatment with Aβ42 also led to a specific reduction in mature ADAM10, implicating Aβ in the disruption of ADAM10 maturation.

CONCLUSIONS: Our study links a compromise in α-secretase to AD pathology. It demonstrates a selective reduction of the mature forms of ADAM10 in AD that may contribute to an impaired non-amyloidogenic APP processing. Aβ42 appears to be a key modulator of this dysfunction, suggesting that ADAM10 downregulation may be an early event in AD pathogenesis. The results don’t evidence any major role for ADAM17 in AD pathogenesis.},
}

@article {pmid41864901,
year = {2026},
author = {Kim, N and Kahm, SH},
title = {Association between dental implants and health outcomes in Korean patients with dementia: a retrospective cohort study.},
journal = {BMC oral health},
volume = {26},
number = {1},
pages = {},
pmid = {41864901},
issn = {1472-6831},
abstract = {BACKGROUND: Alzheimer’s disease (AD) is a growing global health concern, and emerging evidence suggests that oral health—particularly tooth loss—may be linked to cognitive decline. While implant therapy effectively restores oral function, its systemic health implications in dementia patients have not been fully investigated.

METHODS: We retrospectively analyzed 1,445 dementia patients treated at two tertiary hospitals in Korea between 2011 and 2020. Clinical data, panoramic radiographs, and laboratory biomarkers were assessed to compare systemic and oral health outcomes between implant and non-implant groups. Statistical analyses included parametric and nonparametric tests with Bonferroni post-hoc validation.

RESULTS: Baseline demographics were similar between groups. Mortality was lower in the implant group (10.6% vs. 15.6%, p = 0.014). Laboratory markers showed statistically significant but clinically modest differences in serum calcium (8.90 vs. 8.78 mg/dL) and C-reactive protein (1.94 vs. 2.17 mg/dL). Oral health outcomes were significantly superior in implant recipients, including more remaining teeth (23.4 vs. 19.7) and greater posterior occlusal support (all p < 0.05).

CONCLUSIONS: Dental implant therapy in dementia patients was associated with lower mortality and superior oral health. However, these associations likely reflect inherent selection bias and better healthcare access among implant recipients rather than direct treatment effects. Prospective longitudinal studies with neurocognitive assessments are required to confirm potential causal relationships.},
}

@article {pmid42055498,
year = {2026},
author = {Zheng, W and Zhou, Y and Lu, M and Wang, Y},
title = {Associations of obstructive sleep apnea with A/T/N biomarkers, neuroimaging abnormalities, neurodegenerative progression, and CPAP-related changes in Alzheimer's disease.},
journal = {Sleep medicine},
volume = {144},
number = {},
pages = {108975},
doi = {10.1016/j.sleep.2026.108975},
pmid = {42055498},
issn = {1878-5506},
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) has been increasingly linked to cognitive impairment and dementia, yet its relationship with core Alzheimer's disease (AD) pathology, multimodal brain injury, longitudinal neurodegenerative progression, and potential treatment responsiveness remains incompletely understood.

METHODS: Cross-sectional analyses compared amyloid/tau/neurodegeneration (A/T/N) biomarkers and multimodal neuroimaging measures between groups, including cerebrospinal fluid (CSF) biomarker quantification, amyloid positron emission tomography (PET), structural MRI, white matter imaging, the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, and choroid plexus volume, the latter two used as indirect imaging markers reflecting potential alterations in glymphatic-related fluid transport and waste-clearance pathways. Among OSA participants who initiated continuous positive airway pressure (CPAP) therapy, changes over the approximately 6-month follow-up period were compared according to adherence status.

RESULTS: Compared with patients without OSA, those with OSA showed a more adverse A/T/N biomarker profile, including lower CSF Aβ42 (528.19 ± 147.83 vs 612.37 ± 158.46 pg/mL), lower CSF Aβ42/40 ratio (0.064 ± 0.013 vs 0.071 ± 0.014), higher amyloid PET SUVR (1.38 ± 0.21 vs 1.24 ± 0.18), higher CSF p-tau181 (74.92 ± 26.15 vs 63.48 ± 21.37 pg/mL), higher plasma NfL (31.79 ± 13.27 vs 24.68 ± 10.42 pg/mL), and higher plasma GFAP (233.47 ± 104.26 vs 196.54 ± 82.71 pg/mL). Neuroimaging analyses further showed smaller hippocampal volume, greater white matter injury, a lower DTI-ALPS index (1.27 ± 0.18 vs 1.43 ± 0.19), and a larger choroid plexus volume (3291.73 ± 768.61 vs 2814.56 ± 712.48 mm[3]) in the OSA group. Longitudinally, OSA was associated with faster annual increases in NfL (2.37 vs 0.72 pg/mL/year) and GFAP (15.19 vs 4.54 pg/mL/year), as well as faster hippocampal atrophy over time. Among treated participants, CPAP adherence was associated with improved cognition (MoCA: +0.59; ADAS-Cog: -1.48) and reductions in IL-6 (-0.95 pg/mL), GFAP (-14.67 pg/mL), and NfL (-2.33 pg/mL).

CONCLUSIONS: In patients with AD, OSA was associated with a more adverse A/T/N biomarker profile, broader neuroimaging abnormalities, including altered DTI-ALPS index and choroid plexus volume as indirect imaging markers of potential glymphatic-related dysfunction, and faster neurodegenerative progression. CPAP adherence was associated with more favorable short-term trajectories, suggesting that OSA may be a clinically relevant and potentially modifiable contributor to disease burden in AD.},
}

@article {pmid42055956,
year = {2026},
author = {Ivanidze, J and Gardella, J and Olson, A and Sun, SM and Thomas, C and Wong, OL and Intorcia, B and Moirano, J and Tanavde, V and Gershon, B and Pahlajani, S and Roytman, M and Nordvig, A and Lin, M and Hamed, M and Alport, A and Salgado, M and Keil, S and O'Dwyer, E and Lantos, J and Huicochea Castellanos, S and Ebani, EJ and Agee, M and Fink, ME and Osborne, JR and Chiang, GC and Blum, S},
title = {PET-guided Assessment of Amyloid Clearance and Outcomes in a Real-World Cohort of Patients with Alzheimer Disease undergoing Anti-Amyloid Therapy.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9387},
pmid = {42055956},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Beta-amyloid (Aβ)-PET is central to confirming Alzheimer disease (AD) before treatment with anti-amyloid monoclonal antibody therapies (AAT), however its role in treatment response monitoring in routine clinical practice remains unclear. This study aimed to evaluate longitudinal Aβ-PET changes following AAT and their association with clinical and safety outcomes in a real-world cohort.

MATERIALS AND METHODS: We conducted a retrospective single-center study of patients with mild cognitive impairment (MCI) or mild dementia due to AD who underwent Aβ-PET before and after treatment with AAT (lecanemab or donanemab). Aβ-PET scans were assessed using visual interpretation and quantitative measures including Centiloid level (CL) and regional Z-scores. Treatment-related amyloid clearance (TRAC) was determined based on magnitude of CL changes (ΔCL). Associations between Aβ-PET changes and baseline Fazekas score, amyloid-related imaging abnormalities (ARIA) and APOE-ε4 carrier status were examined. Associations between ΔCL and cognitive performance from baseline to post-AAT as assessed per Mini-Mental State Examination (ΔMMSE) were examined using multivariable linear regression models incorporating baseline CL and adjusting APOE-ε4 status and occurrence of ARIA. Region-specific multivariable analyses evaluated associations between regional Z-score changes and ΔMMSE.

RESULTS: Thirty-two patients met inclusion criteria (lecanemab, N=15; donanemab, N=17). Significant Aβ reduction was observed across the cohort (median ΔCL 59.11; p < 0.001) as well as within each treatment group. Most patients meeting TRAC criteria achieved full or partial TRAC (26/29, 89.7%). Baseline Aβ burden, as well as cognitive outcomes, did not differ significantly across TRAC categories (p = 0.25). ΔCL was not significantly associated with APOE-ε4 status or ARIA occurrence. In adjusted analyses, greater global CL reduction was associated with greater MMSE improvement, particularly at lower baseline burden. Region-specific analyses demonstrated marked, highly significant decrease in Z-scores across all regions.

CONCLUSIONS: Longitudinal Aβ-PET demonstrated substantial Aβ clearance following AAT in routine clinical practice. Aβ reduction was not significantly associated with baseline Aβ burden, ARIA, APOE-ε4 status. In adjusted analyses, greater Aβ reduction was associated with greater MMSE improvement. Our findings support Aβ-PET as a sensitive biomarker of biological treatment effect, while highlighting the complexity of linking Aβ clearance to short-term cognitive outcomes.},
}

@article {pmid42056682,
year = {2026},
author = {Song, Z and Huang, X and Jannu, AJ and Johnson, TS and Zhang, J and Huang, K},
title = {Identification of Alzheimer's disease subtypes and biomarkers from human multi-omics data using subspace merging algorithm.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71292},
pmid = {42056682},
issn = {1552-5279},
support = {5U54AG065181//National Institutes of Health (NIH)/ ; R21AG075541//National Institutes of Health (NIH)/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/classification/pathology ; *Algorithms ; *Biomarkers ; Quantitative Trait Loci/genetics ; Male ; Female ; Brain/pathology/metabolism ; Aged ; Cohort Studies ; Genome-Wide Association Study ; Phenotype ; Transcriptome ; Multiomics ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a heterogeneous disease with diverse disease progression trajectories and brain pathology. Identifying AD subtypes is essential for understanding AD etiology, heterogeneity, and developing precise treatment.

METHODS: We applied a subspace-merging algorithm to integrate multi-omics data from brain tissues of three large AD cohorts and identify data-driven AD subtypes. Within each cohort, we performed multiple analyses to characterize subtype-specific biology. A Phenome-wide Association Study (PheWAS) of expression quantitative trait loci (eQTLs) targeting differentially expressed genes (DEGs) was conducted to link molecular differences to disease phenotypes.

RESULTS: We identified AD subtypes that differed in cognitive and pathological phenotypes in three cohorts. Further analyses highlighted synaptic and neurotransmission pathways, and the PheWAS revealed significant associations with disease phenotypes.

DISCUSSION: Our developed integration algorithm successfully merged different data modalities into a common subspace for patient clustering and identified data-driven subtypes. The identified transcriptomic signatures provide valuable insights into the molecular mechanisms underlying AD heterogeneity, paving the way for personalized AD treatment.},
}

Humans
*Alzheimer Disease/genetics/classification/pathology
*Algorithms
*Biomarkers
Quantitative Trait Loci/genetics
Male
Female
Brain/pathology/metabolism
Aged
Cohort Studies
Genome-Wide Association Study
Phenotype
Transcriptome
Multiomics

@article {pmid42057258,
year = {2026},
author = {Yi, Y and Jia, P and Xie, P and Peng, X and Zhu, X and Yin, S and Yan, C and Yu, G},
title = {Natural Products for Alzheimer's Disease: A New Twist Impacting Ferroptosis.},
journal = {The American journal of Chinese medicine},
volume = {},
number = {},
pages = {1-25},
doi = {10.1142/S0192415X26500266},
pmid = {42057258},
issn = {1793-6853},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Despite significant advances in AD research, effective disease-modifying therapies remain unavailable. In recent years, ferroptosis has gained increasing attention for its potential role in the pathogenesis of AD. Accumulating evidence indicates that substantial iron accumulation, dysregulation of anti-oxidant defense systems, and elevated levels of lipid peroxidation are present in the brains of AD patients. These alterations create a conducive environment for ferroptosis and are closely associated with neuronal death and cognitive dysfunction. Therefore, targeting ferroptosis-related signaling pathways holds promise as a novel strategy to delay or halt the progression of AD. Natural products, such as flavonoids, phenolic compounds, and terpenoids, have become a focus of research in the intervention of neurodegenerative diseases due to their structural diversity, broad biological activities, and relatively low toxicity. Increasing studies have demonstrated that various herbal medicines, including Rhodiola rosea, Polygala tenuifolia, Ginkgo biloba, and Poria cocos, can effectively suppress ferroptosis through multiple mechanisms. These mechanisms include scavenging free radicals, enhancing anti-oxidant capacity, modulating iron metabolism, and restoring the function of key regulators like GPX4 or system Xc[-], to thereby ameliorate AD-related neural damage. This review systematically summarizes recent advances in understanding the role of ferroptosis in AD and highlights the therapeutic potential of natural products that target ferroptotic pathways. We aim to provide theoretical support and candidate molecules for the development of novel AD treatment strategies based on ferroptosis regulation, and thus offer valuable insights for future research into new ferroptosis inhibitors.},
}

@article {pmid42057407,
year = {2026},
author = {Lee, M and Kim, M},
title = {Donepezil increases angiogenic potential in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261444020},
doi = {10.1177/13872877261444020},
pmid = {42057407},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the leading cause of dementia in the elderly. Acetylcholinesterase inhibitors are the mainstay of symptomatic treatment, and vascular dysfunction is increasingly recognized as a key contributor to AD pathophysiology. While donepezil is a standard AD treatment, its effects on the vascular system remain poorly understood despite known neurovascular interactions.ObjectiveTo investigate whether donepezil treatment influences endothelial progenitor cell (EPC) populations and differentiation capacity in patients with AD.MethodsEPCs were evaluated in healthy controls and patients with AD (n = 20 per group; N = 80 total): controls (Ctrl), patients initiating donepezil 5 mg (Dp_Start), patients receiving donepezil 5 mg for ≥6 months (Dp_5 mg), and patients escalated to 10 mg after ≥6 months of 5 mg treatment (Dp_10 mg). Peripheral blood samples were collected at baseline, 12 weeks, and 24 weeks. Circulating EPCs were quantified by flow cytometry, and EPC differentiation capacity was assessed by counting early and late EPC colony-forming units (CFUs).ResultsAt baseline, EPC differentiation capacity was reduced in AD patients compared with controls. Circulating EPC levels did not show significant changes across groups or treatment durations. In contrast, both early and late EPC CFU counts were significantly increased in AD patients receiving donepezil, particularly during the first 12 weeks of treatment. This effect was pronounced in patients initiating donepezil therapy.ConclusionsDonepezil enhanced EPC differentiation into early and late populations without altering circulating EPC levels. These findings suggest that donepezil improves EPC functional competence and vascular regenerative capacity beyond its established cognitive effects.},
}

@article {pmid42057743,
year = {2026},
author = {Radhakrishnan, A and Dutta, D and Saha, M and Venkatakrishnan, S and Kulkarni, A and Chandrachari, KP and Salins, PC and Suresh, A},
title = {Neuro-reparative potential of hyperbaric oxygen therapy in animal models of Alzheimer's and Parkinson's diseases: systematic review and meta-analysis.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/17582024.2026.2665357},
pmid = {42057743},
issn = {1758-2032},
abstract = {INTRODUCTION: This systematic review and meta-analysis explored the efficacy of Hyperbaric oxygen therapy (HBOT) in preclinical models of Alzheimer's disease (AD) and Parkinson's disease (PD).

METHODS: Data were extracted as per PRISMA guidelines using specific search criteria, with bias assessed using SYRCLE guidelines. Random-effect models were used for meta-analyses of key outcomes, and forest plots were generated. Outcomes assessed included cognitive and motor performance, neuroinflammation, oxidative stress, mitochondrial function, apoptosis, and dopaminergic neuron survival.

RESULTS: The PRISMA search yielded 8 studies (AD: 3; PD: 5) from a total of 8261 articles identified. A total of 308 animals were reported across the studies; however, 182 were included in the meta-analysis, as only animals from relevant treatment and corresponding control groups with extractable outcome data were eligible for quantitative analysis. HBOT significantly improved cognitive function (reduced escape latency, Standardized Mean Difference; SMD: -2.13), improved spatial memory, and reduced compensatory locomotor activity (decreased distance traveled, SMD: -6.94). The markers of neuroinflammation (lower TNF-α, higher IL-10), oxidative stress (SOD, MDA), mitochondrial biogenesis (SIRT1, PGC-1α, TFAM, VDAC), and anti-apoptotic markers (higher Bcl-xl, lower Bax) showed differences in post-HBO treatment. HBOT also preserved dopaminergic neurons in PD models.

CONCLUSIONS: These preclinical findings support HBOT as a potential complementary neuroprotective therapy for AD and PD, warranting further clinical validation.},
}

@article {pmid41794773,
year = {2026},
author = {Soliman, AR and Fahmy, E and Mahmoud Ahmed, R},
title = {The obesity-brain axis: a comprehensive review of neurological complications and therapeutic interventions in metabolic syndrome.},
journal = {Diabetology & metabolic syndrome},
volume = {18},
number = {1},
pages = {},
pmid = {41794773},
issn = {1758-5996},
abstract = {BACKGROUND: Obesity has emerged as a major global health issue, affecting multiple organ systems. Within the central nervous system obesity causes a series of disruptions that can significantly affect neurological function. Identifying obesity as a modifiable risk factor presents opportunities for preventive and therapeutic strategies that may significantly diminish neurological sequelae.

OBJECTIVE: This narrative review aims to summarize current evidence on how obesity contributes to different neurological diseases and focusing on biological mechanisms linking obesity to these conditions, outlines the characteristic clinical presentations of obesity-related neurological diseases across different age groups and potential therapeutic strategies.

METHODS: This narrative review integrates findings from comprehensive search of PubMed, EMBASE, and Cochrane Library to investigate how obesity and metabolic syndrome relate to a broad spectrum of neurological disorders. After screening 1,950 records, 48 studies were included supplemented by nine manually identified articles.

RESULTS: Obesity triggers a range of biological changes in the nervous system such as increased oxidative stress, persistent low‑grade inflammation, disruption of the blood–brain barrier, and impaired mitochondrial function. Together, these changes raise the risk of several neurological problems, including cognitive decline, Alzheimer’s disease, stroke, faster progression of multiple sclerosis, greater epilepsy‑related complications, transformation of episodic into chronic migraine, idiopathic intracranial hypertension, and various peripheral neuropathies. The impact of body mass index on neurological health differs across diseases and age groups with obesity in midlife representing a high risk. Lifestyle‑based strategies especially Mediterranean or ketogenic dietary patterns, regular physical activity and weight reduction show encouraging potential in reducing these neurological risks.

CONCLUSIONS: Obesity is a modifiable contributor to many neurological disorders. Identifying at‑risk individuals early and adopting healthier daily habits, following tailored diets and managing weight effectively may help lessen the neurological consequences of obesity. Continued research is essential to clarify underlying mechanisms and refine treatment strategies for different patient groups.},
}

@article {pmid41851792,
year = {2026},
author = {Zhang, JW and Li, R and Niu, YX and Liu, SY and Li, CH and Hao, XD and Wang, SH and Chen, S and Wang, FY},
title = {Clinical, neuroimaging, and biomarker profiling of four Alzheimer's disease pedigrees caused by pathogenic APP variants.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41851792},
issn = {1758-9193},
support = {82171196//the National Natural Science Foundation of China/ ; 241111313500//the Key Research and Development Program of Henan Province/ ; SBGJ202402012//the Medical Science and Technology Research Project of Henan Province/ ; },
abstract = {BACKGROUND: Current understanding of the fluid biomarker profile in early-onset Alzheimer’s disease (EOAD) associated with pathogenic APP variants remains limited. We characterized four EOAD pedigrees carrying pathogenic APP variants using clinical, neuroimaging, and biofluid biomarkers, comparing them with contemporaneous sporadic AD (SAD) to inform early detection.

METHODS: Between December 2022 and December 2024, we enrolled 206 individuals from four APP-associated families harboring the D678G, V717I, or M722K variants; 92 individuals underwent genetic testing. Based on genotype and clinical status, participants were classified into three groups: symptomatic APP variant carriers (SMC; n = 11), asymptomatic APP variant carriers (AMC; n = 19), and cognitively normal non-carriers (NC; n = 62). In addition, 60 patients with sporadic Alzheimer’s disease and an age at onset of ≤ 65 years (SAD; sporadic EOAD) were included as a comparison group for fluid biomarker analyses. All participants included in the plasma analyses underwent clinical assessments, and plasma levels of P-tau217, P-tau181, Aβ42, Aβ40, GFAP, NfL, and the Aβ42/Aβ40 ratio were quantified. Structural MRI, PET, and cerebrospinal fluid biomarkers were obtained in a subset of participants, where available. Group comparisons were performed using the Kruskal-Wallis and Mann-Whitney U tests, with false discovery rate adjustment for multiple comparisons using the Benjamini-Hochberg procedure (P_FDR). Additionally, two patients treated with lecanemab underwent longitudinal follow-up during the first 15 infusions.

RESULTS: Based on family informant reports and clinical observations, the median age at onset (AAO) among affected individuals in these pedigrees was 48.50 (44.0, 51.8) years. Plasma biomarker analyses showed that P-tau181, P-tau217, and GFAP levels were significantly higher in the SMC and SAD groups than in the AMC and NC groups (P_FDR < 0.05). Compared with the SMC group, the SAD group exhibited higher Aβ40 levels and a lower Aβ42/Aβ40 ratio (P_FDR < 0.05). Among V717I carriers, multiple biomarkers differed significantly between SMC and AMC (P_FDR < 0.05), whereas no significant differences were detected in the D678G or M722K subgroups. In addition, given the current sample size, APOE ε4 status was not associated with additional modification of plasma biomarker levels or AAO. No amyloid-related imaging abnormalities (ARIA) were observed during the lecanemab treatment period. From the pre-infusion baseline to immediately before the 15th infusion, one patient showed decreases in P-tau181 (− 5.70%), P-tau217 (− 12.23%), and GFAP (− 42.93%), accompanied by a mild improvement in cognitive performance; the other patient showed a reduction in P-tau181 (− 28.30%) but increases in GFAP (+ 36.59%) and NfL (+ 174.01%), with overall stable cognition.

CONCLUSIONS: Plasma biomarkers provide critical evidence to advance our understanding of APP variant-associated EOAD. Both APP variant-associated EOAD and sporadic EOAD showed a similar biomarker profile, with higher plasma P-tau181, P-tau217, and GFAP levels than those in AMC and NC. In contrast, the two groups exhibited divergent patterns in Aβ40 levels and the Aβ42/Aβ40 ratio. In addition, given the current sample size, APOE ε4 status was not found to have an additional modifying effect on plasma biomarkers among APP variant carriers.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02016-5.},
}

@article {pmid41851829,
year = {2026},
author = {Gupta, A and Thirugnanam, K and Bice, Z and Lowman, AK and Rarick, KR and LaViolette, PS and Pan, A and Franczak, M and Ramchandran, R},
title = {Ciliary p75 neurotrophin receptor (p75NTR) facilitates the enrichment of exogenous amyloid beta (Aβ 1-42) peptide and promotes oxidative stress in human hippocampal astrocytes.},
journal = {BMC molecular and cell biology},
volume = {27},
number = {1},
pages = {},
pmid = {41851829},
issn = {2661-8850},
support = {R33HL154254 and R01HL179583/NH/NIH HHS/United States ; NA//Brain 5K Run/ ; NA//Ryan M. Schaller Foundation/ ; R33HL154254 and R01HL179583/NH/NIH HHS/United States ; },
abstract = {UNLABELLED: Accumulation of amyloid beta 1–42 (Aβ42) peptide in the extracellular space in the brain is a major observation in Alzheimer’s Disease (AD)-related pathology. Astrocytes are known to play pivotal role in clearing the extracellular aβ peptide from the brain, and the underlying mechanism of Aβ42 peptide clearance remains underappreciated. Like other cell types in the brain, astrocytes have primary cilia, a nonmotile microtubule-based organelle. Aβ42 peptide is reported to affect cilia length or structure in multiple cell types including neurons and inhibit ciliary p75 neurotrophin receptor (p75NTR). To date, the relationship between the extracellular Aβ42 and the astrocytic cilia has not been established. In this work, using primary human hippocampal astrocytes and post-mortem brain specimens obtained from AD patients, we performed molecular, flow cytometry and imaging approaches to investigate the relationship of astrocytic cilia and extracellular Aβ42 peptide. Our data demonstrate that the exogenous Aβ42 peptide treatment in vitro, induces expression of p75NTR in astrocyte cilia in a dose-dependent fashion. We also observed the enrichment of exogenous Aβ42 peptide in the astrocyte cilia and the plasma membrane of astrocytes. In exogenous Aβ42 peptide-treated groups, we observed aberrant proliferation and cell cycle, increased oxidative stress and apoptosis. Interestingly, we observed an enrichment of astrocytic p75NTR expression in the human post-mortem AD-brain. Silencing RNA (siRNA)-mediated knockdown of p75NTR gene significantly minimized the enrichment of exogenous Aβ peptide and the oxidative stress in primary hippocampal astrocytes in vitro. These studies unravel a molecular signaling mechanism that involves Aβ42 peptide-induced p75NTR-mediated oxidative stress that affects overall astrocyte health in AD-associated pathology.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12860-026-00581-z.},
}

@article {pmid41857623,
year = {2026},
author = {Agosta, F and Cecchetti, G and Spinelli, EG and Ghirelli, A and Rugarli, G and Pisano, S and Coraglia, F and Canu, E and Castelnovo, V and Sibilla, E and Gilioli, A and Tripodi, C and Freri, F and Bianchi, A and Vezzulli, P and Calloni, S and Falini, A and Samanes Gajate, AM and Panzacchi, A and Pepe, G and Ferri, C and Chiti, A and Filippi, M},
title = {Real-world implementation of lecanemab and donanemab in an Italian memory center: a 1-year experience.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41857623},
issn = {1758-9193},
abstract = {BACKGROUND: Anti-amyloid monoclonal antibodies are entering clinical practice for early symptomatic Alzheimer’s disease (AD), but European real-world data on feasibility, safety, and biomarker monitoring remain limited. We report the first year of implementation of lecanemab and donanemab in an Italian tertiary memory center.

METHODS: We conducted a prospective observational real-world cohort study at the Center for Alzheimer’s and Related Diseases of IRCCS Ospedale San Raffaele (Milan, Italy). Twenty-nine treatment courses were administered in patients with early symptomatic AD (lecanemab, n = 9; donanemab, n = 20) under European Medicines Agency–aligned safety monitoring and risk-mitigation protocols. Given the unbalanced treatment groups, results are descriptive and not intended for direct comparison between treatments. Safety surveillance included serial magnetic resonance imaging for amyloid-related imaging abnormalities (ARIA) and systematic recording of infusion-related reactions. Biological monitoring included amyloid positron emission tomography with Centiloid quantification and plasma biomarkers (phosphorylated tau 181 and 217, glial fibrillary acidic protein, neurofilament light chain, and amyloid-β 42/40 ratio) at baseline and follow-up. Baseline comparisons and longitudinal changes were assessed using appropriate parametric or nonparametric statistical methods.

RESULTS: ARIA were infrequent. In donanemab-treated patients, mildly symptomatic ARIA-E occurred in 10% (2/20) and asymptomatic ARIA-H in 15% (3/20). In lecanemab-treated patients, asymptomatic ARIA-H occurred in 11% (1/9). Infusion-related reactions occurred in 21% (6/29) of treatment courses and were manageable with standardized premedication. Among 11 patients with six-month follow-up, amyloid burden decreased significantly (mean change − 52.4 Centiloids), and 75% of donanemab-treated patients (6/8) and 0% of lecanemab-treated patients reached amyloid positron emission tomography negativity (< 11CL). Plasma phosphorylated tau 181 and glial fibrillary acidic protein showed directional declines, consistent with expected biomarker trajectories under anti-amyloid therapy, while cognitive measures showed no significant change.

CONCLUSIONS: In a structured multidisciplinary framework, lecanemab and donanemab were feasibly implemented with a preliminary favorable early safety profile, substantial amyloid reduction, and measurable plasma biomarker changes in routine practice. This experience supports the feasibility of structured real-world pathways for deployment and monitoring of disease-modifying therapies in European memory clinics, within the limitations of a small cohort and short follow-up.},
}

@article {pmid42047940,
year = {2026},
author = {He, DL and Wu, Z and Jia, RJ and Wu, TY and Qiu, YM and Fan, YG},
title = {AS1842856 Reduces β-Amyloid Burden via Inhibiting PLA2G4A-Mediated Lysosomal Dysfunction in APP/PS1 Mice.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {4},
pages = {e70910},
pmid = {42047940},
issn = {1755-5949},
support = {82301626//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Lysosomes/drug effects/metabolism ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Mice ; *Group IV Phospholipases A2/metabolism/antagonists & inhibitors ; *Amyloid beta-Peptides/metabolism ; Presenilin-1/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics/pathology ; Disease Models, Animal ; Male ; Humans ; Mice, Inbred C57BL ; Cell Line, Tumor ; },
abstract = {AIMS: Both cytosolic phospholipase A2 (PLA2G4A)-induced lysosomal membrane disruption and glycogen synthase kinase-3α/β (GSK3α/β)-mediated lysosomal dysfunction have been implicated in neurodegeneration, with a potential regulatory relationship between these two pathways. We recently identified AS1842856 (AS) as a suppressor of GSK3α/β. This study was therefore designed to investigate whether AS mitigates Alzheimer's disease (AD) progression by targeting PLA2G4A to restore lysosomal homeostasis.

METHODS: The therapeutic potential of AS was investigated in APP/PS1 mice by analyzing cognitive function, β-amyloid (Aβ) load, and lysosomal integrity, with its mechanism of action further explored in N2a-sw cells.

RESULTS: AS treatment reduced GSK3α/β expression in both APP/PS1 mice and N2a-sw cells. This suppression led to decreased PLA2G4A levels, restoration of lysosomal membrane integrity, and enhanced lysosomal degradation of Aβ. Consequently, AS administration alleviated Aβ burden and improved cognitive function in APP/PS1 mice. Moreover, AS was found to inhibit NF-κB-mediated PLA2G4A expression. Knockdown experiments further revealed that reduced GSK3β-but not GSK3α-reproduced the suppressive effect on PLA2G4A.

CONCLUSION: Our study identified the GSK3β/NF-κB/PLA2G4A signaling axis as a novel therapeutic target in AD, and AS could inhibit this axis to mitigate Aβ pathology by promoting lysosomal degradation of Aβ.},
}

Animals
*Lysosomes/drug effects/metabolism
Mice, Transgenic
Amyloid beta-Protein Precursor/genetics
Mice
*Group IV Phospholipases A2/metabolism/antagonists & inhibitors
*Amyloid beta-Peptides/metabolism
Presenilin-1/genetics
*Alzheimer Disease/drug therapy/metabolism/genetics/pathology
Disease Models, Animal
Male
Humans
Mice, Inbred C57BL
Cell Line, Tumor

@article {pmid42049507,
year = {2026},
author = {Morello, CM and Mnatzaganian, CL and Painter, NA},
title = {Emerging and Off-Label Uses Of Glucagon-Like Peptide-1 Receptor Agonists (GLP1-RA) and Dual GIP/GLP1-RAs.},
journal = {Journal of the American Board of Family Medicine : JABFM},
volume = {39},
number = {1},
pages = {},
doi = {10.3122/jabfm.2025.250158R1},
pmid = {42049507},
issn = {1558-7118},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Diabetes Mellitus, Type 2/drug therapy ; *Off-Label Use ; *Obesity/drug therapy ; *Gastric Inhibitory Polypeptide/therapeutic use ; *Hypoglycemic Agents/therapeutic use ; },
abstract = {BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the glucagon-dependent insulinotropic polypeptide (GIP)/GLP1-RA are approved for type 2 diabetes (T2D) and obesity given their profound impact on glycemic weight management. Additional indications include reducing cardiovascular disease risk and progression of chronic kidney disease (CKD) in T2D as well as obstructive sleep apnea in patients with obesity. These enhanced effects are likely due to their pleiotropic effects, leading to decreased inflammation and other benefits. This review explored emerging evidence for uses of GLP1-RAs and GIP/GLP1-RA that have been researched but not yet approved. Clinicians may use this information to guide treatment decisions.

REVIEW PROCESS: PubMed and Embase literature searches were conducted using Medical Subject Heading terms. Studies referencing GLP1-RAs and GIP/GLP1-RA were included if they were published in approximately the last decade, included adults, and were either a randomized controlled trial, meta-analysis, or observational study. Of 319 articles reviewed, 27 met inclusion criteria.

EMERGING AND COMPELLING USES: Initial positive impacts have been noted for the following conditions: liver disease/liver transplant, CKD/kidney transplant, Alzheimer's disease, Parkinson's disease, substance use disorders, osteoarthritis, rheumatoid arthritis, psoriasis, COVID-19 virus, asthma, chronic obstructive pulmonary disorder, polycystic ovarian syndrome, and short bowel syndrome.

CONSIDERATIONS: Large randomized controlled trials may lead to approvals of these conditions and are encouraged. Safety and adverse effects of these medications must be assessed when initiating or modifying doses.

CONCLUSION: GLP1-RAs and GIP/GLP1-RA have demonstrated early benefits to several conditions beyond their current approved indications. Clinicians can use this information to determine treatment options for patients, particularly in those with T2D, cardiovascular disease, and/or obesity.},
}

Humans
*Glucagon-Like Peptide-1 Receptor Agonists
*Diabetes Mellitus, Type 2/drug therapy
*Off-Label Use
*Obesity/drug therapy
*Gastric Inhibitory Polypeptide/therapeutic use
*Hypoglycemic Agents/therapeutic use

@article {pmid42051019,
year = {2026},
author = {Hacımüftüoğlu, A and Saraçoğlu, N and Saffour, S and Abad, N and Kesgun, Y and Zegheb, N and Gundeger, E and Yeşilyurt, F and Ateş, MN and Bati-Ayaz, G and Altunlu, Ö and Çınar, B and Yörük, MA and Okkay, U and Özkaraca, M and Ateş, O and Taghizadehghalehjoughi, A and Lafzi, F and Türkez, H},
title = {Multi-Target Neuroprotective Compound Exhibits EAAT2-Modulating and Alzheimer's Pathology-Attenuating Effects in In Vitro and In Vivo Models.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00873},
pmid = {42051019},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by cognitive decline and memory loss. Current treatments offer limited efficacy, necessitating the development of innovative multitarget therapeutic strategies. Here, we present N[3],N[5]-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxamide (HCM-01), a novel compound developed to target multiple neurodegenerative pathways implicated in AD. In vitro assays included MTT-based cell viability analyses performed in two complementary experimental settings: primary neuronal cultures and astrocyte-based in vitro cell culture models exposed to glutamate. In primary hippocampal neuronal cultures, glutamate exposure induced a statistically significant reduction in cell viability compared with vehicle-treated controls, consistent with glutamate-induced excitotoxicity. Under these conditions, HCM-01 treatment resulted in a statistically significant improvement in neuronal viability, showing a greater protective effect compared with donepezil and memantine. In contrast, in astrocyte-based in vitro cultures, the applied glutamate concentration did not induce overt cytotoxicity, in line with the intrinsic neuroprotective and glutamate-buffering role of astrocytes. Accordingly, astrocytic experiments were designed to assess functional modulation of glutamate-handling mechanisms rather than cell survival. Western blot analysis in C8-D1A astrocytic cells demonstrated increased expression of excitatory amino acid transporter 2 (EAAT2) following HCM-01 treatment compared with control and reference drug-treated groups, suggesting modulation of astrocyte-mediated glutamate homeostasis. In parallel, redox analyses revealed that HCM-01 improved oxidative/antioxidative balance, as evidenced by increased total antioxidant capacity (TAC) and reduced total oxidant status (TOS), supporting an indirect antioxidant contribution to its functional effects. In vivo behavioral assessment of HCM-01 in a streptozotocin (STZ)-induced Alzheimer's model in female Sprague-Dawley rats demonstrated that administration of HCM-01 at doses of 50 mg/kg orally (oral, P.O. and intraperitoneal, I.P.) and 100 mg/kg (P.O.), significantly improved cognitive and memory functions in the passive avoidance (PA), Morris water maze (MWM), and locomotor activity tests. Moreover, histopathological and immunohistochemical analyses of different hippocampal regions revealed reduced neuronal damage, attenuation of tau pathology, antiamyloidogenic effect, and restoration of cholinergic function. Complementary in silico studies, including molecular docking, molecular dynamics simulations (MDS), and free energy calculations, suggested potential interactions of HCM-01 with the allosteric site of EAAT2. Taken together, these findings suggest that HCM-01 exerts neuroprotective effects against glutamate-induced excitotoxicity in primary hippocampal neurons while additionally modulating glutamatergic homeostasis and redox balance through functional mechanisms in astrocyte-based models, supporting its relevance as a multitarget preclinical candidate for early stage AD mechanisms.},
}

@article {pmid42051092,
year = {2026},
author = {Sun, Y and Chan, TW and Liao, W and Li, M and Mao, X and Feng, Y and Rong, J and Zhao, J},
title = {In Silico Design and Evaluation of Diosmin Analogs for Targeting Peroxisome Proliferator-activated Receptor γ (PPAR-γ) Against Alzheimer's Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X453424260218065734},
pmid = {42051092},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressively declining cognitive abilities and memory impairment. This disease increasingly challenges the quality of life and health of the elderly population, underscoring the need for effective therapeutic strategies. The existing anti-AD medications are designed to improve symptoms but not to cure the disease. Novel drugs are urgently needed to target the specific mechanisms that mediate disease progression. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a potential target for the development of anti-AD therapies. Through virtual screening of natural PPAR-γ ligands, the flavonoid diosmin was found to bind to PPAR-γ with high potency. This study exploited diosmin as a lead compound to design a panel of diosmin analogs via chemical modifications for better biological efficacy in targeting PPAR-γ. These diosmin analogs were evaluated using in silico approaches, including molecular docking, absorption, distribution, metabolism, and excretion (ADME) predictions, and molecular dynamics (MD) simulations. As a result, molecular docking identified 12 di-osmin analogs with better binding affinity to PPAR-γ compared with diosmin. ADME and MD analyses demonstrated that S1DhP1 exhibited lower binding free energy, better water solubility, and stability than diosmin. Thus, this study provides important information via in silico approaches and hypotheses, suggesting S1DhP1 as a promising PPAR-γ agonist for the treatment of AD that warrants further experimental validation.},
}

@article {pmid42051629,
year = {2026},
author = {Cullins, MJ and Converse, AK and Rowe, LM and Hoerst, AG and Hibbard, WK and Russell, JA and Connor, NP and Ciucci, MR},
title = {Oropharyngeal dysphagia and amyloid beta pathology in the TgF344-AD rat model of Alzheimer's disease.},
journal = {Frontiers in behavioral neuroscience},
volume = {20},
number = {},
pages = {1812480},
pmid = {42051629},
issn = {1662-5153},
abstract = {INTRODUCTION: Dysphagia is a major consequence of Alzheimer's disease (AD) that is understudied and undertreated. Neuropathology in AD occurs early in the disease progression, but little is known about pathologies underlying functional swallowing changes; this knowledge gap is a barrier to developing effective treatment. We hypothesized that an established AD rat model (TgF344-AD) would demonstrate significant deficits in oromotor/swallowing function versus Wild Type (WT) with corresponding amyloid beta pathology in brain structures critical to swallowing.

METHODS: Nine male TgF344-AD and 6 Wildtype Fisher 344 rats underwent deglutition assessments and PET imaging using the radiotracer [[11]C]PiB to assess brain and brainstem amyloid beta (Aβ) pathology at 11 months of age-a time point corresponding to early-middle stage AD progression. A priori brain regions of interest (ROIs) included those commonly associated with Aβ pathology and more specific swallowing associated structures such as brainstem nuclei and cortical motor areas. Deglutition was assessed using a videofluoroscopic swallow study and a pasta biting task.

RESULTS: Significantly increased levels of Aβ in the AD group were found in regions critical to swallowing motor control including the secondary motor area, thalamus, nucleus ambiguus, and hypoglossal nuclei. The AD group demonstrated significant changes in aerodigestive coordination, including delayed swallow onset, increased apnea duration, and increased frequency of aberrant post-swallow inhale pattern that was correlated with nucleus ambiguus Aβ levels. The AD group also exhibited altered oral processing including reduced bolus size and mastication rate.

CONCLUSION: The TgF344-AD rat model of Alzheimer's exhibits robust changes in oral processing and respiratory-swallow coordination that parallel clinical AD dysphagia. At this early-middle stage timepoint, Aβ pathology is primarily impacting cerebral swallowing networks as well as the nucleus ambiguus and hypoglossal nuclei in the brainstem. Our finding of increased Aβ in the nucleus ambiguus warrants further study as this motor nucleus plays a role in swallowing, respiration, and vocalization-all factors that are known to be impacted by AD in the clinical population.},
}

@article {pmid42052145,
year = {2026},
author = {Tariot, PN and Chumki, SR and Wang, D and Such, P and Palma, AM and Zhang, Z and Montano, CB},
title = {Brexpiprazole for Agitation in Patients with Alzheimer's Dementia with and without Co-Occurring Psychosis: Post Hoc Analysis of Short- and Long-Term Trials.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {586701},
pmid = {42052145},
issn = {1176-6328},
abstract = {PURPOSE: Patients with Alzheimer's dementia may experience co-occurring agitation and psychosis symptoms. This exploratory post hoc analysis aimed to analyze the efficacy and safety of brexpiprazole for agitation in patients with Alzheimer's dementia with and without co-occurring psychosis.

PARTICIPANTS AND METHODS: Data were pooled from two Phase 3, 12-week, randomized, double-blind, placebo-controlled, fixed-dose trials of brexpiprazole versus placebo in participants with Alzheimer's dementia and agitation, conducted in Europe, Russia, and the US (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Post hoc, participants were stratified into subgroups with or without co-occurring psychosis at baseline, defined as a score ≥4 on the Neuropsychiatric Inventory Delusions domain, Hallucinations domain, or both. Efficacy was assessed by the Cohen-Mansfield Agitation Inventory Total score. Safety was assessed by treatment-emergent adverse events (TEAEs).

RESULTS: 142/607 participants (23.4%) had co-occurring psychosis at baseline. Brexpiprazole 2 or 3 mg/day was associated with greater improvement in agitation compared with placebo in participants with co-occurring psychosis (least squares mean difference at Week 12, -9.18 [95% confidence interval -15.2 to -3.12]; P=0.004; Cohen's d=0.52) and in participants without co-occurring psychosis (-4.22 [-6.91 to -1.54]; P=0.002; Cohen's d=0.29). In participants with co-occurring psychosis, for brexpiprazole and placebo respectively, 52.9% and 40.0% had TEAEs, and 3.4% and 9.1% discontinued due to TEAEs. No deaths occurred among participants with co-occurring psychosis. In participants without co-occurring psychosis, for brexpiprazole and placebo respectively, 49.3% and 38.2% had TEAEs, and 5.5% and 2.6% discontinued due to TEAEs. Two participants without co-occurring psychosis died; neither death was considered related to brexpiprazole treatment.

CONCLUSION: In this post hoc analysis, brexpiprazole improved agitation and was generally well tolerated in patients with Alzheimer's dementia with and without co-occurring psychosis. These exploratory data suggest that brexpiprazole may be of value to patients with Alzheimer's dementia who present with agitation and psychosis in clinical practice.},
}

@article {pmid42052655,
year = {2026},
author = {Zhao, R and Guo, M and Yang, F and Yan, Y and Tian, D and Deng, L and Wang, Q and Xie, M},
title = {A microglia membrane biomimetic platinum-based MOF-loaded quercetin nanodrug delivery system for the treatment of Alzheimer's disease.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6tb00201c},
pmid = {42052655},
issn = {2050-7518},
abstract = {The aberrant deposition of β-amyloid (Aβ) is a central pathological hallmark of Alzheimer's disease (AD), triggering oxidative stress, metal ion dyshomeostasis, and excessive microglial activation in a self-perpetuating pathological cascade. To address these interconnected processes, a platinum-based metal-organic framework (Pt-MOF) with intrinsic antioxidant enzyme-mimetic activity was constructed and loaded with quercetin (Qu) to regulate microglial dysfunction. To enhance blood-brain barrier (BBB) penetration and inflammation-targeting capability, Pt-MOF/Qu was further camouflaged with microglial cell membranes (BV2), yielding Pt-MOF/Qu/BV2 nanoparticles. In vitro studies demonstrated that Pt-MOF/Qu/BV2 efficiently scavenged reactive oxygen species and effectively chelated Cu[2+] ions via surface functional groups, thereby inhibiting Aβ aggregation and promoting the disassembly of preformed Aβ aggregates. In addition, the Pt-MOF enabled efficient loading and controlled release of Qu, which significantly restored mitochondrial membrane potential and alleviated microglial over-activation. The BV2 membrane coating markedly improved the biocompatibility and BBB translocation efficiency of the nanoplatform. Furthermore, Pt-MOF/Qu/BV2 significantly reduced reactive oxygen species (ROS) in vivo and Aβ brain plaque accumulation in the head region, alleviated neurotoxicity and improved the behavioral phenotype in the C. elegans AD model. Overall, this biomimetic multifunctional MOF-based nanoplatform represents a promising multi-target therapeutic strategy for AD.},
}

@article {pmid42052761,
year = {2026},
author = {Guo, Y and Zhang, Z and Chen, B and Liu, H and Wei, F and Liu, X and Guo, Z},
title = {Functional Connectivity Alterations in the Cholinergic Neural Circuits of Patients With Alzheimer's Disease: A Donepezil Intervention Study Using Resting-State Functional Magnetic Resonance Imaging.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {50039},
doi = {10.31083/JIN50039},
pmid = {42052761},
issn = {0219-6352},
support = {2017KY109//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2020358406//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2018KY031//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2024KY873//General Project of the Department of Science and Technology of Zhejiang Province/ ; [2024]90662//National Leading Medical Specialty Development Project-Department of Geriatrics, Tongde Hospital of Zhejiang Province/ ; [2024]10//Zhejiang Provincial Alliance of Traditional Chinese Medicine Advantage Specialty for Geriatric Diseases/ ; },
mesh = {Humans ; *Donepezil/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/diagnostic imaging/physiopathology ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *Cholinesterase Inhibitors/pharmacology/administration & dosage ; *Nerve Net/diagnostic imaging/drug effects/physiopathology ; Middle Aged ; *Connectome ; *Basal Forebrain/diagnostic imaging/drug effects/physiopathology ; Longitudinal Studies ; *Nootropic Agents/pharmacology/administration & dosage ; Cerebellum/diagnostic imaging/physiopathology/drug effects ; Aged, 80 and over ; },
abstract = {BACKGROUND: Although donepezil alleviates Alzheimer's disease (AD) symptoms by raising acetylcholine levels, its impact on cholinergic pathways remains unclear. In this longitudinal, resting-state functional magnetic resonance imaging (rs-fMRI) study, we investigated donepezil-induced changes in cholinergic pathway networks in AD.

METHODS: AD patients and healthy controls (HCs) were enrolled. AD patients received 24 weeks of donepezil treatment. Cognitive and emotional symptoms were assessed using the Mini-Mental State Examination (MMSE), Cornell Scale for Depression in Dementia (CSDD), and Neuropsychiatric Inventory (NPI) pre- and post-treatment. rs-fMRI was used to examine basal forebrain (BF) functional connectivity.

RESULTS: Sixteen AD patients and 16 HCs completed the study. Post-treatment MMSE scores improved, and NPI and CSDD scores decreased. Reduced BF functional connectivity in the left cerebellar lobule VI, post-treatment, was revealed by rs-fMRI. Compared with HCs, post-treatment AD patients showed lower BF functional connectivity in the right postcentral gyrus (PoG); pre-treatment patients exhibited higher BF functional connectivity in the left cerebellar lobule VI. Right PoG functional connectivity was negatively correlated with disease duration pre-treatment and positively correlated with MMSE post-treatment.

CONCLUSIONS: Donepezil improved clinical symptoms in AD by modulating the BF-PoG cholinergic pathway.},
}

Humans
*Donepezil/pharmacology/administration & dosage
*Alzheimer Disease/drug therapy/diagnostic imaging/physiopathology
Male
Female
Magnetic Resonance Imaging
Aged
*Cholinesterase Inhibitors/pharmacology/administration & dosage
*Nerve Net/diagnostic imaging/drug effects/physiopathology
Middle Aged
*Connectome
*Basal Forebrain/diagnostic imaging/drug effects/physiopathology
Longitudinal Studies
*Nootropic Agents/pharmacology/administration & dosage
Cerebellum/diagnostic imaging/physiopathology/drug effects
Aged, 80 and over

@article {pmid42052762,
year = {2026},
author = {Balakrishnan, J and Kannan, S and Shanmugam, K and Sugasini, D},
title = {Targeting Lipid Metabolism in Alzheimer's Disease: Emerging Insights and Future Directions.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {48436},
doi = {10.31083/JIN48436},
pmid = {42052762},
issn = {0219-6352},
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/drug therapy ; *Lipid Metabolism/physiology ; Animals ; Lipidomics ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that is conventionally characterized by amyloid-β and tau pathology. There is growing evidence, however, that lipid metabolic disturbances are part of the biology of the disease, and not a secondary phenomenon. Lipid signaling controls membrane organization, amyloid precursor protein, tau phosphorylation, mitochondrial energetics, neuroinflammatory signaling, and synaptic stability. The accumulating genetic evidence, including risk variants in the APOE (apolipoprotein E), ABCA1 (ATP-binding cassette subfamily A member 1), ABCA7 (ATP-binding cassette subfamily A member 7), and TREM2 (Triggering receptor expressed on myeloid cells 2) genes, further makes lipid transport and lipid-sensing pathways central to late-onset AD vulnerability. Recent developments in lipidomics based on mass spectrometry have revealed concerted changes in phospholipids, sphingolipids, sterols, and oxidized lipid derivatives in brain tissue and peripheral biofluids. Instead of single abnormalities, directional metabolic imbalance is indicated by pathway changes, including decreased sphingomyelin-to-ceramide ratios and decreased polyunsaturated phospholipids. Co-analysis of lipidomic, genomic, and proteomic data has shown the existence of metabolically different subgroups, which aids genotype stratified risk evaluation and the lipid responder phenotype concept. Protein-centered therapies are complemented by therapeutic strategies that focus on lipid homeostasis, such as the regulation of cholesterol efflux, sphingolipid metabolism, pro-resolving lipid mediators, and metabolic reprogramming. There is also emerging evidence that implicates peroxisomal dysfunction and compromised glymphatic clearance in interfering with lipid balance. Although this field of research has come a long way, the issues of proving causality, standardizing lipidomic techniques, and converting pathway signatures into clinically useful resources persist. Restructuring AD as a lipid network instability disorder offers a systems level model of earlier diagnosis and targeted treatment.},
}

Humans
*Alzheimer Disease/metabolism/genetics/drug therapy
*Lipid Metabolism/physiology
Animals
Lipidomics

@article {pmid42052769,
year = {2026},
author = {Wang, Z and Pan, Y and Shu, M and Zou, L},
title = {The Lysosomal-Associated Protein Transmembrane Family and Neurological Disorders: Therapeutic Potential and Future Research Directions.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {47903},
doi = {10.31083/JIN47903},
pmid = {42052769},
issn = {0219-6352},
support = {82201590//National Natural Science Foundation of China/ ; 2022CFB721//Natural Science Foundation of Hubei Province/ ; ZNJC202536//The Translational Medicine, the Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University/ ; CXPY202535//Science and Technology Innovation Cultivation Fund of Zhongnan Hospital of Wuhan University/ ; },
mesh = {Humans ; *Nervous System Diseases/metabolism/therapy ; Animals ; *Membrane Proteins/metabolism ; Lysosomes/metabolism ; *Oncogene Proteins/metabolism ; },
abstract = {Lysosomal-associated protein transmembrane (LAPTM) family members-including LAPTM4A, LAPTM4B, and LAPTM5-are key regulators of lysosomal integrity, autophagy-lysosome flux, lipid metabolism, and immune responses. Dysregulation of LAPTM proteins contributes to neurological disorders such as Alzheimer's disease, Parkinson's disease, ischemic stroke, and gliomas, affecting neuronal survival, glial homeostasis, neuroinflammation, and tumor progression. In this review, we summarize recent insights into the structural features and molecular mechanisms of LAPTM proteins in the nervous system and highlight their therapeutic potential in promoting protein aggregate clearance, mitigating oxidative stress, regulating microglial polarization, and enhancing tumor immunotherapy. Future research integrating gene therapy, small-molecule modulators, multi-omics profiling, and advanced delivery platforms may enable translation of LAPTM-targeted interventions into clinical practice, offering new avenues for diagnosis, prognosis, and treatment of neurological diseases.},
}

Humans
*Nervous System Diseases/metabolism/therapy
Animals
*Membrane Proteins/metabolism
Lysosomes/metabolism
*Oncogene Proteins/metabolism

@article {pmid42053112,
year = {2026},
author = {Dharshan, SS and Madesh, S and Ramamurthy, K and Radhakrishnan, J and Salamuthu, K and Almutairi, MH and Almutairi, BO and Namasivayam, SKR and Kumaradoss, KM and Arockiaraj, J},
title = {Combating Cadmium-Induced Neurotoxicity, Oxidative Stress, and Inflammatory Pathways Using DOPA-31, a Dioxopiperidinamide Derivative in an In Vivo Zebrafish Model.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70872},
doi = {10.1002/jbt.70872},
pmid = {42053112},
issn = {1099-0461},
mesh = {Animals ; Zebrafish ; *Oxidative Stress/drug effects ; *Cadmium/toxicity ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; *Inflammation/chemically induced/metabolism/drug therapy ; *Neurotoxicity Syndromes/metabolism/drug therapy/pathology ; Antioxidants/pharmacology ; },
abstract = {Cadmium (Cd), a prevalent environmental toxin and pollutant capable of causing neurodegenerative diseases (NDs) like Alzheimer's and Parkinson's, primarily through oxidative stress, calcium imbalance, and neuroinflammation-induced mechanisms. Cd exposure increases the level of reactive oxygen species (ROS) and disrupts neurotransmitters by lowering antioxidants, leading to neuron death. Cd exposure in zebrafish results in neurodegeneration, with motor, mental, and behavioral impairments. The efficacy of the DOPA-31 intervention at varying concentrations was evaluated through the behavioral tests, biochemical assays for antioxidant enzyme activities (SOD, CAT, GSH, MDA), and histopathological analysis. Additionally, the alterations in expression levels of inflammation (tnf-α, il-1β) and neuroprotective (bdnf, syn2a) genes were also assessed. The Cd exposure exhibited the major deficits in the key behavioral parameters (motor, anxiety, and cognitive impairment). It disrupted antioxidant enzyme activity, increased lipid peroxidation, and elevated acetyl cholinesterase (AChE) activity, leading to cholinergic dysfunction. Histopathology showed extensive neuronal damage and amyloid-like protein aggregation. DOPA-31 at a 20 µM concentration, substantially exhibited antioxidant and AChE activity by reducing oxidative stress and improving motor and cognitive functions. Molecular analysis of DOPA-31 treatment showed significant downregulation of pro-inflammatory markers and upregulation of neuroprotective factors. In addition, DOPA-31 restored behavioral changes by potentially mitigating neuronal damage and protein aggregation caused by the Cd-induced neurotoxicity. This research investigation suggests the novel drug candidate DOPA-31 as a preliminary treatment for Neurodegenerative Disorder (NDD)-like features and warrants further exploration in higher animal models to assess clinical relevance.},
}

Animals
Zebrafish
*Oxidative Stress/drug effects
*Cadmium/toxicity
Disease Models, Animal
*Neuroprotective Agents/pharmacology
*Inflammation/chemically induced/metabolism/drug therapy
*Neurotoxicity Syndromes/metabolism/drug therapy/pathology
Antioxidants/pharmacology

@article {pmid42053135,
year = {2026},
author = {Arslan, B and Gobom, J and Simrén, J and Fahlén, H and Andreasson, U and Andrea Lessa Benedet, and Kvartsberg, H and Zetterberg, H},
title = {Real-world performance of Lumipulse G plasma p-tau217: a six-month experience of a specialized clinical neurochemistry laboratory.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {42053135},
issn = {1437-4331},
abstract = {OBJECTIVES: Plasma p-tau217 is a leading blood-based biomarker for Alzheimer's disease (AD), offering high diagnostic accuracy and potential utility for treatment eligibility and monitoring. However, real-world data on concordance between cerebrospinal fluid (CSF) Aβ42/40 and plasma p-tau217 in routine clinical laboratory settings remain limited.

METHODS: We retrospectively evaluated all plasma p-tau217 tests performed in the Clinical Neurochemistry Laboratory at Sahlgrenska University Hospital between August 2025 and March 2026. De-identified plasma p-tau217, additional blood biomarkers, and available CSF results were extracted from the laboratory information system. Concordance between plasma p-tau217 and CSF Aβ42/40 was evaluated by calculating positive and negative percent agreement, with CSF Aβ42/40 used as the reference standard. In addition, diagnostic accuracy for brain amyloid positivity was assessed using two predefined clinical cutoffs for plasma p-tau217 (<0.22 vs. >0.34 ng/L). Internal analytical performance was monitored over a six-month period using commercial quality control materials, with additional evaluation of lot-to-lot consistency for plasma p-tau217.

RESULTS: Among 1,352 plasma p-tau217 measurements, paired CSF Aβ42/40 data were available for 121 individuals. Based on plasma p-tau217 probability categories, 541 samples (40.0 %) were classified as low probability, 228 (16.9 %) as intermediate probability, and 583 (43.1 %) as high probability for amyloid pathology. Using CSF Aβ42/40 as the reference standard, plasma p-tau217 demonstrated a positive percent agreement of 84.5 % (95 % CI: 72.6-92.7 %) and a negative percent agreement of 87.5 % (95 % CI: 73.2-95.8 %). Internal quality control analyses showed good within-batch precision, with coefficients of variation below 7.3 %. Batch-dependent bias was observed in QC measurements, most notably for one batch (+14.4-18.4 %); however, subsequent QC investigations indicated that this deviation originated from the QC material rather than from assay-related performance. Lot-to-lot consistency assessment did not reveal systematic reagent lot-dependent effects during the study period.

CONCLUSIONS: Lumipulse plasma p-tau217 demonstrated stable analytical performance and consistent concordance with CSF Aβ42/40 in routine clinical practice. The observed agreement supports the feasibility of plasma p-tau217 as a supportive tool in the clinical evaluation of AD, while underscoring the need for continued quality control monitoring and prospective evaluation of assay performance.},
}

@article {pmid42053700,
year = {2026},
author = {Lin, C and Qi, L and Gao, X and Hu, L and Qian, B and Deng, Y and Zhou, C and Wang, C and Liu, G and Ding, Q and Lin, Z and Zhu, X and Zhang, M},
title = {Therapeutic Mechanisms of Stem Cell-Derived Exosomes for Neurological Disorders: An Overview.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42053700},
issn = {1559-1182},
support = {82271747//the National Natural Science Foundation of China/ ; 82505180//the National Natural Science Foundation of China/ ; ZY2023013//Wenzhou Major Scientific and Technological Innovation Project/ ; 2025C02081//he Zhejiang Provincial Key Research and Development Program/ ; 2025M783998//the China Postdoctoral Science Foundation/ ; },
mesh = {*Exosomes/metabolism/transplantation ; Humans ; Animals ; *Nervous System Diseases/therapy ; *Stem Cells/metabolism ; *Stem Cell Transplantation/methods ; },
abstract = {The current management of neurological disorders remains largely symptomatic. In recent years, stem cell-derived exosomes have emerged as a promising alternative therapeutic strategy. This narrative review synthesizes evidence from preclinical studies investigating the mechanisms and efficacy of exosome-based therapy for neurological conditions. The included studies encompass animal models and in vitro systems. Accumulating preclinical evidence consistently supports the therapeutic potential of stem cell-derived exosomes across several neurological disorders. In Alzheimer's disease models, stem cell-derived exosomes reduce β-amyloid plaque deposition and attenuate neuroinflammation. For Parkinson's disease, they exert neuroprotective effects on dopaminergic neurons. They also inhibit α-synuclein aggregation. In ischemic stroke and spinal cord injury, stem cell-derived exosomes promote functional recovery through multiple mechanisms. These include suppressing ferroptosis, promoting angiogenesis, and stimulating axonal regeneration. Improved delivery strategies, such as intranasal administration and hydrogel encapsulation, have further enhanced brain targeting and treatment durability. Despite these promising preclinical findings, several challenges remain. A primary issue is the lack of standardized preparation protocols. Significant uncertainties also exist regarding long-term safety. Furthermore, pathways for clinical translation are still unclear. Future research should prioritize elucidating the underlying mechanisms of exosome therapy. The refinement of targeted delivery systems is equally important. Finally, advancing rigorously designed clinical trials is crucial to facilitate the translation of these therapies into clinical practice.},
}

*Exosomes/metabolism/transplantation
Humans
Animals
*Nervous System Diseases/therapy
*Stem Cells/metabolism
*Stem Cell Transplantation/methods

@article {pmid42054332,
year = {2026},
author = {Kolmakova, KA and Lobzin, VY and Emelin, AY},
title = {[Sleep disorders in Alzheimer's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4. Vyp. 2},
pages = {56-62},
doi = {10.17116/jnevro202612604256},
pmid = {42054332},
issn = {1997-7298},
mesh = {Humans ; *Alzheimer Disease/complications/physiopathology ; *Sleep Wake Disorders/therapy/etiology/physiopathology ; Memantine/therapeutic use ; Cognitive Behavioral Therapy ; Polysomnography ; },
abstract = {This article investigates the progression of sleep disturbances in Alzheimer's disease (AD) and the mechanisms by which these disturbances may accelerate neurodegeneration. Key electrophysiological patterns identified through polysomnography in patients with AD and sleep disorders are analyzed. Therapeutic interventions are reviewed, with non-pharmacological and pharmacological approaches considered separately. The roles of cognitive behavioural therapy, relaxation techniques, and optimization of sleep conditions are emphasized. Current pharmacological treatment options are discussed, highlighting the need for careful drug selection due to the high risk of adverse effects and the potential dangers of certain medications, such as benzodiazepines and cyclopyrroles, in elderly patients with cognitive impairment. The use of memantine as a foundational therapy is given particular attention, as it may improve both cognitive function and sleep quality.},
}

Humans
*Alzheimer Disease/complications/physiopathology
*Sleep Wake Disorders/therapy/etiology/physiopathology
Memantine/therapeutic use
Cognitive Behavioral Therapy
Polysomnography