@article {pmid41863079,
year = {2026},
author = {Li, J and Guo, L and Cai, W and Mei, J and Liu, J and Liu, Y},
title = {Overcoming the blood‒brain barrier: nanomedicine strategies for targeted delivery and multimodal therapy in Alzheimer's disease.},
journal = {Drug delivery},
volume = {33},
number = {1},
pages = {2645830},
doi = {10.1080/10717544.2026.2645830},
pmid = {41863079},
issn = {1521-0464},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Blood-Brain Barrier/metabolism/drug effects ; *Nanomedicine/methods ; Animals ; *Drug Delivery Systems/methods ; Nanoparticles/chemistry ; Drug Carriers/chemistry ; Nanoparticle Drug Delivery System ; Combined Modality Therapy ; },
abstract = {Alzheimer's disease (AD) remains a significant therapeutic challenge, primarily because the formidable blood‒brain barrier (BBB), which drastically limits the brain bioavailability of most drugs. Nanoparticle-based drug delivery systems offer a promising strategy to overcome this central obstacle. This review systematically examines the design, mechanisms, and applications of nanomedicine in AD therapy. We analyze key strategies for enhancing BBB penetration through surface engineering and the utilization of various nanocarriers, including liposomes, exosomes, dendrimers, and carbon dots. Furthermore, we discuss how stimuli-responsive release mechanisms (e.g. responsive to pH, enzymes, reactive oxygen species, light, or ultrasound) enable targeted and precise drug delivery. A critical focus is placed on how these multifunctional nanoplatforms can address multiple AD pathogenic pathways simultaneously, such as amyloid-β and tau aggregation, cholinergic dysfunction, oxidative stress, neuroinflammation, and gut‒brain axis dysregulation. Although preclinical evidence is compelling, the clinical translation of these nanotherapies is hindered by challenges related to long-term biocompatibility, scalable manufacturing, patient heterogeneity, and regulatory frameworks. This review highlights the translational potential of nanomedicine in AD treatment while outlining the key hurdles that must be addressed for its successful implementation.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Blood-Brain Barrier/metabolism/drug effects
*Nanomedicine/methods
Animals
*Drug Delivery Systems/methods
Nanoparticles/chemistry
Drug Carriers/chemistry
Nanoparticle Drug Delivery System
Combined Modality Therapy

@article {pmid41863272,
year = {2026},
author = {Liang, Y and Li, M and Zhang, L and Zhu, R and He, X and Wei, Z},
title = {Akkermansia muciniphila in Central Nervous System Disorders: Mechanisms, Controversies, and Therapeutic Potential.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X419923251231071255},
pmid = {41863272},
issn = {1875-6190},
abstract = {Akkermansia muciniphila (A. muciniphila) is an intestinal mucus-dwelling mucindegrading bacterium that has recently attracted great interest due to its involvement in several metabolic diseases, including obesity, diabetes, and non-alcoholic fatty liver disease. Recent findings have indicated that A. muciniphila plays an important role in central nervous system (CNS) disorders via the microbiota-gut-brain axis (MGBA). This review highlights its dual roles in neuroprotection and pathogenesis, focusing on three key mechanisms, including immunomodulation, metabolic regulation, and barrier reinforcement. Although A. muciniphila has a beneficial role in the treatment of Alzheimer's disease, stroke, and depression, it is controversial for multiple sclerosis and Parkinson's disease because of context-dependent effects. We herein summarize recent progress in an understanding of the complex interplay between A. muciniphila and CNS disorders, highlighting that more work is needed to elucidate this relationship's causality and applicability toward treatment. Finally, we discuss the potential of A. muciniphila as a diagnostic biomarker and a target for nextgeneration probiotics in CNS disease management.},
}

@article {pmid41863273,
year = {2026},
author = {Singh, DD},
title = {PROTAC-Based Therapeutics: From Design to Clinical Potential in Neurodegenerative Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X438970260115164001},
pmid = {41863273},
issn = {1875-6190},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and ALS, are characterized by a progressive loss of neuronal function and a direct correlation between their progression and proteins with misfolded and aggregated structures. Although significant efforts have been made, and various therapies are available for their treatment, they show only a modest beneficial response to their progression. The main reasons for this phenomenon can be correlated with a loss of target specificity, low permeability in crossing the BBB, and their ineffectiveness in clearing proteins from neurons. Within this therapeutic paradigm, proteolysis-targeting chimaeras, or PROTACS, have been identified as a novel therapeutic strategy. Unlike traditional smallmolecule inhibitors, PROTACS take advantage of the natural ubiquitin proteasome system to specifically degrade target proteins. At a molecular level, PROTACS consist of a ligand that specifically recognizes a target protein, a linker, and an E3 ligand-recruiting ligand that specifically recruits an E3 ligase. At a therapeutic level, this offers the advantage of catalytic protein degradation that should allow for reduced dosing. Preclinical studies carried out using neurodegenerative disease models have shown the potential for selective targeting of major pathologic proteins, such as tau, α- synuclein, TDP-43, and mHTT, which are crucial for pathogenesis. In addition, developments in the formulation of brain-permeable PROTACS, understanding of E3 ligase expression levels in the central nervous system, and application of iPSC-derived neuronal systems have contributed to rapid developments in this area. Although pharmacokinetic modification and degradation-specific approaches are still required, evidence suggests a major therapeutic potential for PROTAC-based approaches for the treatment of neurodegenerative disorders.},
}

@article {pmid41863402,
year = {2026},
author = {van Rooij, JR and Vasilkovska, T and Van Spilbeeck, I and Van Audekerke, J and Kosten, L and Bertoglio, D and Verhoye, M},
title = {Resveratrol supplementation and caloric restriction exert sex-specific effects on cerebrovascular function in a rat model of Alzheimer's Disease.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261433498},
doi = {10.1177/0271678X261433498},
pmid = {41863402},
issn = {1559-7016},
abstract = {Cerebrovascular dysfunction, including reduced cerebral blood flow (CBF) and cerebrovascular reactivity (CVR), contributes to Alzheimer's disease (AD). Caloric restriction (CR) and resveratrol (Rsv) benefit vascular health, yet their impact on CBF and CVR in AD remains unclear. Here, we investigated the cerebrovascular effects of 40% CR or Rsv supplementation in WT and TgF344-AD rats. Using pseudo-continuous arterial spin labelling (pCASL) MRI, we observed that male Tg control (Ctrl) rats exhibited reduced relative CBF (rCBF) and absolute CBF (aCBF) in the caudate-putamen at baseline compared to WT Ctrl and Tg Rsv rats, while Rsv restored CBF to WT levels. Male Rsv rats also showed higher rCBF than CR rats in the somatosensory cortex, irrespective of genotype. In the cingulate cortex, male Tg rats had lower rCBF than WT, irrespective of treatment. During hypercapnia, Tg males displayed lower rCBF and aCBF across multiple regions, while Rsv increased rCBF in cingulate cortex and somatosensory cortex, regardless of genotype. In females, treatments did not affect baseline or hypercapnic CBF, although CR and Rsv reduced CVR compared to Ctrl. In summary, these findings suggest Rsv reverses AD-related hypoperfusion in males, whereas CR may impair cerebrovascular responsiveness in females, highlighting the need for sex-specific therapeutic strategies.},
}

@article {pmid41863469,
year = {2026},
author = {Qi, F and Chen, H and Li, S and Zhang, Y and Chen, X and Wang, A},
title = {From Mechanism to Therapy: Isoliquiritigenin as a Novel Anti-Inflammatory Agent for Inflammatory Disease Management.},
journal = {Endocrine, metabolic & immune disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715303395815250904075148},
pmid = {41863469},
issn = {2212-3873},
abstract = {INTRODUCTION: Accumulating evidence has multilaterally proved the indispensable contribution of inflammation in mediating various diseases over the last decade, including sepsis, obesity, diabetes, and neurological disorders. This established correlation between inflammation and disease progression has positioned anti-inflammatory intervention as a promising therapeutic strategy for disease prevention and treatment. Naturally occurring flavonoids have emerged as a subject of extensive investigation due to their well-documented anti-inflammatory properties and molecular mechanisms. The current review provides a comprehensive analysis of isoliquiritigenin (ISL), a bioactive flavonoid compound isolated from Glycyrrhiza glabra (licorice), with particular emphasis on its pharmacological activities and molecular mechanisms in modulating inflammation- associated disorders.

METHODS: A systematic literature review was executed across the PubMed and Google Scholar electronic databases spanning the period from January 2000 to December 2024, employing the following keyword combination: "isoliquiritigenin" (MeSH) AND "inflammation" (MeSH).

RESULTS: ISL was found to exhibit significant therapeutic potential in mitigating both acute and chronic inflammatory responses. Particular attention was devoted to elucidating ISL's multi-target regulatory mechanisms in acute organ injury models, including neurological, pulmonary, hepatic, and renal systems. Furthermore, the compound's therapeutic effects were found to extend to chronic inflammatory pathologies associated with metabolic and neurodegenerative disorders, notably diabetes mellitus, obesity-related complications, and Alzheimer's disease-associated tissue damage, particularly manifesting in ocular, pulmonary, and cardiovascular systems. Systematic characterization of ISL's molecular targets and associated signalling cascades, like MAPK, JAK/STAT3, Nrf2, and SIRT1 pathways, substantially enhanced our mechanistic understanding of its anti-inflammatory properties.

DISCUSSION: ISL demonstrated extensive protection in many inflammatory models. Its multi-target action implied broad therapeutic applicability. However, despite its excellent anti-inflammatory efficacy and safety profile, further study is required to investigate its effectiveness for clinical translation.

CONCLUSION: This comprehensive analysis has provided a pharmacological foundation for developing ISL-based therapeutic interventions against inflammation-driven human pathologies.},
}

@article {pmid41863585,
year = {2026},
author = {Yeh, PY and Liao, RM and Chang, HY and Lin, WT and Chen, YZ and Lane, HY and Lin, CH},
title = {Gender-specific effects of sodium benzoate on cognitive improvement in individuals with dementia: a meta-analysis of randomized controlled trials.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41863585},
issn = {1433-8491},
support = {NHRI-EX113-11133NI//National Health Insurance Administration/ ; NSTC 113-2622-B-039-003//National Science and Technology Council/ ; MOST 111-2314-B-182A-024 -MY3//National Science and Technology Council/ ; DMR-HHC-113-11 and DMR-113-211//China Medical University Hospital/ ; NHRI-EX111-10816NC//National Health Research Institutes/ ; CMRPG8M1311//Chang Gung Memorial Hospital/ ; },
abstract = {BACKGROUND: Previous double-blind randomized controlled trials (RCTs) have shown that sodium benzoate, a D-amino acid oxidase inhibitor enhancing D-serine availability and NMDA receptor-mediated function, is able to improve cognition in patients with cognitive decline. Accordingly, this study aimed to compare cognitive outcomes between patients receiving sodium benzoate and those receiving placebo.

METHODS: Following the PRISMA guidelines, this meta-analytic study utilized appropriate keyword strings to systematically search the PubMed, Embase, and Cochrane databases for RCTs published in all languages from inception to June 2024. Included criteria were: (1) patients aged 50 or older; (2) those diagnosed with dementia (probable Alzheimer's disease or vascular dementia) or those with mild cognitive impairment (MCI) having a clinical dementia rating score of 0.5; (3) RCTs comparing the effect of benzoate treatment with that of placebo controls; and (4) the use of cognitive tests as therapeutic effect outcomes.

RESULTS: Of 351 articles screened, five RCTs were included (246 sodium benzoate, 178 placebo; mean age 72.6 years; mean education 6.01 years; 62% female). The overall effect size for the therapeutic effect of sodium benzoate on cognitive improvement was significant (p = 0.02), with females outperforming males (p = 0.02). Additionally, regression analysis found the cognitive outcome generated from sodium benzoate was not influenced by the use of anti-dementia medication.

CONCLUSION: Our findings highlighted a better understanding of the effect of sodium benzoate on cognitive improvement, particularly in female patients with MCI and dementia.},
}

@article {pmid41863761,
year = {2026},
author = {Bhardwaj, V and Goel, F and Rajput, MS},
title = {Targeting oxidative stress and neurodegeneration: the role of Putranjiva roxburghii in Alzheimer's.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41863761},
issn = {1568-5608},
abstract = {AD is a complex neurodegenerative disease that leads to progressive memory loss, worsening cognitive abilities, and synaptic dysfunction. The pathophysiology of the disease is driven by oxidative stress and neuroinflammation, which cause neuronal damage and may facilitate amyloid-beta aggregation and tau hyperphosphorylation. Current treatment strategies provide symptomatic improvement but do not address the multifactorial causes of the disease; therefore, multi-targeted approaches are critical. Putranjiva roxburghii is a medicinal plant with a wealth of ethnomedicinal literature from India. It contains a variety of phytochemicals, including flavonoids, lignans, glycosides, and triterpenoids, that collectively exhibit antioxidant, anti-inflammatory, and neuroprotective effects. Preclinical studies suggest that it can scavenge ROS, decrease LPO, modulate cholinergic systems, and interfere with amyloid and tau pathology, supporting potential cognitive benefits. Notwithstanding the promising potential of these findings, challenges remain, including variable extraction methods, limited pharmacokinetic information, and the absence of clinical validation, which are obstacles to translation. This manuscript provides a limited examination of the phytochemical profile, neuroprotective mechanisms, and potential therapeutic applications in Alzheimer's disease (AD) attributed to P. roxburghii, and highlights the necessity for standardized formulations, molecular docking methodology, and rigorously designed clinical studies to determine its efficacy and safety in humans.},
}

@article {pmid41864176,
year = {2026},
author = {Li, J and Zhang, H and Zhou, X and Wang, Y and Wei, C and Yan, H and Wang, J},
title = {Molecular insights into SEN177 binding to human glutaminyl cyclase: a combined MD and DFT study.},
journal = {Journal of molecular graphics & modelling},
volume = {145},
number = {},
pages = {109372},
doi = {10.1016/j.jmgm.2026.109372},
pmid = {41864176},
issn = {1873-4243},
abstract = {Aberrant upregulation of human glutaminyl cyclase (hQC) is associated with the onset and progression of neurodegenerative disorders, notably Alzheimer's disease and Huntington's disease. Consequently, inhibition of hQC activity represents a potential avenue for treatment. SEN177, a potent small-molecule hQC inhibitor, has demonstrated notable preclinical efficacy but its binding mechanism remains incompletely understood. Herein, an integrated computational investigation was performed to elucidate the molecular basis of SEN177-hQC recognition. Notably, we implemented an integrated MD-energy decomposition-DFT scheme to rationalize the molecular mechanism of SEN177-hQC recognition. Molecular dynamics simulations indicated that SEN177 binding constrained the intrinsic conformational mobility of hQC, thereby stabilizing the protein-ligand complex. Energy decomposition analyses indicated that the P1 pharmacophore contributed significantly to binding affinity, with key interactions involving hotspot residues D159, E201, E202, W207, and L249. Complementary DFT analyses identified the frontier molecular orbitals and mapped electrophilic and nucleophilic regions that facilitated specific noncovalent contacts. Collectively, these results provide detailed mechanistic insight into the interaction landscape of SEN177 with hQC and provide a conceptual framework for designing more potent and selective hQC-targeting agents.},
}

@article {pmid41864514,
year = {2026},
author = {Wang, B and Cheng, K and Chen, Z and Chen, Y and Wang, Z and Ni, J},
title = {Transcranial Ultrasound Stimulation and Vagus Nerve Stimulation: Potential Therapeutic Strategies for Alzheimer's Disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111837},
doi = {10.1016/j.brainresbull.2026.111837},
pmid = {41864514},
issn = {1873-2747},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder with limited efficacy from existing medications and conventional neuromodulation therapies. In recent years, emerging neuromodulation techniques have demonstrated promising therapeutic potential. This review focuses on exploring the therapeutic value of transcranial ultrasound stimulation (TUS) and vagus nerve stimulation (VNS) for AD. We systematically review the evidence for these techniques in AD basic research and clinical practice, elucidating their unique mechanisms of action. The review further contrasts the advantages of TUS and VNS over traditional AD therapies and explores their potential for synergistic application with conventional treatments. Finally, we propose future research directions, including combined VNS and TUS treatment strategies based on complementary mechanisms, aiming to provide theoretical foundations for developing multi-targeted, personalized AD therapies.},
}

@article {pmid41864895,
year = {2026},
author = {Na, Y and Bai, J and Zhang, N and Geng, F and Wang, X},
title = {Nanomaterials for Alzheimer's disease: emerging strategies in diagnosis and therapy.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04281-w},
pmid = {41864895},
issn = {1477-3155},
support = {LH2023H050//Heilongjiang Province Natural Science Foundation/ ; LSLSKL 20240105//the Open Research Project of the State Key Laboratory for Integration and Innovation of Classic Formula and Modern Chinese Medicine/ ; JT120924080306//Lateral Project of Lunan Pharmaceutical Group Co., Ltd/ ; 22042240002//Lateral Project of Dong'e Ejiao Co., Ltd/ ; },
abstract = {Alzheimer's disease (AD) is a prevalent and progressive neurodegenerative disease characterized by behavioral abnormalities, memory loss, and cognitive decline, presenting significant challenges for early diagnosis and effective treatment. Given the multifactorial pathology of AD and the limited efficacy of conventional approaches, nanotechnology-based strategies have attracted increasing attention as promising solutions to address these unmet clinical needs. Nanomaterials offer distinct advantages for the sensitive and selective detection of AD-related biomarkers due to their high specific surface area, variable surface functions, and capacity to cross biological barriers. This review discusses recent advances in sensing and imaging technologies for AD detection via nanotechnology. Beyond diagnostics, nanomaterials also hold significant therapeutic potential. A variety of nanosystems have been developed to improve drug solubility, promote blood-brain barrier penetration, and achieve controlled or stimulus-responsive drug release. This review presents a comprehensive landscape of recent advances in nano-enabled targeting techniques, with a focus on the target therapy of neuron, microglia, astrocyte, Aβ, Tau, mitochondria and iron. Moreover, the designs of multifunctional nanostructures has enabled synergistic multi-target therapies, which concurrently modulate several pathological pathways. These integrated strategies that integrate antioxidant, anti-inflammatory, anti-aggregative, and neuroprotective mechanisms represent a new paradigm for personalized and precision nanomedicine in AD management.},
}

@article {pmid41865200,
year = {2026},
author = {Leelaprachakul, N and Visitnonthachai, D and Niyomchan, A and Maliphol, K and Watcharasit, P and Satayavivad, J},
title = {Arsenic Promotes Intracellular Aβ(1-42) Accumulation via Enhanced APP but Reduced NEP Expression, and Indirectly Stimulates Extracellular Aβ Aggregation through AChE Induction in Differentiated SH-SY5Y Cells.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {41865200},
issn = {1559-0720},
support = {PHD/0207/2559//The Royal Golden Jubilee Ph.D. Program/ ; Grant no. 49892/4778750//Thailand Science Research and Innovation (TSRI)/ ; },
abstract = {Arsenic exposure is associated with Alzheimer's disease (AD) development through unclear mechanisms. This study investigated the effects of arsenic on amyloid-β (Aβ), a peptide linked to AD pathogenesis, in differentiated SH-SY5Y neuroblastoma cells. Arsenic increased intracellular Aβ(1-42) while decreasing its extracellular levels. It elevated amyloid precursor protein (APP) while decreasing a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a non-amyloidogenic secretase, suggesting a shift in APP processing toward an amyloidogenic pathway. Arsenic reduced intracellular neprilysin (NEP), an Aβ-degrading enzyme, while increasing its extracellular levels. Interestingly, Aβ(1-42) detection by immunogold transmission electron microscopy revealed that NEP restoration by humanin G (HNG) reduced arsenic-induced intracellular Aβ(1-42). Thus, the inhibition of NEP moderately contributed to the arsenic-induced intracellular Aβ(1-42). Thioflavin T (ThT) assay revealed that arsenic enhanced extracellular Aβ aggregation. Arsenic upregulated extracellular acetylcholinesterase (AChE), known to promote Aβ aggregation. Co-treatment with HNG, which reportedly prevented AChE-promoted Aβ aggregation, attenuated Aβ aggregation by arsenic. Accordingly, arsenic-elevated AChE possibly promotes extracellular Aβ aggregation. Overall, arsenic promotes intracellular Aβ(1-42) accumulation, possibly through the upregulation of APP and a decrease in the Aβ-degrading enzyme, NEP, and extracellular Aβ aggregation by AChE upregulation. As both Aβ intracellular accumulation and extracellular aggregation play pivotal roles in AD, our findings may provide insightful mechanistic links between arsenic and AD.},
}

@article {pmid41865758,
year = {2026},
author = {Cummings, JL and Atri, A and Sano, M and Zetterberg, H and Scheltens, P and Knop, FK and Johannsen, P and Wichmann, CA and Abschneider, RM and Leon, T and Feldman, HH},
title = {Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(26)00459-9},
pmid = {41865758},
issn = {1474-547X},
abstract = {BACKGROUND: Evidence, including animal, clinical, and real-world studies in individuals with type 2 diabetes and/or obesity, suggests reduced risk of dementia and Alzheimer's disease after GLP-1 receptor agonist exposure. The evoke and evoke+ trials aimed to investigate the efficacy and safety of oral semaglutide in individuals with early Alzheimer's disease.

METHODS: evoke and evoke+ were multicentre, randomised, double-blind, placebo-controlled phase 3 trials conducted across 566 sites in 40 countries. The trials assessed the efficacy and safety of oral semaglutide up to 14 mg once daily in participants with amyloid-confirmed Alzheimer's disease, aged 55-85 years, with mild cognitive impairment or mild dementia due to Alzheimer's disease. In evoke+, participants with significant small vessel pathology were included. Participants were randomly assigned (1:1) to once-daily semaglutide 14 mg (flexible dose) or placebo for up to 156 weeks. The primary endpoint was change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score from baseline to week 104, assessed in all randomised participants. Safety was assessed in all randomised participants and reported for those receiving at least one dose of study drug. These trials were registered at ClinicalTrials.gov (NCT04777396 and NCT04777409); both trials have been discontinued due to negative clinical outcome.

FINDINGS: Between May 18, 2021, and Sept 8, 2023, 9981 participants were screened, of whom 3808 were randomly assigned; 1855 in evoke (semaglutide, n=928; placebo, n=927) and 1953 in evoke+ (semaglutide, n=976; placebo, n=977). Mean age was 72·2 years (SD 7·1), and mean CDR-SB score was 3·7 (SD 1·6) at baseline. In evoke+, 54 (2·8%) participants had small vessel pathology. In evoke and evoke+, mean changes in CDR-SB score from baseline to week 104 were 2·3 (SE 0·1) and 2·2 (0·1) with semaglutide, compared with 2·3 (0·1) and 2·1 (0·1) with placebo (estimated difference -0·08 [95% CI -0·35 to 0·20], p=0·57 in evoke and 0·10 [-0·17 to 0·38], p=0·46 in evoke+). Treatment-emergent adverse events were reported in 1729 (91·2%) of 1896 participants receiving semaglutide versus 1613 (84·8%) of 1902 receiving placebo. There were five fatalities considered treatment-related by the investigators (one in the semaglutide group and four in the placebo group).

INTERPRETATION: Oral semaglutide was not efficacious in slowing clinical progression in participants with early Alzheimer's disease. Safety and tolerability of semaglutide in early Alzheimer's disease is consistent with studies in other indications.

FUNDING: Novo Nordisk.},
}

@article {pmid41865782,
year = {2026},
author = {Cai, Y and Kang, J and Xie, H and Wu, D},
title = {From mechanisms to clinical applications: Advances in 40 Hz gamma oscillation modulation for the treatment of neurological disorders.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115741},
doi = {10.1016/j.expneurol.2026.115741},
pmid = {41865782},
issn = {1090-2430},
abstract = {This review systematically summarizes the mechanisms of 40 Hz gamma rhythm neuromodulation and its research advances in neurological disorders. As a key rhythm for brain information integration, 40 Hz gamma oscillations are generated by the interaction between excitatory and inhibitory neurons, and play a central role in cognitive functions such as attention and memory. They are commonly characterized by decreased power or loss of synchrony in various diseases including Alzheimer's disease, Parkinson's disease, and schizophrenia, serving as a shared electrophysiological hallmark. Extrinsic 40 Hz stimulation (e.g., transcranial alternating current stimulation, light flickering, acoustic stimulation) can restore endogenous gamma rhythms through the entrainment effect, improve excitation-inhibition balance, enhance synaptic plasticity, and promote the clearance of pathological proteins by activating microglia and other mechanisms. Clinical studies have shown that this technology improves cognitive, emotional, and motor functions, with advantages of non-invasiveness and high safety. Despite challenges such as individual variability, marked methodological heterogeneity (e.g., inconsistent stimulation parameters, small sample sizes, and lack of multicenter randomized controlled trials), and unclear long-term effects, 40 Hz neuromodulation still demonstrates broad therapeutic potential and provides a novel rhythmic intervention strategy for neurological disorders.},
}

@article {pmid41861975,
year = {2026},
author = {Huang, S and Lai, W and Zhao, Y and Pan, K and Xu, H and Lin, S and Liao, M and Liu, X and Lu, P and Wu, Y and Yang, W and Song, P and He, H and Hu, Y and Li, C},
title = {Hypertension, Antihypertensive Treatment, and Memory Decline: Consistent and Divergent Patterns in Aging Populations across Four Countries, 2010-2019.},
journal = {American journal of preventive medicine},
volume = {},
number = {},
pages = {108343},
doi = {10.1016/j.amepre.2026.108343},
pmid = {41861975},
issn = {1873-2607},
abstract = {INTRODUCTION: Memory decline is a hallmark of all-cause dementia. Hypertension, a highly prevalent and modifiable risk factor, is a critical intervention target. Cross-national, long-term studies examining the relationship between hypertension management and 10-year memory decline remain limited.

METHODS: We analyzed 2010-2019 data from four nationally representative aging cohorts. Hypertension (BP ≥140/90 mmHg or antihypertensive medications use) was categorized as treated and untreated. Memory was assessed using immediate and delayed word recall tasks. Linear mixed-effects models evaluated memory trajectories by hypertension and treatment status. Pooled analyses examined cross-country differences. Data analysis occurred from December 2024-January 2026.

RESULTS: Compared with non-hypertensive participants, hypertensive participants had a faster annual decline in the US (-0.010; 95% CI: -0.015, -0.006) and England (-0.011; 95% CI: -0.018, -0.004). Compared with treated hypertensive participants, untreated hypertensive participants had a slower annual decline among hypertensive participants in the US (0.010; 95% CI: 0.003, 0.017), but a faster decline in China (-0.022; 95% CI: -0.034, -0.011). Pooled analyses showed no cross-country differences in the association between hypertension and memory; however, compared with treated hypertension in the US, untreated hypertension was associated with faster memory decline in Mexico (-0.028; 95% CI: -0.051, -0.006) and China (-0.032; 95% CI: -0.045, -0.020).

CONCLUSIONS: Hypertension and treatment status are associated with memory decline in country-specific patterns. These findings highlight hypertension as a key modifiable risk factor and support prevention and treatment to promote cognitive health. Tailored approaches that align with local healthcare systems and population needs are essential.},
}

@article {pmid41856254,
year = {2026},
author = {Lu, S and Qiu, S and Guan, Y and Zhang, A and Zhao, Q},
title = {Tau phosphorylation homeostasis: Mechanisms, targets, and therapeutic implications in Alzheimer's disease.},
journal = {Ageing research reviews},
volume = {118},
number = {},
pages = {103097},
doi = {10.1016/j.arr.2026.103097},
pmid = {41856254},
issn = {1872-9649},
abstract = {Neurofibrillary tangles, composed of excessively phosphorylated tau, are a core neuropathological hallmark of Alzheimer's disease (AD). However, therapeutic strategies aimed at directly clearing neurofibrillary tangles have demonstrated limited clinical efficacy, shifting the research focus towards the fundamental underlying mechanism- the dysregulation of tau phosphorylation. Evidence indicates that tau physiological phosphorylation is indispensable for microtubule stability and normal neuronal function, while its aberrant hyperphosphorylation drives neurodegeneration. Consequently, restoring tau phosphorylation homeostasis, rather than merely eliminating the pathological protein, has emerged as a promising therapeutic paradigm. This review systematically delineates the physiological functions and pathological mechanisms of tau phosphorylation, highlighting its central role in AD pathogenesis. We summarize recent advances in drug development targeting key kinases and phosphatases, and discuss the diagnostic value and application prospects of tau phosphorylation biomarkers. Ultimately, this study aims to provide a theoretical framework for novel precision treatment strategies in AD.},
}

@article {pmid41858175,
year = {2026},
author = {Lin, CH and Wang, SH and Lane, HY},
title = {Sodium benzoate, a D-amino acids oxidase inhibitor, for the treatment of mild cognitive impairment: Pooled data from three randomized, double-blind, placebo-controlled trials.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70052},
pmid = {41858175},
issn = {1440-1819},
support = {DMR-115-102//China Medical University Hospital/ ; CMRPG8M1311//Kaohsiung Chang Gung Memorial Hospital/ ; CMRPG8M1361//Kaohsiung Chang Gung Memorial Hospital/ ; CMRPG8N1201//Kaohsiung Chang Gung Memorial Hospital/ ; CMRPG8N1121//Kaohsiung Chang Gung Memorial Hospital/ ; CMRPG8N1212//Kaohsiung Chang Gung Memorial Hospital/ ; NHRI-EX111-10816NC//National Health Research Institutes/ ; NHRI-EX113-11133NI//National Health Research Institutes/ ; NSTC 112-2314-B-039-020-MY3//National Science and Technology Council/ ; NSTC 113-2314-B-039-045-MY3//National Science and Technology Council/ ; NSTC 114-2314-B-182A-058-MY3//National Science and Technology Council/ ; NSTC 114-2622-B-039 -001//National Science and Technology Council/ ; NSTC 114-2629-B-039-001//National Science and Technology Council/ ; MOST 109-2628-B-182A-002//Ministry of Science and Technology, Taiwan/ ; MOST 111-2314-B-182A-024-MY3//Ministry of Science and Technology, Taiwan/ ; },
abstract = {BACKGROUND: Previous studies found that sodium benzoate (the pivotal D-amino acid oxidase [DAO] inhibitor) improved cognitive function in patients with mild Alzheimer's disease (AD); however, its efficacy for mild cognitive impairment (MCI) remained inconclusive. This study aims to evaluate the efficacy and safety of sodium benzoate in treating amnestic MCI (aMCI).

METHODS: Data were pooled from three randomized, double-blind, placebo-controlled trials. One hundred thirty-three patients with aMCI were enrolled from three major medical centers in Taiwan to receive 24-week treatment of 250-1500 mg/day of sodium benzoate or placebo. The cognitive outcome was Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog), and the functional outcome was Instrumental Activities of Daily Living (IADL). Both were measured at weeks 0, 8, 16, and 24.

RESULTS: Among 133 participants, sodium benzoate therapy improved ADAS-cog scores more than placebo (P = 0.033 at week 16, 0.026 at week 24). Among 84 women, benzoate surpassed placebo in ADAS-cog (P = 0.046 at week 16, 0.029 at week 24), as well as IADL (P = 0.043 at week 24). In contrast, among 49 men, the two treatment groups did not differ significantly in both ADAS-cog and IADL scores. Both sodium benzoate and placebo were well tolerated and benzoate therapy produced no additional side effect.

CONCLUSIONS: This study is the first to demonstrate that a DAO inhibitor, sodium benzoate herein, can enhance overall cognitive function in MCI individuals. Furthermore, it can improve female patients' IADL. The finding lends support for DAO inhibition as a novel approach for early dementing processes.},
}

@article {pmid41858425,
year = {2026},
author = {Xu, M and Xiong, L and Qin, Z and Yu, X and Chen, T and Zhang, X and Jin, M and Wang, L and Cai, L and Wei, Y and Liu, H and Wang, C and Hu, H and Zou, Z},
title = {Epigenetic Changes in Alzheimer's Disease and Interventions for Therapy.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {576404},
pmid = {41858425},
issn = {1176-6328},
abstract = {With the ageing of society, the number of Alzheimer's disease (AD) patients has increased rapidly, imposing a heavy burden on families and society. This article reviews the causes of AD, particularly the epigenetic changes associated with AD, including DNA methylation, histone modifications, and noncoding RNA changes. The development of diagnostic reagents based on biomarkers specific to epigenetic changes and attempts to intervene in adverse epigenetic factor changes in AD for the treatment of AD are discussed. This review contributes to a better understanding of the relationship between epigenetics and AD and provides guidance for exploring diagnostic and therapeutic strategies.},
}

@article {pmid41858558,
year = {2026},
author = {Tran, MH and Pruitt, K and Bryarly, M and Emordi, I and Ali, A and Ma, L and Fei, B},
title = {Development and validation of a high-resolution hyperspectral imaging system for the retina.},
journal = {Journal of biomedical optics},
volume = {31},
number = {3},
pages = {036006},
pmid = {41858558},
issn = {1560-2281},
mesh = {Animals ; *Hyperspectral Imaging/methods/instrumentation ; Mice ; *Retinal Vessels/diagnostic imaging ; Algorithms ; Phantoms, Imaging ; *Retina/diagnostic imaging ; *Image Processing, Computer-Assisted/methods ; Oxygen/metabolism ; Deep Learning ; Mice, Inbred C57BL ; },
abstract = {SIGNIFICANCE: Early detection of Alzheimer's diseases, diabetic retinopathy, or macular degeneration with advanced retinal imaging technologies can help improve patient care and treatment outcome.

AIM: We aim to create a high-resolution hyperspectral imaging (HSI) system for the retina. Retinal vessel diameter and oxygenation rate will be extracted simultaneously from HSI data.

APPROACH: Our hyperspectral retinal imaging system consists of a snapshot hyperspectral camera, a high-resolution RGB camera, a beamsplitter, and an imaging endoscope. Multiple pansharpening algorithms, including deep learning methods, were developed to generate high-resolution hyperspectral images that were further used for the measurement of vessel size and oxygenation rate in mice.

RESULTS: The hyperspectral retinal imaging system was tested for its spatial resolution and spectral fidelity in retina phantoms. In vivo imaging experiments were performed in mice. The deep learning-based pansharpening algorithm achieved a root mean square error (RMSE) of 2.15 ± 0.64 , a correlation coefficient (CC) of 0.96 ± 0.05 , a spectral angle score of 0.06 ± 0.03 radians, and an error relative global dimensionless synthesis (ERGAS) score of 2.37 ± 1.71 . Oxygen saturation (sO 2) and lumen diameters of blood vessels were measured in the retina. The average lumen diameter of the venules was 45.7 ± 13.6    μ m , whereas the average lumen diameter of the arterioles was 31.5 ± 8.7    μ m . The average arteriole sO 2 was 98%, whereas the average venule sO 2 was 58%.

CONCLUSIONS: A high-resolution hyperspectral imaging system was developed and validated for retina imaging and measurement of blood vessels and oxygen saturation.},
}

Animals
*Hyperspectral Imaging/methods/instrumentation
Mice
*Retinal Vessels/diagnostic imaging
Algorithms
Phantoms, Imaging
*Retina/diagnostic imaging
*Image Processing, Computer-Assisted/methods
Oxygen/metabolism
Deep Learning
Mice, Inbred C57BL

@article {pmid41858791,
year = {2026},
author = {Su, CW and Chen, K and Wu, T and Reiman, EM and Wang, Q},
title = {TAS2R38 taster variants-linked MGAM expression in Alzheimer's disease: a novel target for precision drug repurposing.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1768436},
pmid = {41858791},
issn = {1663-4365},
abstract = {INTRODUCTION: TAS2R38 is a taste receptor gene located on human chromosome 7 that influences sensitivity to bitter tastes and has been implicated in innate immunity, glucose level, and human longevity. However, its potential association with Alzheimer's Disease (AD) has not been explored. Identifying such a genetic connection could support developing new drugs or repurposing existing ones for AD treatment.

METHODS: In this work, we examined the relationship between allele counts of TAS2R38 taster variants and AD risk using linear mixed-effects models, utilizing genetic, clinical, and biomarker data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We investigated the potential molecular mechanisms of the association by identifying expression quantitative trait loci (eQTLs) using RNA-seq data from postmortem tissues across brain regions from the Religious Orders Study/Memory and Aging Project (ROSMAP). We evaluated whether FDA-approved drugs targeting the identified e-gene could reduce dementia risk using 1:1 propensity score-matched groups from longitudinal data in the National Alzheimer's Coordinating Center (NACC) study, by comparing clinical dementia progression trends between the drug-taking and non-taking groups with linear mixed-effects models.

RESULTS: Our results show that TAS2R38 supertasters were connected to a reduced AD risk with advancing age due to its association with various AD biomarkers (p < 0.001). eQTL analysis linked the nontaster allele to increased expression of the gene MGAM in AD-affected brain regions (p < 0.001). Furthermore, elevated MGAM expression correlated with more severe Tau burden (p < 0.05) and implicated in mitochondrial dysfunction in AD subjects. Notably, MGAM is a known drug target for diabetes mellitus. In NACC data, individuals taking MGAM-inhibiting drugs (acarbose and miglitol) showed slower clinical dementia rating progression (p < 0.01) in comparison with the non-taking group.

DISCUSSION: This study is the first to report a genetic association between TAS2R38 and AD biomarkers. Our findings, validated in multiple cohorts/matching groups, suggest MGAM as a novel AD drug target with existing FDA-approved inhibitors and demonstrate the potential of TAS2R38 haplotypes to inform precision drug repurposing strategies for AD, which warrants further in-depth preclinical and clinical studies.},
}

@article {pmid41858824,
year = {2026},
author = {Fu, W and Wang, K and Chen, H and Liu, T and Liu, X and Jin, Q and Tan, Z and Dong, W and Liu, W and Sang, Z},
title = {Design, synthesis and biological evaluation of novel 3,4-dihydro-2(1H)-quinoline-O-carbamate derivatives as AChE/MAO-B dual inhibitors for the treatment of Alzheimer's disease.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41858824},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is an irreversible degenerative disorder of the brain, and there is no effective drug for it to date. Given its complex pathogenesis, the multi-target-directed ligand (MTDL) strategy is considered as a promising approach against AD. Herein, a series of 3,4-dihydro-2(1H)-quinoline-O-carbamate derivatives were designed and synthesized based on the MTDL strategy. The in vitro biological results indicated that 3c was a potent AChE/MAO-B dual inhibitor with an IC50 value of 0.81 μM and 0.17 μM, respectively. Molecular modeling and molecular dynamics (MD) simulations offered possible insights into the AChE/MAO-B inhibition of 3c. Moreover, 3c showed good stability and BBB permeability, as well as favorable neuroprotective effects. In vivo evaluation exhibited that 3c impressively improved the AlCl3-induced zebrafish AD model by elevating ACh, decreasing APP and inflammatory factors. Further, 3c effectively alleviated the scopolamine-induced cognitive impairment model. Therefore, 3c is a promising AChE/MAO-B dual inhibitor for treating AD.},
}

@article {pmid41860347,
year = {2026},
author = {Zhu, W and Li, H and Wang, K and Sun, M and Xiang, K and Shan, S and Ke, C},
title = {Evidence integration of acupuncture for prevention and treatment of Alzheimer's disease and mild cognitive impairment from a neuroimaging perspective.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261420235},
doi = {10.1177/13872877261420235},
pmid = {41860347},
issn = {1875-8908},
abstract = {BackgroundAcupuncture has clinical potential in treating Alzheimer's disease (AD) and mild cognitive impairment (MCI), but there is a lack of systematic review and presentation of clinical evidence from the perspective of neuroimaging in this field.ObjectiveTo conduct a systematic review of clinical studies on acupuncture for AD and MCI from the perspective of neuroimaging, and to comprehend the evidence distribution of relevant research.MethodsThis article retrieved all the neuroimaging clinical studies on acupuncture treatment for AD and MCI that were published and included in the seven databases from their establishment until February 22, 2025. It analyzed and organized the data based on the PICOS (Population, Intervention, Comparison, Outcome, Study design) principle, and presented the quality and distribution of evidence.ResultsA total of 58 studies were included. The diagnostic criteria for the research subjects mainly refer to the standards of Western medicine. The task design was mostly two-arm before-and-after comparisons and single-group immediate studies, with the intervention measures mainly including hand acupuncture and electroacupuncture. The study employed 8 neuroimaging techniques and 29 outcome measures, with a primary focus on brain functional activation regions and brain functional connectivity. Included studies had high bias risk in blinding design/implementation; overall evidence quality was acceptable.ConclusionsAcupuncture for AD and MCI demonstrates clear efficacy, which is supported by imaging evidence. In the future, more large-sample, multi-center joint clinical studies using neuroimaging methods will be needed to further investigate AD and MCI, providing more high-quality evidence-based medical evidence in this field.},
}

@article {pmid41860361,
year = {2026},
author = {Høilund-Carlsen, PF and Alavi, A and Costa, T and Neve, RL and Revheim, ME and Barrio, JR},
title = {Serious doubts about amyloid-β (Aβ) biomarkers and anti-Aβ immunotherapy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261417548},
doi = {10.1177/13872877261417548},
pmid = {41860361},
issn = {1875-8908},
abstract = {Reports highlight new Alzheimer's disease treatments using anti-amyloid-β immunotherapy, but we see major concerns. The trials supporting lecanemab and donanemab approvals have methodological flaws, and the benefits may be smaller than the minimal clinically important difference-or absent-since patients with poor tolerance were excluded from efficacy analyses. Moreover, treatment increases amyloid-related imaging abnormalities, suggesting local tissue damage, and is linked to brain volume loss. These issues raise doubts about whether regulators are adequately balancing risks and benefits compared to academic critics.},
}

@article {pmid41860528,
year = {2026},
author = {Rubin, R},
title = {Lithium for Alzheimer Disease-Pilot Study Sets the Stage for Larger Trials.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.3046},
pmid = {41860528},
issn = {1538-3598},
}

@article {pmid41861574,
year = {2026},
author = {Denev, R and Berkov, S},
title = {A fast and simple method for GC-MS quantification of galanthamine in Hippeastrum papilio (Ravena) Van Sheepen and assessment of its alkaloid fractions.},
journal = {Journal of chromatography. A},
volume = {1774},
number = {},
pages = {466902},
doi = {10.1016/j.chroma.2026.466902},
pmid = {41861574},
issn = {1873-3778},
abstract = {BACKGROUND: Galanthamine, an AChE inhibitor marketed for symptomatic treatment of mild to moderate Alzheimer's disease, is produced by both chemical synthesis and extraction from plant of the Amaryllidoideae subfamily. There are a few validated GC-MS and HPLC-MS methods for its quantification in plant material. All of these methods apply multi-step sample preparation procedures including toxic solvents. The assessment of plant material and development of extraction methodologies from new plant sources (e.g. Hippeastrum papilio) requires validation of quantitative analytical methods considering the species alkaloid pattern.

RESULTS: The extraction of galanthamine from H. papilio raw material was optimized selecting 0.072% of HCl water solution as the most effective extractant. An aliquot (1 µL) of the total extract (1 mL) was directly injected into the GC-MS system avoiding any purification steps with toxic solvents. Selectivity, linearity, sensitivity, precision, accuracy, stability and robustness were determined. The LLOQ and LLOD in SIM mode were found at a concentration of 10 ng/mL and 2 ng/mL, respectively. The method was used for assessment of plant raw material, alkaloid fractions and extraction effectiveness.

SIGNIFICANCE: The method describes the fastest and simplest extraction procedure and direct aqueous injection into the GC-MS for quantification of galanthamine in plant material. As compared to the LC-MS, the use of EIMS detector provides important information and advantage in the assessment of alkaloid fractions from new plant sources of galanthamine.},
}

@article {pmid41652415,
year = {2026},
author = {Tang, F and Li, Y and Bai, X and Zhu, Z and Dong, H and Chen, J and Ye, B and Yuan, M and Wu, Q and Fu, W and Zhang, Y and Wang, C},
title = {BMAL1-GPX3 axis in the choroid plexus mitigates Aβ pathology in an amyloid mouse model.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41652415},
issn = {1742-2094},
support = {2024NSCQ-MSX0951//Natural Science Foundation of Chongqing Municipal Bureau of Science and Technology/ ; 2023NSCQ-MSX3605//Natural Science Foundation of Chongqing Municipal Bureau of Science and Technology/ ; KJQN202400476//Scientific and Technological Research Program of Chongqing Municipal Education Commission/ ; KZD-JI202400406//Scientific and Technological Research Program of Chongqing Municipal Education Commission/ ; 82271470//National Natural Science Foundation of China/ ; STI2030-Major Projects 2021ZD0202400//National Key Research and Development Program of China/ ; LG-GG-202401-ADA010100//Lingang Laboratory AD Special Project/ ; },
abstract = {UNLABELLED: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with circadian rhythm disturbances strongly linked to its pathogenesis. The choroid plexus (ChP) is a circadian-regulated structure in the brain ventricles, but the role of the core clock gene brain and muscle ARNT-like protein 1 (BMAL1) in ChP in relation to AD pathology remains unclear. Here, we report that knockdown of Bmal1 in ChP epithelial cells of 5xFAD mice alleviates amyloid-β (Aβ) pathology, primarily by improving the function of astrocytes and border-associated macrophages (BAMs), with the latter potentially mediated by the upregulation of the secreted protein glutathione peroxidase 3 (GPX3), which reduces lipid peroxidation in BAMs. Collectively, our findings establish the ChP-driven BMAL1-GPX3 axis as a new Aβ clearance mechanism, with GPX3 representing a promising therapeutic target. These findings provide new mechanistic insights into AD and suggest innovative treatment approaches.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03691-9.},
}

@article {pmid41673758,
year = {2026},
author = {Zheng, D and Gu, J and Nao, J and Sun, M and Dong, X},
title = {APOE4-driven T cell dysregulation in Alzheimer's disease: single-cell genomics and Mendelian randomization reveal novel therapeutic targets.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41673758},
issn = {1742-2094},
support = {No. 2024-MS-024//Natural Science Foundation of Liaoning Province/ ; },
abstract = {UNLABELLED: The ɛ4 allele of the apolipoprotein E gene (APOE4) has been identified as a significant risk factor for late-onset AD. However, the specific genetic differences in T lymphocytes between APOE4 and APOE3 carriers are poorly understood. This study aimed to identify these important genetic distinctions and investigate the causal relationship between these differences and the risk of Alzheimer’s disease (AD), offering insights that could lead to novel treatment approaches. We sequenced single peripheral blood cells from three APOE3 and three APOE4 patients using the BD Rhapsody sequencing technology. We conducted a single-cell locus analysis, explored cell communication and signaling pathways. Finally, we selected CD8 central memory cells (CD8_CM) for differential gene, enrichment, and protein interaction analyses. Mendelian randomization (MR) analysis of expression quantitative trait loci (eQTLs) of differential genes and a genome-wide association study (GWAS) of AD were performed to verify causality and sensitivity. We selected CD8_CM as the primary target and identified 108 differentially expressed genes (DEGs). Through MR analysis, we identified nine genes with causal relationships with AD: ANXA1, BHLHE40, ATP2B4, RUNX3, CD3G, PFN1, AHNAK, C1orf21, and CAPNS1. In the replication phase, based on Wald ratios or the IVW method, the causal relationships of five genes (RUNX3, ATP2B4, C1orf21, AHNAK, and CD3G) with AD were successfully validated in another GWAS dataset. We identified the core role of CD8_CM, yielding 108 DEGs. Our integrative analysis suggests that genetically determined levels of circulating BHLHE40, ANXA1, and RUNX3, may be promising biomarkers for AD and warrant further clinical investigation.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03727-0.},
}

@article {pmid41851031,
year = {2026},
author = {Sun, J and Zufiria-Gerbolés, B and Passaretti, M and Volpe, G and Mijalkov, M and Pereira, JB and , },
title = {Tracking early cognitive decline in preclinical AD with brain MRI similarity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71170},
doi = {10.1002/alz.71170},
pmid = {41851031},
issn = {1552-5279},
support = {2025-03210//Swedish Research Council/ ; FO2025-0059//Swedish Brain Foundation/ ; 2-3980/2025//Blomqvist Foundation/ ; //StratNeuro/ ; 760250/28.12.2023//Romanian Government through Romania's National Recovery Romania's National Recovery and Resilience Plan (Romanian Ministry of Research, Innovation and Digitalization under Component 9, Investment 8)/ ; PNRR-C9-I8-CF109/31.07.2023//Romanian Government through Romania's National Recovery Romania's National Recovery and Resilience Plan (Romanian Ministry of Research, Innovation and Digitalization under Component 9, Investment 8)/ ; //KID funding/ ; //KI Consolidator Grant/ ; //King Gustaf V and Queen Victoria's Foundation/ ; //Gamla Tjänarinnor/ ; //Gun och Bertil Stohnes Stiftelse/ ; //Dementia Foundation/ ; //Lars Hierta Memorial Foundation/ ; AF-1032782//Alzheimer Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Magnetic Resonance Imaging ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Male ; Female ; *Brain/pathology/diagnostic imaging ; Aged ; Biomarkers/cerebrospinal fluid ; Neuroimaging ; Prodromal Symptoms ; Aged, 80 and over ; Amyloid beta-Peptides/cerebrospinal fluid ; Early Diagnosis ; Disease Progression ; },
abstract = {INTRODUCTION: Early detection of neuroanatomical changes in preclinical Alzheimer's disease (AD) is critical for timely intervention. However, conventional magnetic resonance imaging (MRI) and fluid biomarkers often lack sensitivity to subtle structural alterations in early disease stages.

METHODS: To identify early brain alterations, we applied a perturbation-based brain similarity approach to cognitively normal participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Open Access Series of Imaging Studies (OASIS), stratified by amyloid status. We evaluated its predictive performance for cognition and diagnostic conversion against cortical thickness, volumetric MRI, and fluid biomarkers.

RESULTS: In both cohorts, brain similarity consistently outperformed other biomarkers across cognitive domains and amyloid groups. It also achieved superior accuracy in predicting clinical conversion and exhibited associations with cytoarchitectural organization.

DISCUSSION: These findings highlight brain similarity as a sensitive marker of early neuroanatomical disruption in AD. Its ability to detect subtle structural changes before overt atrophy underscores its potential for early disease monitoring and treatment assessment in preclinical AD trials.

HIGHLIGHTS: Brain similarity captures early brain changes in preclinical Alzheimer's disease (AD). Brain similarity outperforms conventional biomarkers such as cortical thickness, volume measures, and fluid biomarkers in predicting cognitive decline. Brain similarity predicts conversion to mild cognitive impairment and AD more accurately than traditional imaging markers, and its predictive performance is further improved when combined with fluid biomarkers. Brain similarity captures structural disruptions associated with cortical layer II of the cytoarchitectonic lamina of human neocortex.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
*Magnetic Resonance Imaging
*Cognitive Dysfunction/diagnostic imaging/pathology
Male
Female
*Brain/pathology/diagnostic imaging
Aged
Biomarkers/cerebrospinal fluid
Neuroimaging
Prodromal Symptoms
Aged, 80 and over
Amyloid beta-Peptides/cerebrospinal fluid
Early Diagnosis
Disease Progression

@article {pmid41851960,
year = {2026},
author = {Bhoopal, B and Gollapelli, KK and Damuka, N and Krizan, I and Miller, M and Fitzgerald, RW and Amesar, N and Mumbaraddi, D and Zhu, D and Cervera-Juanes, R and Jadiya, P and Whitlow, CT and Solingapuram Sai, KK},
title = {Synthesis, Radiochemistry, and Preclinical Assessment of the First GPR39 PET Imaging Agent.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c03351},
pmid = {41851960},
issn = {1520-4804},
abstract = {GPR39 is a zinc-sensing G protein-coupled receptor with critical roles in neurophysiological and metabolic processes across brain, pancreas, gut, liver, and fat tissues. Activated by extracellular zinc ions, GPR39 is involved in neurodegenerative diseases including altered levels in Alzheimer's disease (AD). Quantifying GPR39 levels in vivo could significantly advance understanding of its role in various metabolic and disease processes, enabling drug development and treatment monitoring. Our study reports the synthesis, radiolabeling, and comprehensive preclinical evaluation of the first radiotracer for GPR39 imaging: [[11]C]TMN-OMe. The radiotracer demonstrated high radiochemical purity, molar activity, and stability in human serum. In vivo microPET/CT imaging, biodistribution, and autoradiography analyses confirmed selective binding to GPR39, with significantly reduced brain uptake in GPR39 knockout and AD mice, and in blockade conditions. Collectively, these findings support using [[11]C]TMN-OMe to quantify GPR39 levels in vivo and define GPR39-based imaging as a novel platform to study mechanistic changes in neurological disorders.},
}

@article {pmid41852095,
year = {2026},
author = {Zecca, V and Palombelli, G and Vanacore, N and Canese, R},
title = {The Role of Magnetic Resonance Spectroscopy (MRS), Diffusion-Tensor-Imaging (DTI) and Structural MRI in the Alzheimer's Disease and Mild Cognitive Impairment Diagnosis: A Review.},
journal = {Journal of magnetic resonance imaging : JMRI},
volume = {},
number = {},
pages = {},
doi = {10.1002/jmri.70296},
pmid = {41852095},
issn = {1522-2586},
abstract = {Alzheimer's disease (AD) is one of the most common neurological disorders affecting older adults, with approximately 7.2 million cases only in the United States. This number is projected to increase to 13.8 million in the United States by 2060, leading to increased expenditures for healthcare, long-term care and hospice services. Consequently, great emphasis is placed on prevention and the development of early diagnosis techniques, which can lead to timely treatment and the prevention of the consequences of full-blown disease. In this review, we analyze the potential diagnostic value of biomarkers derived from a multimodal approach based on magnetic resonance spectroscopy, diffusion tensor imaging, and magnetic resonance imaging, capable of detecting metabolic, microstructural, and anatomical changes, respectively, that precede the cognitive and behavioral changes observed in AD by years. The primary aim is to evaluate whether the combined and complementary use of these methods can identify early biomarkers useful for recognizing AD in its early stages, predicting progression from MCI to AD, supporting patient stratification, and monitoring cognitive decline or response to treatment. We identified regions more susceptible to metabolic alterations (PCC and hippocampus) and trajectories of structural brain alterations (atrophy or diffusivity abnormalities). The assessment of such imaging biomarkers may serve as the foundation for future prospective studies aimed at developing differential diagnostic methods, a crucial goal within the broader context of dementias, by adopting standardized multimodal MRI protocols. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 1.},
}

@article {pmid41852131,
year = {2026},
author = {Jin, MX and Qiu, JY and Jiang, HY},
title = {Marine-Derived Chitosan Oligosaccharides and Their Derivatives: A New Hope for Alzheimer's Prevention and Treatment - A Critical Review.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {3},
pages = {e02777},
doi = {10.1002/cbdv.202502777},
pmid = {41852131},
issn = {1612-1880},
support = {81760207//National Natural Science Foundation project/ ; 2024AY10021//Jiaxing Municipal Public Welfare Research Program Project/ ; },
mesh = {*Alzheimer Disease/drug therapy/prevention & control/metabolism ; *Chitosan/chemistry/pharmacology/therapeutic use ; Humans ; *Oligosaccharides/chemistry/pharmacology/therapeutic use ; Animals ; *Aquatic Organisms/chemistry ; Antioxidants/chemistry/pharmacology ; *Neuroprotective Agents/chemistry/pharmacology ; Acetylcholinesterase/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive degenerative disease of the central nervous system. Its clinical manifestations are mainly cognitive and memory disorders, and its incidence rate and mortality are increasing year by year. Chitosan oligosaccharides (COS), also known as β-1,4-oligoglucosamine, are natural alkaline polysaccharides and the only positively charged ones in nature. Due to its low molecular weight, good water solubility, and excellent biocompatibility, non-toxicity, and biodegradability, in recent years, it has received increasing attention from domestic and foreign researchers and enterprises. COS is of great significance in the prevention and treatment of AD; the main mechanisms of action include inhibiting acetylcholinesterase and beta-secretase activity, preventing abnormal phosphorylation of tau protein, chelating copper ions, protecting neuronal cells, and exhibiting antioxidant effects. This review primarily combines the latest research results, both domestic and international, to summarize and analyze the anti-AD effects and possible mechanisms of COS, aiming to provide the theoretical basis and the reference for the in-depth study of COS in the fields of biomedicine and functional foods and for its wider application in the fields of medicine and health food.},
}

*Alzheimer Disease/drug therapy/prevention & control/metabolism
*Chitosan/chemistry/pharmacology/therapeutic use
Humans
*Oligosaccharides/chemistry/pharmacology/therapeutic use
Animals
*Aquatic Organisms/chemistry
Antioxidants/chemistry/pharmacology
*Neuroprotective Agents/chemistry/pharmacology
Acetylcholinesterase/metabolism

@article {pmid41852627,
year = {2026},
author = {Toledano-Pinedo, M and Iriepa, I and Rodríguez-Fernández, MM and Marco-Contelles, J},
title = {Masupirdine, a Selective Serotonin 5‑HT6 Receptor Antagonist for Alzheimer's Disease.},
journal = {ACS pharmacology & translational science},
volume = {9},
number = {3},
pages = {761-763},
pmid = {41852627},
issn = {2575-9108},
abstract = {Masupirdine is an oral, small, and safe molecule, readily available by a robust, two-step synthetic scheme, showing a potent, selective serotonin 5-HT6 receptor antagonist profile, pro-cognitive effects in various behavioral animal models in Phase 3 clinical trials for the treatment of agitation in patients with Alzheimer's dementia.},
}

@article {pmid41853003,
year = {2026},
author = {Khushi, P and Parmar, NJ and Daga, R and Sethumadhavan, J and Kale, PK and Laddha, R},
title = {Neuroprotectants: The Next Frontier in Neurology.},
journal = {Journal of pharmacy & bioallied sciences},
volume = {18},
number = {Suppl 1},
pages = {S1-S3},
pmid = {41853003},
issn = {0976-4879},
abstract = {Neuroprotectants are drugs or substances that help protect the brain and nerves from damage caused by injuries or diseases like stroke, Alzheimer's disease, and Parkinson's disease. This review looks at different types of neuroprotective agents, including those that reduce inflammation, prevent cell death, or improve blood flow to the brain. While many of these substances show good results in lab studies, only a few have been successful in human trials. This is often due to problems like delayed treatment, difficulty reaching the brain, and differences between patients. The review also discusses future clinical trials and how new technologies and targeted treatments may improve outcomes. Understanding how these agents work and how to test them better could lead to more effective treatments for brain disorders.},
}

@article {pmid41853217,
year = {2026},
author = {Karthikeyan, A and Gopinath, N and Krishna, N and Joseph, A and Krishnamurthy, RG and Nair, BG},
title = {Neuroprotective potential of a novel marine metabolite from S. rhizophila BGNAK1 targeting acetylcholinesterase in Alzheimer's disease.},
journal = {3 Biotech},
volume = {16},
number = {4},
pages = {143},
pmid = {41853217},
issn = {2190-572X},
abstract = {UNLABELLED: Secondary metabolites from the marine bacterium Stenotrophomonas rhizophila strain BGNAK1 were evaluated for neuroprotective activity using biochemical and cellular assays relevant to Alzheimer's disease. The crude extract exhibited significant acetylcholinesterase (AChE) inhibitory activity with an IC50 value of 106.0163 µg/mL, indicating effective modulation of cholinergic function. Antioxidant evaluation revealed strong free radical scavenging capacity, with DPPH radical inhibition of and 97% at 1.0 mg/ml. The extract also significantly reduced intracellular reactive oxygen species levels, showing a reduction compared to untreated control cells at the highest tested concentration. Cytotoxicity analysis using PC12 and SH-SY5Y neuroblastoma cell lines demonstrated > 85% cell viability across all tested concentrations, confirming good biocompatibility. No significant morphological alterations or growth inhibition were observed under treatment conditions. Overall, these results demonstrate that metabolites derived from S. rhizophila BGNAK1 exert multi-target neuroprotective effects through combined cholinesterase inhibition and antioxidant mechanisms. Although direct neuronal injury models were not employed, the integrated biochemical and cellular findings provide quantitative evidence supporting the neurotherapeutic potential of marine bacterial metabolites and justify further investigation into their role in Alzheimer's disease-oriented drug discovery.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04751-w.},
}

@article {pmid41853467,
year = {2026},
author = {Teipel, S and Grazia, A and Peters, O and Priller, J and Schneider, A and Wiltfang, J and Bartels, C and Schott, BH and Jessen, F and Duezel, E and Yakupov, R and Buerger, K and Perneczky, R and Laske, C and Spottke, A and Wagner, M and Peltner, J and Kilimann, I and Haenisch, B},
title = {Associations of anticholinergic burden of medication with cognitive decline and longitudinal brain atrophy in the Alzheimer's disease spectrum.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1751326},
pmid = {41853467},
issn = {1663-4365},
abstract = {BACKGROUND: Anticholinergic side effects of pharmacological treatment are a risk factor for cognitive decline in older people. Here, we aimed to assess the effect of anticholinergic burden of treatment on longitudinal rates of cognitive change and atrophy in functionally related brain regions in people from the Alzheimer's disease (AD) spectrum.

METHODS: We determined associations of anticholinergic burden of pharmacological treatment with rates of global cognition, episodic memory and executive function decline as well as basal forebrain and hippocampus atrophy in participants of the memory clinic based DELCODE cohort, spanning the range from cognitively normal through subjective cognitive decline, mild cognitive impairment and AD dementia. We had 794 cases with neuropsychological outcomes, and a subset of 703 cases with MRI outcomes. Effects were assessed using mixed effect models in a Bayesian framework using prior-insensitive cross-validated Bayes factors (CV-BF) and parameter estimates.

RESULTS: We found moderate evidence for an association of anticholinergic burden with baseline levels of cognitive impairment for the PACC5 as a global cognitive function score (CV-BF = 9.0) with more impairments with higher burden, but not with basal forebrain and hippocampus volumes, and weak evidence for an association of anticholinergic burden with longitudinal rates of change in the trail-making test B as an executive function score (CV-BF = 2.5), but not for other cognitive scores and not for brain volumes.

CONCLUSION: In the presence of prodromal or manifest AD, in a memory clinic-based cohort anticholinergic burden had only a modest effect on cognitive decline and no effect on atrophy in brain regions that are related to the cholinergic system.},
}

@article {pmid41853851,
year = {2026},
author = {Jun, JE and Kim, S and Jeong, IK and Kim, JH},
title = {Dementia Risk in Type 1 and 2 Diabetes: A Nationwide Population-Based Comparison.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.70677},
pmid = {41853851},
issn = {1463-1326},
abstract = {AIMS: Diabetes is increasingly recognised as a major contributor to cognitive decline and dementia, but the risk varies by diabetes type and treatment intensity. We compared the risk of all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VaD) among individuals with and without diabetes.

METHODS: This population-based retrospective cohort study analysed data from the Korean National Health Insurance Service (2013-2024). A total of 1 322 651 adults aged ≥ 40 years without prior dementia were included. Participants were classified as non-diabetic, type 2 diabetes (T2DM) with oral hypoglycemic agents (OHAs), T2DM with insulin, or type 1 diabetes (T1DM). Incident dementia was identified using ICD-10 codes and anti-dementia prescriptions. Multivariable Cox proportional hazards models adjusted for demographic, lifestyle and clinical factors estimated adjusted hazard ratios (aHRs) for dementia.

RESULTS: Dementia incidence rates per 1000 person-years were 4.3 (non-diabetic), 12.7 (T2DM with OHA), 17.9 (T2DM with insulin) and 21.1 (T1DM). Compared with non-diabetic participants, aHRs for all-cause dementia were 1.29 (95% CI 1.26-1.32) for T2DM with OHA, 2.14 (2.00-2.28) for T2DM with insulin and 2.35 (2.12-2.59) for T1DM. Similar trends were observed for AD and VaD. Dementia risk was highest in individuals with T1DM and insulin-treated T2DM, with no significant difference between these groups.

CONCLUSIONS: Diabetes was associated with a higher risk of dementia, particularly among individuals with T1DM and insulin-treated T2DM, suggesting that insulin-requiring diabetes represents a high-risk phenotype for cognitive decline. Proactive cognitive screening and optimised glycemic management, including strategies to reduce glycemic variability such as continuous glucose monitoring, may help mitigate dementia risk in these vulnerable populations.},
}

@article {pmid41854365,
year = {2026},
author = {Oliveira, LM and Frasier, M and Hutten, SJ},
title = {Collaborative action for biomarker breakthroughs: Validating α-synuclein seed amplification assays in Parkinson's disease.},
journal = {Journal of Parkinson's disease},
volume = {},
number = {},
pages = {1877718X261431949},
doi = {10.1177/1877718X261431949},
pmid = {41854365},
issn = {1877-718X},
abstract = {The alpha-synuclein seed amplification assay in cerebrospinal fluid is the first validated molecular measurement of alpha-synuclein biology in a living person. The SAA test is transforming our understanding of aging and neurodegenerative diseases by detecting abnormal synuclein biology, and data suggests SAA positivity can occur across Parkinson's disease, Alzheimer's disease, and Dementia with Lewy Bodies. To accelerate development of this important research tool, the Michael J. Fox Foundation proactively funded a community of researchers to work both independently and collaboratively, leading to rapid and iterative progress and validation. The collective validation of the assay across industry and academic groups culminated in a Food and Drug Administration Letter of Support for the test in clinical trials for PD. This article describes the principles that accelerated the development of the assay including patient engagement, collaboration, a commitment to open science through data, sample, and knowledge sharing, and showcases how an international community of experts rallied together towards a common goal.},
}

@article {pmid41854733,
year = {2026},
author = {Liu, K and Zhang, XY and Wang, YT and Wang, R and Jin, RH and Bing, YH},
title = {Therapeutic Potential of Somatostatin and Its Analogues in Alzheimer's Disease: From Molecular Mechanisms to Preclinical Studies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41854733},
issn = {1559-1182},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Somatostatin/analogs & derivatives/therapeutic use/pharmacology ; Animals ; Drug Evaluation, Preclinical ; Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Currently approved agents, such as acetylcholinesterase inhibitors and NMDA receptor antagonists, provide only modest symptomatic benefit without modifying disease progression. Increasing evidence highlights the somatostatin (SST) system and its analogues (SSAs) as potential multitarget therapies. Somatostatin receptors (SSTR1-5) are widely expressed in cognition-related brain regions and participate in amyloid-β metabolism, tau phosphorylation, neuroinflammation, and synaptic plasticity. Preclinical studies suggest that SSAs enhance amyloid clearance via neprilysin activation, attenuate tau pathology through PI3K/Akt signaling, regulate APOE4 expression, and modulate microglial function, thereby protecting synaptic integrity. Compared with current monotherapies, SSAs may provide broader therapeutic benefits, particularly if applied in prodromal or early stages of AD. Advances in delivery strategies, including peptide modification, nanocarrier-based transport, and physically assisted blood-brain barrier (BBB) penetration, further improve translational potential. However, challenges such as poor BBB permeability, incomplete mechanistic understanding, and limited clinical data remain. Integration of systems biology, biomarker-driven precision medicine, and novel delivery technologies may facilitate the development of SSA-based interventions as complementary strategies for AD management.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Somatostatin/analogs & derivatives/therapeutic use/pharmacology
Animals
Drug Evaluation, Preclinical
Amyloid beta-Peptides/metabolism
Blood-Brain Barrier/metabolism/drug effects

@article {pmid41855773,
year = {2026},
author = {Ouk, K and Fernández-Klett, F and Schormann, E and Greiner, A and Santaella, A and Fernández-Zapata, C and Böttcher, C and Krüger, E and Priller, J},
title = {Rapamycin treatment reduces CD11c[+] microglia and increases amyloid plaque load in 5xFAD mice.},
journal = {Experimental neurology},
volume = {401},
number = {},
pages = {115709},
doi = {10.1016/j.expneurol.2026.115709},
pmid = {41855773},
issn = {1090-2430},
abstract = {The mammalian target of rapamycin (mTOR) is involved in immune regulation and in the metabolism of β-amyloid (Aβ) and tau peptides in Alzheimer's disease (AD). In this study, we investigated the effects of the mTOR inhibitor, rapamycin, on central and peripheral immune profiles, proteasome activity, Aβ pathology, and spontaneous exploratory activity and place recognition in the 5xFAD mouse model of amyloid pathology. Using flow cytometry, we found that rapamycin induced changes in immune cell numbers and phenotypes in 5xFAD mice, notably a significant decrease of CD11c[+] microglia in cortex and hippocampus of 5xFAD mice. This was associated with increased Aβ plaque load. Concomitantly, we observed a decrease in immunoproteasome content and activity. In peripheral blood, rapamycin treatment resulted in higher percentages of granulocytes, whereas splenic T lymphocytes were reduced. No changes in the open field and modified Y-maze tests were observed following rapamycin treatment in wild-type and 5xFAD mice. Our results reveal detrimental effects of rapamycin on amyloid plaque accumulation and CD11c[+] disease-associated microglial subsets in cortex and hippocampus of 5xFAD mice, which is an important finding given two ongoing phase 2 clinical studies of rapamycin treatment in AD.},
}

@article {pmid41856031,
year = {2026},
author = {Wang, X and Wang, X and Zhao, H and Zhao, C and Wang, P and Song, T},
title = {A compound pulsed magnetic field achieves superior cognitive benefits against Alzheimer's disease progression via multi-level restoration of neural oscillations and cerebral perfusion.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {2},
pages = {e00887},
doi = {10.1016/j.neurot.2026.e00887},
pmid = {41856031},
issn = {1878-7479},
abstract = {The link between impaired gamma oscillations and Alzheimer's disease (AD) has inspired therapies using rhythmic physical stimuli. However, given that cognition requires cross-frequency interactions like theta-gamma coupling, single-frequency stimulation may yield limited benefits. This study therefore applied a compound pulsed magnetic field (cPMF) with theta rhythm-modulated gamma frequency to evaluate its efficacy and mechanisms against AD pathology compared with single gamma-frequency pulsed magnetic field (sPMF). Local field potential results showed that cPMF outperformed sPMF by significantly enhancing hippocampal oscillations and particularly rescuing the impaired theta-gamma phase-amplitude coupling in AD mice, which was positively correlated with improved cognitive performance in behavioral tests. Correspondingly, cPMF treatment enhanced blood flow perfusion in the prefrontal and cerebral cortices of AD mice, which may contribute to amyloid-β clearance and neuroinflammation attenuation. At the molecular level, cPMF rescued AD-related transcriptional alterations by upregulating key genes involved in cholinergic signaling (Chat, Chrm1), glymphatic function (Aqp4), and synaptic plasticity (Gria1, an AMPA receptor subunit). These findings indicated that cPMF stimulation achieved multi-level restorative effects by enhancing neuronal activity, promoting cerebral perfusion, facilitating amyloid-β clearance, and rectifying aberrant gene expression, ultimately leading to cognitive improvement in AD mice. This cPMF stimulation paradigm highlights the therapeutic potential of targeting endogenous oscillatory interactions for treating neurological disorders.},
}

@article {pmid41844465,
year = {2026},
author = {Liu, J and Cao, F and Li, Z and Zeng, H and Zhou, M and He, Q and Jiang, W and Li, Y and Yan, J},
title = {Association between exogenous hormone use and dementia: A prospective cohort study and synthetic analysis.},
journal = {Maturitas},
volume = {208},
number = {},
pages = {108895},
doi = {10.1016/j.maturitas.2026.108895},
pmid = {41844465},
issn = {1873-4111},
abstract = {OBJECTIVES: To investigate the controversial association between exogenous hormone use (EHU) and dementia, with a focus on subtype-specific risks.

STUDY DESIGN: This prospective cohort study followed 273,069 women in the UK Biobank over 3,802,608 person-years, identifying 4,710 dementia cases.

MAIN OUTCOME MEASURES: Cox models assessed use of oral contraceptive (OC) and hormone replacement therapy (HRT) in relation to all-cause dementia, Alzheimer's disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD) across treatment durations. Subgroup analyses were stratified by age, ethnicity, APOE status, education, income, and reproductive factors. A systematic review was conducted to synthesize existing evidence.

RESULTS: In the cohort study, OC use was associated with reduced risks of all-cause dementia (HR 0.90, 95%CI 0.84-0.95), AD (HR 0.87, 95%CI 0.79-0.95), and VaD (HR 0.81, 95%CI 0.70-0.93), particularly after 4-14 years of use. HRT showed no significant association with increased dementia risk. Synthesized results largely corroborated these findings: OC use was associated with reduced risks of dementia (HR 0.90, 95%CI 0.89-0.92); and although four European studies reported a moderately increased AD risk after post-menopausal HRT use, neither cohort-based studies (HR 0.98, 95%CI 0.90-1.06) nor traditional case-control studies (OR 1.00, 95%CI 0.90-1.11) found an association between HRT and dementia.

CONCLUSIONS: Our combined evidence does not support an increased risk of dementia associated with OC use; similarly, no clear association was observed between HRT and increased dementia risk. Clinical decisions on EHU should be individualized, balancing overall benefits against potential risks.},
}

@article {pmid41844585,
year = {2026},
author = {Yang, M and Tong, L and Guo, Z and Tan, Z and Holmes, TC and Yu, Z and Xu, X},
title = {Evaluating the potential of acupuncture for Alzheimer's disease treatment: A meta-analysis and systematic review of mouse model studies.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-03923-9},
pmid = {41844585},
issn = {2158-3188},
abstract = {Acupuncture is an ancient practice that was developed within the framework of traditional Chinese medicine. While acupuncture has been recently proposed as a therapy for Alzheimer's disease (AD), acupuncture effects are not well understood in terms of neural mechanisms. Here, we review and examine the studies that used AD mouse models and analyze the experiments where researchers administered electroacupuncture (EA) to AD mice to assess the potential therapeutic impact of acupuncture on disease pathology and cognitive function in controlled laboratory settings. We analyzed 29 relevant PubMed articles published between January 2014 and July 2025. Our results reveal that EA significantly reduces both amyloid-beta (Aβ) and phosphorylated tau (p-tau) levels and neuroinflammatory biomarkers, including molecular signatures for activated microglia and astrocytes in the brain. EA also enhances cognitive functions. While no study directly compared acupoint strategies, the indirect comparisons in our network analysis suggest that GV20 has potential as a therapeutic target for AD. Our present meta-analysis and review of literature add to the evidence of integrative health practices for acupuncture-based Alzheimer's disease treatment.},
}

@article {pmid41845487,
year = {2026},
author = {Wu, J and Ge, Y and Zhang, L and Huang, J and Huang, N and Luo, Y},
title = {Tanshinone IIA-pretreated mesenchymal stem cells alleviate neuroinflammation in 3×Tg-AD mice via the TREM2/PI3K/Akt pathway.},
journal = {Stem cell research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13287-026-04954-1},
pmid = {41845487},
issn = {1757-6512},
support = {ZK [2024]-680//Science and Technology Department of Guizhou Province/ ; ZK [2021]-570//Science and Technology Department of Guizhou Province/ ; 82160858//National Natural Science Foundation of China/ ; HZ-2022-45, [2024] No. 6, HZ-2025-06//Zunyi Science and Technology Bureau/ ; ZSYS(2025)040//Guizhou Provincial Science and Technology Department/ ; },
abstract = {Neuroinflammation is a key pathogenic factor for neurodegenerative diseases. Mesenchymal stem cell (MSC) transplantation, as a potential strategy for regulating neuroinflammation, has received extensive attention. Our previous research revealed that compared with ordinary MSC, MSC pretreated with tanshinone IIA (TIIA), referred to as TIIA-MSC, exhibited superior anti-neuroinflammatory activity, but the mechanism of action remains unclear. To clarify the underlying mechanism, this study integrated in vitro and in vivo experiments and evaluated the therapeutic effect of TIIA-MSC in a triple-transgenic Alzheimer's disease mouse model (3×Tg-AD mice) and explored its mechanism of action in a lipopolysaccharide (LPS)-induced BV2 microglial cell inflammation model. The results showed that TIIA-MSC could significantly improve the cognitive function of 3×Tg-AD mice, increase brain glucose metabolism levels, promote the recovery of synaptic and mitochondrial structures, and effectively alleviate neuroinflammatory responses. In vitro experiments further verified the superior inhibitory effect of TIIA-MSC on microglial cell activation and proinflammatory factor release. Mechanistic studies have indicated that the triggering receptor expressed on myeloid cells 2 (TREM2) is the key molecule that mediates this process. The knockdown of TREM2 expression significantly weakened the anti-inflammatory effect of TIIA-MSC, suggesting that TREM2 plays a central role in this process. Further analysis revealed that by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway downstream of TREM2, TIIA-MSC may promote the transformation of the functional state of microglia from mainly proinflammatory to having neuroprotective and repair properties. This study systematically revealed the molecular mechanism by which TIIA-MSC regulate microglial cell phenotypic transformation through the TREM2/PI3K/Akt pathway and exert anti-neuroinflammatory effects, providing new ideas and an experimental basis for expanding the application of MSC in the treatment of neurodegenerative diseases.},
}

@article {pmid41845577,
year = {2026},
author = {Zhao, J and Huang, R and Bu, N and Wang, H and Zhang, S and Pan, Y and Su, Y and Wei, Z and Chen, Y and Li, Y and Dong, X and Li, Y and Wei, J and Zhao, X and Lin, L and Sun, K},
title = {Advances in the Use of Traditional Chinese Medicine Prescriptions for Alzheimer's Disease.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {3},
pages = {e70157},
doi = {10.1111/psyg.70157},
pmid = {41845577},
issn = {1479-8301},
support = {NGBJ-2020-30//The Doctoral Scientific Research Foundation for Returned Scholars from Nanyang Institute of Technology/ ; YJS2025GZZ58//Postgraduate Education Reform and Quality Improvement Project of Henan Province/ ; 242102111123//Henan Provincial Science and Technology Research Project/ ; 222102310357//Science and Technology Research Project of Henan Provincial/ ; },
mesh = {*Alzheimer Disease/drug therapy/therapy ; Humans ; *Medicine, Chinese Traditional/methods ; *Drugs, Chinese Herbal/therapeutic use ; Gastrointestinal Microbiome ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterised by progressive cognitive and memory impairment. Recent research on neurodegenerative diseases has demonstrated the importance of the brain-gut axis, which has gradually become a hotspot in the field of AD research. The gut microbiota has been shown to be involved in the pathogenesis and treatment of neurodegenerative diseases such as AD. Traditional Chinese medicine (TCM) has been used for millennia in China for the treatment of disease. This article summarises recent research on the use of TCM prescriptions for treating AD. It is hoped that this review will provide new ideas for the treatment of AD.},
}

*Alzheimer Disease/drug therapy/therapy
Humans
*Medicine, Chinese Traditional/methods
*Drugs, Chinese Herbal/therapeutic use
Gastrointestinal Microbiome

@article {pmid41845988,
year = {2026},
author = {Zhu, X and Lai, X and Deng, J and Long, Y},
title = {Naturally occurring antibodies against ASC reduced in Alzheimer's disease and alleviating AD-type pathology in APP/PS1 mouse.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115728},
doi = {10.1016/j.expneurol.2026.115728},
pmid = {41845988},
issn = {1090-2430},
abstract = {The disruption or increased permeability of the blood-brain barrier (BBB) results in dysregulated autoantibody profiles in Alzheimer's disease (AD) patients. Naturally occurring antibodies against ASC (NAbs-ASC), which are present in human blood, can block the ability of ASC specks to seed Aβ aggregation. However, the characteristics and functions of NAbs-ASC in AD remain unclear. In this study, we found that plasma levels of NAbs-ASC were reduced in AD patients and showed a negative correlation with the severity of cognitive impairment and with plasma Aβ42/40 ratios. NAbs-ASC treatment reduced Aβ production and attenuated Aβ-induced cytotoxicity in AD cell models. Furthermore, passive immunization with NAbs-ASC or active immunization with ASC peptides improved cognitive function, attenuated Aβ deposition, reduced Tau phosphorylation, inhibited neuroinflammation and apoptosis, and improved synaptic plasticity in APP/PS1 mice. These findings support that NAbs-ASC may be an important physiological protective factor for AD, and that Immunotherapy targeting ASC may be a potential therapeutic intervention for the disease.},
}

@article {pmid41845989,
year = {2026},
author = {Zhao, Y and Chen, W and Zhou, F},
title = {IL-1β neutralization ameliorates cognitive deficits and tau pathology in a mouse model of Alzheimer's disease with Hyperhomocysteinemia.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115729},
doi = {10.1016/j.expneurol.2026.115729},
pmid = {41845989},
issn = {1090-2430},
abstract = {BACKGROUND: Hyperhomocysteinemia (HHcy) is an important risk factor for Alzheimer's disease (AD), but its differential effects on tau pathology and beta-amyloid (Aβ) deposition, as well as the key mediating molecules involved, remain unclear. This study investigates how HHcy influences AD pathology and examines whether interleukin-1β (IL-1β) neutralization can mitigate HHcy-accelerated neurodegeneration.

METHODS: Female 12-month-old 3 × Tg-AD mice were supplemented with methionine water for 7 weeks to induce HHcy. Brain tissues were analyzed for Aβ deposition, tau phosphorylation, oligomerization, and neurofibrillary tangle formation using ELISA, immunohistochemistry, Western blot, and Thioflavin S staining. To assess the role of IL-1β, HHcy-AD mice were treated with an anti-IL-1β monoclonal antibody (mAb; 100 μg, twice weekly for two weeks). Moreover, behavioral performance was evaluated using the Morris water maze for the effect of IL-1β neutralization.

RESULTS: HHcy significantly exacerbated tau pathology, increasing oligomeric tau levels, hyperphosphorylation (AT-8, Ser396, Thr231), and neurofibrillary tangles, particularly in the cortex. In contrast, HHcy had minimal effects on Aβ deposition, only increasing insoluble Aβ1-40. Anti-IL-1β mAb treatment reduced tau phosphorylation and oligomerization, coinciding with inactivation of hippocampal GSK3β (increased p-Ser9). The mAb also improved cognitive function but showed selective effects on Aβ pathology and differentially modulated glial responses across brain regions.

CONCLUSION: HHcy preferentially exacerbates tauopathy rather than amyloidosis in 3 × Tg-AD mice. IL-1β neutralization ameliorates tau-related pathology and cognitive deficits, likely through regional suppression of GSK3β activity, highlighting its potential as a therapeutic strategy for tau-focused AD interventions.},
}

@article {pmid41847148,
year = {2026},
author = {Yuan, X and Tang, Q and Wang, T},
title = {Nanotechnology-based targeted delivery strategies for the treatment of Alzheimer's disease.},
journal = {Nanoscale advances},
volume = {},
number = {},
pages = {},
pmid = {41847148},
issn = {2516-0230},
abstract = {Alzheimer's disease (AD), as a common neurodegenerative disorder, seriously affects human health. However, the treatment of AD has always faced significant challenges and has attracted extensive attention in medical research. In recent years, nanoparticle-based therapeutic strategies have been identified as a promising direction in AD research due to their unique advantages and potential. These strategies leverage the distinctive physical and chemical properties of nanomaterials, enabling them to effectively traverse the blood-brain barrier and directly target pathological sites, thereby minimizing damage to normal tissues and enhancing therapeutic efficacy. This approach holds considerable promise for AD treatment. Current literature indicates that nanomedicines can deliver therapeutic agents, such as approved pharmaceuticals, natural compounds, antibodies, and metal nanoparticles, directly to lesion sites, thereby reducing collateral damage to healthy tissues and improving treatment outcomes. With continuous advancements in nanotechnology and ongoing scientific investigations, there is potential for developing safer and more effective treatment options for AD patients in the future. This review aims to summarize recent developments in nanoparticle-based strategies for AD therapy and elucidate their mechanisms of action, providing new insights for the future development and advancement of nanomedicines in this domain.},
}

@article {pmid41847265,
year = {2025},
author = {Agtas, G and Singh, K and Park, H and Mukerji, S},
title = {Plasma Biomarkers and Cognitive Decline in HIV: Findings from Two U.S. Cohorts.},
journal = {TouchREVIEWS in infectious diseases},
volume = {4},
number = {1},
pages = {22-27},
pmid = {41847265},
issn = {2755-113X},
abstract = {With advances in antiretroviral treatment, the population of older people living with HIV (PLWH) is increasing rapidly, leading to a rise in cognitive impairment related to both HIV and aging. Plasma biomarkers have been extensively investigated as non-invasive tools to help detect neurodegeneration in PLWH. This review compares cross-sectional and longitudinal findings from two recent substudies conducted within U.S. cohorts, the AIDS Clinical Trials Group HAILO study and the Women's Interagency HIV Study (WIHS), both of which investigated the relationship between plasma biomarkers and cognitive performance in PLWH. This review focuses on the common biomarkers evaluated in both studies: neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Both studies demonstrated longitudinal associations between elevated NfL levels and poor cognitive performance, particularly in processing speed. In contrast, GFAP showed inconsistent associations, suggesting its utility will be limited in clinical settings. Given that effect sizes across both studies ranged from small to modest, further validation in diverse aging cohorts with domain specific cognitive assessments is needed before routine clinical use.},
}

@article {pmid41847685,
year = {2026},
author = {Si, C and Ma, L and Ding, W and Tian, Y and Zhang, J and Cao, H and Shao, Y and Fan, Z},
title = {Human umbilical cord mesenchymal stem cells therapy for Alzheimer's disease: a systematic review and meta-analysis of mouse models.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1783757},
pmid = {41847685},
issn = {1664-2295},
abstract = {OBJECTIVE: Given the limitations of current treatments for Alzheimer's disease (AD), this study aims to comprehensively evaluate the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) in AD mouse models through a systematic review and meta-analysis. Additionally, we explore the impact of transplantation dose and route on treatment outcomes to identify the optimal window for clinical application.

METHODS: In accordance with the PRISMA guidelines, we systematically searched four major databases to identify randomized controlled trials involving hUCMSCs in AD mouse models. We used the standardized mean difference (SMD) to synthesize effect sizes and performed subgroup analyses based on pre-defined transplantation routes and doses.

RESULTS: A total of 13 studies were included in the analysis. The meta-analysis revealed that hUCMSCs transplantation significantly improved spatial learning and memory in AD model mice, with a marked reduction in escape latency (SMD = -2.55; 95% CI: -3.34 to -1.75; I [2] = 77.9%, random-effects model). Additionally, it significantly lowered brain β-amyloid levels (SMD = -5.34; 95% CI: -7.21 to -3.47; I [2] = 80.3%), increased brain-derived neurotrophic factor (SMD = 4.25; 95% CI: 3.18 to 5.31), and reduced neuronal apoptosis (SMD = -4.96; 95% CI: -6.52 to -3.41). Subgroup analyses further revealed that efficacy was significantly dose- and route-dependent. For cognitive improvement, intravenous injection of medium to high doses (≥1 × 10[6] cells) was most effective and robust. For amyloid-β clearance, low-dose administration via intravenous, lateral ventricle, and cortical routes showed significant efficacy, whereas bilateral hippocampal injection did not yield significant benefits.

CONCLUSION: Human umbilical cord mesenchymal stem cells can improve behavioral and pathological outcomes in AD mouse models via multiple mechanisms of action. The intravenous route using medium to high doses emerges as a critical factor for achieving optimal effects, providing important evidence and informing future experimental design and clinical translational research.},
}

@article {pmid41848189,
year = {2026},
author = {Shrewsbury, SB},
title = {DHE - past, present, and future: a narrative review.},
journal = {Pain management},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/17581869.2026.2644524},
pmid = {41848189},
issn = {1758-1877},
abstract = {Dihydroergotamine (DHE) was first approved in 1946 for the acute treatment of migraine. Its efficacy when administered as an intravenous (IV) injection explains its enduring use in the management of migraine today. More recently, attention has been focused on the development of formulations delivered by the inhalational route to either the nasal mucosa or lung with the objective of providing a product that enables easy, needle-free, "at-home" use that is rapidly effective. Three new DHE products for migraine (two administered by nasal delivery) have been Food and Drug Administration (FDA) approved in the past five years with two others using pulmonary delivery in clinical development attempting to optimize outcomes for subjects requiring "at-home" migraine treatment. This narrative review describes those DHE development programs, and others that have failed, with the objective of providing a broad perspective on various approaches, including those that may be more likely to achieve the goals of high efficacy rates, rapid relief, and convenience of use. In addition, DHE has been investigated for potential repurposing of other indications. These too are described.},
}

@article {pmid41849958,
year = {2026},
author = {Iwata, A and Sakata, Y and Koizumi, K and Endo, A and Kuang, W and Sumitomo, K and Ishii, M},
title = {Interim analysis of all-case post-marketing surveillance study in Japan: lecanemab in patients with early Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100541},
doi = {10.1016/j.tjpad.2026.100541},
pmid = {41849958},
issn = {2426-0266},
abstract = {BACKGROUND: Lecanemab is a monoclonal antibody targeting amyloid-beta protofibrils, indicated for patients with mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease.

OBJECTIVES: This study reports interim findings of an ongoing, multicenter, prospective, observational post-marketing study for all patients treated with lecanemab in routine clinical practice in Japan, focusing on amyloid-related imaging abnormalities (ARIAs) and infusion-related reactions primarily observed during up to 28 weeks after treatment initiation.

METHODS: Patients treated with lecanemab at any medical institutions across Japan are included in the study. Data are collected using an electronic data capture system via standardized case report forms (CRFs). Study items included the incidence of ARIA, ARIA-edema or effusion (-E), ARIA-hemorrhage (-H: cerebral microhemorrhages, superficial siderosis, and macrohemorrhage), and infusion-related reactions, reported as adverse drug reactions.

RESULTS: As of July 5, 2025, CRFs from 2675 patients were collected, of whom 2672 had data available for the interim analysis. The median age was 76.0 years, and 62.6 % (1672/2672) of patients were diagnosed with MCI. At Week 28, 7.3 % (195/2672) of patients discontinued treatment, with a mean treatment duration of 189.6 ± 34.4 days. Among 2634 patients confirmed to have undergone MRI scans after treatment initiation, ARIA was observed in 7.1 % (188/2634) of patients, ARIA-E in 3.0 % (78/2634), and ARIA-H in 5.2 % (137/2634). Serious ARIA-H (macrohemorrhage) occurred in two patients (0.1 %). Infusion-related reactions were observed in 17.0 % (455/2672), including 0.7 % (18/2672) serious cases. The proportion of patients who experienced ARIA was highest in patients with apolipoprotein E (APOE) ε4 homozygotes.

CONCLUSION: This interim analysis represents one of the largest real-world lecanemab cohorts reported globally to date. Although absolute rates are not directly comparable with those from clinical trials, the trends in ARIA distributions across APOE genotypes and infusion-related reactions were comparable to those observed in clinical trials.},
}

@article {pmid41839135,
year = {2025},
author = {Cortés-Rodríguez, A and Alves-Gomes, L and Losa-Iglesias, ME and Gómez-Salgado, J and Becerro-de-Bengoa-Vallejo, R and Saavedra-García, MA and López-López, D and Jiménez-Cebrián, AM},
title = {Repercussion of kinesiophobia in ankylosing spondylitis: a case-control study.},
journal = {Gaceta medica de Mexico},
volume = {161},
number = {4},
pages = {379-384},
doi = {10.24875/GMM.25000033},
pmid = {41839135},
issn = {0016-3813},
mesh = {Humans ; Male ; Case-Control Studies ; *Spondylitis, Ankylosing/psychology/complications ; Female ; Middle Aged ; *Phobic Disorders/epidemiology/etiology ; Adult ; *Alzheimer Disease/psychology/complications ; Surveys and Questionnaires ; *Fear/psychology ; Aged ; Movement ; Kinesiophobia ; },
abstract = {BACKGROUND: Kinesiophobia, or fear of movement, is closely related to ankylosing spondylitis. This fear can make it profoundly difficult to relieve symptoms by discouraging participation in therapeutic exercises.

OBJECTIVES: The aim of this study was to assess and contrast the perceived levels of safety and confidence during movement tasks.

MATERIALS AND METHODS: A total of 104 individuals were recruited. This group was divided into cases and controls, ensuring alignment in terms of age, sex, and body mass index. Demographic information was collected and scores on the Tampa Scale for Kinesiophobia -11 questionnaire were recorded for further comparison.

RESULTS: All individuals with Alzheimer's disease (AD) suffered from some degree of kinesiophobia, and 77% had moderate to maximum scores. In contrast, in the control group, without AEs, none presented maximum levels, and 76.9% presented scores with mild or no levels of kinesiophobia. The comparison between groups showed a statistically significant difference.

CONCLUSION: Kinesiophobia was significantly higher in AD patients compared to healthy individuals, emphasizing the need for specific interventions to manage this condition in treatment plans.},
}

Humans
Male
Case-Control Studies
*Spondylitis, Ankylosing/psychology/complications
Female
Middle Aged
*Phobic Disorders/epidemiology/etiology
Adult
*Alzheimer Disease/psychology/complications
Surveys and Questionnaires
*Fear/psychology
Aged
Movement
Kinesiophobia

@article {pmid41839797,
year = {2026},
author = {Fallone, M and Sivananthan, M and Joseph, M},
title = {Donepezil for Korsakoff Syndrome.},
journal = {American journal of therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1097/MJT.0000000000002102},
pmid = {41839797},
issn = {1536-3686},
abstract = {BACKGROUND: Korsakoff syndrome is a neurocognitive disorder characterized by memory impairment and confabulation caused by severe or prolonged thiamine deficiency. It is preceded by a type of delirium called Wernickes Encephalopathy, which is reversible. However, once a patient progresses to Korsakoff syndrome, treatment options are limited because there are currently no FDA-approved medications for Korsakoff syndrome. Donepezil is an acetylcholinesterase inhibitor that has shown efficacy in Alzheimer disease and has been theorized to have benefit in other neurologic disorders as well. In this case, we present a patient with Korsakoff syndrome who had improvement in symptoms after starting donepezil.

DATA SOURCE: The information presented here is derived directly from the clinical records and observations of the patient under our care.

FINDINGS AND LIMITATIONS: The case presented here demonstrates improvement in cognition, motivation, and affect in Korsakoff dementia with the use of donepezil. Limitations of this case study and those alike include lack of generalizability, retrospective design, and absence of a control.

CONCLUSIONS: The off-label use of donepezil for Korsakoff syndrome in this case and others has been shown to be beneficial and well tolerated. Ultimately, larger studies are needed to determine safety and efficacy.},
}

@article {pmid41839802,
year = {2026},
author = {Xu, YR and Tao, Y and Lish, AM and Li, S and Ostaszewski, BL and Anderson, AK and Young-Pearse, T and Lawton, TL and Yang, HS and Walsh, DM and Yang, T and Selkoe, DJ},
title = {Novel Monoclonal Antibody Detects Small Aβ Oligomers More Sensitively Than Lecanemab in Alzheimer's Disease CSF, Serum and Culture Media.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78196},
pmid = {41839802},
issn = {1531-8249},
abstract = {OBJECTIVE: Aqueously diffusible oligomers of the amyloid β-protein (oAβ) are neurotoxic and play a role in neuronal dysfunction in Alzheimer's disease (AD). Accurate quantification of oAβ in brains and biofluids could be valuable for understanding and monitoring AD. In this study, we aimed to examine the ability of 2 antibodies to quantify diffusible oAβ in AD tissue and biofluids.

METHODS: Two oligomer preferring antibodies, 71A1 and lecanemab, were compared to quantify oAβ assemblies in AD brain tissue, cerebrospinal fluid (CSF), serum, and culture media of human neurons expressing Aβ-altering mutations.

RESULTS: Both antibodies recognized synthetic aggregates of Aβ and detected significantly elevated oAβ levels in aqueous extracts of AD versus control brain tissues. Only 71A1 sensitively quantified diffusible oAβ species in CSF, neuronal media, and serum.

INTERPRETATION: Whereas lecanemab is an effective plaque-clearing immunotherapy that robustly detects higher-order Aβ aggregates in AD brain, its preferred Aβ targets are present at very low levels in biofluids. Our results demonstrate that 71A1 detects low-n, diffusible Aβ oligomers that predominate in CSF, serum, and neuronal media that associate with AD-related pathology. Together, these findings indicate that Aβ oligomer populations distribute differently in brain tissue versus biofluids and inform the selection of assays for monitoring oligomers during AD progression and treatment. ANN NEUROL 2026.},
}

@article {pmid41840318,
year = {2026},
author = {Paliwal, S and Bhardwaj, JS and Yang, CH and Taliyan, R},
title = {Unravelling Epigenetic Modulation via MicroRNA Delivery: A Therapeutic Frontier for Alzheimer's.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41840318},
issn = {1559-1182},
support = {BT/INF/22/SP42545/2021//Department of Biotechnology- BUILDER/ ; },
mesh = {*MicroRNAs/administration & dosage/genetics/metabolism ; *Alzheimer Disease/genetics/therapy ; Humans ; *Epigenesis, Genetic ; Animals ; *Gene Transfer Techniques ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is a common form of dementia that primarily affects the elderly population. Several signalling pathways, including Wnt/β-catenin and PI3K/Akt, are significantly affected, disrupting normal physiological processes such as neurogenesis, neuronal survival, neuroinflammation, and BBB disruption, all of which contribute to the progression of AD-like conditions. The current study seeks to investigate and evaluate the involvement of the PI3K-Akt and Wnt/β-catenin pathways in AD, as well as epigenetic regulators that may alter these pathways and be employed as a treatment to improve AD-like conditions. A class of epigenetic regulators known as miRNAs, or short non-coding RNAs, greatly affects gene expression by preventing translation or encouraging target gene destruction. This review will focus on how miRNAs affect Aβ peptide accumulation, hyperphosphorylated tau protein aggregation, and neuroinflammation. In addition, miRNA delivery through exosomes, a lipid nanoparticle, has also been explored in later sections. Our knowledge will assist in creating new miRNA-based therapeutics involving mimics/inhibitors and advance our understanding of how miRNAs control gene expression.},
}

*MicroRNAs/administration & dosage/genetics/metabolism
*Alzheimer Disease/genetics/therapy
Humans
*Epigenesis, Genetic
Animals
*Gene Transfer Techniques
tau Proteins/metabolism

@article {pmid41843546,
year = {2026},
author = {Stingl, J and Guyette, FX and Drábek, T},
title = {Accidental Environmental Hypothermia in a Nonagenarian Resulting in Cardiac Arrest.},
journal = {Prague medical report},
volume = {127},
number = {1},
pages = {39-43},
doi = {10.14712/23362936.2026.6},
pmid = {41843546},
issn = {1214-6994},
mesh = {Humans ; Female ; *Heart Arrest/etiology/therapy ; *Hypothermia/complications/therapy ; Aged, 80 and over ; },
abstract = {Accidental hypothermia after environmental exposure and/or impaired thermoregulation resulting in significant decrease in body temperature and cardiac arrest (CA) is linked to 1,500 deaths annually in the United States. Hypothermic CA treatment has specific presentation and clinical features. With appropriate treatment, its survival can reach 27-70%, contrasting ~ 10% in medical CA. Majority of accidental hypothermic CA survivors recover with favourable neurologic outcome. An integrated, dedicated multi-disciplinary team-approach is essential to maximize the chances of survival. We report on a 91-year-old female who was found outside and unresponsive in freezing temperatures. During transport, she required bag-and-mask ventilation. An esophageal temperature recorded 24.5 °C. Shortly after rapid sequence intubation, she developed CA. She was successfully resuscitated with chest compressions, epinephrine, atropine, and two defibrillations. Due to persistent hypothermia and bradycardia, she was rewarmed using extracorporeal membrane oxygenation. Perioperative transesophageal echocardiography showed normal cardiac function. She was extubated the next day. She remained stable for the rest of her hospital stay without focal neurological deficits on serial examinations. However, her post-arrest stay was complicated by acute delirium, likely from underlying dementia, with a waxing and waning level of consciousness, confusion, agitation and hallucinations. She was discharged on post-operative day 5. Her long-term recovery was complicated by repeated aspiration pneumonias, and gradual decline of her mental status due to Alzheimer's dementia. She died approximately two years later at the age of 93. Thus, full neurologic recovery remains possible after CA induced by severe hypothermia from environmental exposure, despite extreme age and frailty.},
}

Humans
Female
*Heart Arrest/etiology/therapy
*Hypothermia/complications/therapy
Aged, 80 and over

@article {pmid41844366,
year = {2026},
author = {Duan, J and Engelman, CD and Lu, Q and Kang, H},
title = {Comparison of Methods for Sensitivity Analysis of Heterogeneous Treatment Effects in Observational Studies and Application to Alzheimer's Disease and Cognitive Decline.},
journal = {Statistics in medicine},
volume = {45},
number = {6-7},
pages = {e70446},
doi = {10.1002/sim.70446},
pmid = {41844366},
issn = {1097-0258},
mesh = {Humans ; *Alzheimer Disease/therapy ; *Cognitive Dysfunction/therapy/etiology ; *Observational Studies as Topic/statistics & numerical data/methods ; Male ; Models, Statistical ; Female ; Treatment Outcome ; Sleep Wake Disorders/complications ; Treatment Effect Heterogeneity ; },
abstract = {In Alzheimer's disease (AD) research, many observational studies have shown that the effect of sleeping quality, a modifiable risk factor, on cognitive decline is heterogeneous, where some adults experience faster rates of cognitive decline compared to others. However, these effects are likely confounded by unmeasured confounders, and the sensitivity of these effects to unmeasured confounders may be heterogeneous, where one subgroup's treatment effect is more sensitive than that of another subgroup. Unfortunately, compared to the overall treatment effect, there are limited investigations about the sensitivity of heterogeneous treatment effects to unmeasured confounding. The paper presents and compares methods for sensitivity analysis of heterogeneous effects in observational studies based on Rosenbaum's model for sensitivity analysis. We show that, unlike the sensitivity analysis of the overall treatment effect, the sensitivity of heterogeneous treatment effects depends on the variation in the effect sizes across subgroups and the correction for multiple testing. The data analysis further supports our findings where the overall effect of sleep disturbances on cognitive decline is significant (p $$ p $$ -value = 5 . 55 × 1 0 - 5 $$ 5.55\times 1{0}^
{-5}
$$). Also, the effect is more severe among males (p $$ p $$ -value = 2 . 00 × 1 0 - 4 $$ 2.00\times 1{0}^
{-4}
$$) and insensitive to a moderate degree of unmeasured confounding. Finally, we offer an easy-to-use R software to carry out the sensitivity analyses for heterogeneous treatment effects.},
}

Humans
*Alzheimer Disease/therapy
*Cognitive Dysfunction/therapy/etiology
*Observational Studies as Topic/statistics & numerical data/methods
Male
Models, Statistical
Female
Treatment Outcome
Sleep Wake Disorders/complications
Treatment Effect Heterogeneity

@article {pmid41844398,
year = {2026},
author = {Hou, Y and Huang, G and Liu, Y and Qiu, Y and Ye, P and Bi, L and Zheng, P and Xu, Y and Wu, S and Wei, C and Jin, H},
title = {Rescue of Cognitive Deficits in a Mouse Model of Alzheimer's Disease with a Novel Brominated P2 × 7 Receptor Antagonist.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00127},
pmid = {41844398},
issn = {1948-7193},
abstract = {P2 × 7 receptor (P2 × 7R) represents a promising therapeutic target for Alzheimer's disease (AD), given its marked upregulation in neuroinflammation and involvement in amyloid-β (Aβ) and tau pathology. Although several P2 × 7R antagonists with high central nervous system (CNS) penetration and cross-species activity have been developed, none have yet reached clinical use, underscoring the need for optimized agents suitable for chronic neurological conditions. In this study, we designed a series of brominated P2 × 7R antagonists based on a prominent antagonist Lu AF27139, among which the lead compound YH1 exhibited favorable lipophilicity, brain penetration, plasma stability, and receptor binding. In transgenic AD mice, YH1 treatment significantly alleviated cognitive deficits, reduced cerebral P2 × 7R expression, and decreased Aβ load. Using [18]F-GSK1482160 positron emission tomography (PET) imaging, we observed a significant decline of P2 × 7R binding, indicating that YH1-mediated cognitive improvement involves targeted suppression of P2 × 7R-driven neuroinflammation. These results establish a precision AD-oriented optimization of the Lu AF27139 scaffold, demonstrate measurable PK improvements, and provide the first PET-verified P2 × 7R target engagement in an AD model, supporting translational relevance.},
}

@article {pmid41830246,
year = {2026},
author = {Li, H and Zhou, HL and Chen, L and Wu, B},
title = {[Occurrence Characteristics and Associated Factors of Alzheimer's Disease Drugs in Wastewater in China].},
journal = {Huan jing ke xue= Huanjing kexue},
volume = {47},
number = {3},
pages = {1657-1664},
doi = {10.13227/j.hjkx.202503326},
pmid = {41830246},
issn = {0250-3301},
mesh = {China ; *Wastewater/chemistry/analysis ; *Alzheimer Disease/drug therapy ; *Water Pollutants, Chemical/analysis ; Humans ; Memantine/analysis/therapeutic use ; Environmental Monitoring ; Rivastigmine/analysis ; Galantamine/analysis/therapeutic use ; Donepezil ; Indans/analysis ; Piperidines/analysis ; Waste Disposal, Fluid ; },
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disease. The usage of its therapeutic drugs is increasing with the intensification of population aging. These drugs cannot be completely metabolized in the human body and enter wastewater systems in the form of the originals or metabolites. In-depth investigation of the occurrence characteristics of these drugs in wastewater is of great significance for effective control and management. The concentrations and associated factors of four main AD drugs (donepezil, rivastigmine, galantamine, and memantine) and their metabolites in the influent of 210 wastewater treatment plants across 31 Chinese provinces were analyzed. The results indicated that detection rates of the above drugs in wastewater were high, with concentrations ranging from 7.47-21.60 ng·L[-1]. Among them, the concentration of donepezil was significantly higher in East China and the Northwest and Northeast regions than that in Central China; the concentrations of rivastigmine and galantamine in Southwest China were significantly higher than those in East China; and the concentrations of memantine in Northwest and North China were significantly higher than those in East China. The above results indicated that the occurrence of these drugs showed a significant regional difference. Further, the AD drugs and metabolites with detection rates above 90% and excretion rates exceeding 20% (donepezil, rivastigmine metabolite, galantamine metabolite, and memantine) were chosen as biomarkers to evaluate AD prevalence. The prevalence of AD in different regions was estimated by wastewater-based epidemiology method, and the results were highly consistent with official statistical data. These results showed that the concentrations of AD drugs in wastewater influent were closely related to the AD prevalence. Additionally, correlation analysis also found that socioeconomic factors (such as stress, aging population, level of economic development, and health care services) had a significant positive correlation with the AD prevalence, indicating that socioeconomic factors may influence the occurrence of AD drugs in wastewater by affecting the AD prevalence. These results provide a scientific basis for further understanding of the characteristics of AD drugs in wastewater treatment plants and the development of corresponding control measures.},
}

China
*Wastewater/chemistry/analysis
*Alzheimer Disease/drug therapy
*Water Pollutants, Chemical/analysis
Humans
Memantine/analysis/therapeutic use
Environmental Monitoring
Rivastigmine/analysis
Galantamine/analysis/therapeutic use
Donepezil
Indans/analysis
Piperidines/analysis
Waste Disposal, Fluid

@article {pmid41830758,
year = {2026},
author = {Thibault, EG and Del Carmen Montenegro, G and Becker, JA and Price, JC and Healy, BC and Hanseeuw, BJ and Buckley, RF and Jacobs, HIL and Properzi, MJ and Sperling, RA and Johnson, KA and Farrell, ME},
title = {Amyloid spatial extent with florbetapir-PET for early detection of preclinical Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100529},
doi = {10.1016/j.tjpad.2026.100529},
pmid = {41830758},
issn = {2426-0266},
abstract = {BACKGROUND: Prevention of Alzheimer's disease (AD) requires biomarkers sensitive to the earliest amyloid-β (Aβ) deposits.

OBJECTIVES: To characterize performance of a recently-developed Aβ-PET spatial extent metric (EXT) for early Aβ detection using [18][F]-florbetapir (FBP)-PET, evaluating its sensitivity, reliability, and associations with plasma pTau217, tau-PET, and cognition.

DESIGN: Longitudinal study with up to 5.5 years of PET, plasma and cognitive measures.

SETTING: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) Study and its companion screen-fail study Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) conducted across 67 international sites.

PARTICIPANTS: 1118 cognitively unimpaired older adults from the A4 placebo arm and LEARN.

MEASUREMENTS: EXT (% of neocortex above region-specific thresholds), global Aβ SUVR, plasma pTau217, medial temporal (MTL) and temporal neocortical (nTEMP) tau-PET SUVR, and Preclinical Alzheimer Cognitive Composite (PACC).

RESULTS: EXT showed high cross-sectional reliability and longitudinal stability. Using EXT reclassified 21.4% of SUVR-participants from Aβ- to Aβ+ and predicted who would progress to SUVR+ 5.5 years later with 83% sensitivity and 94% specificity. In SUVR- individuals, higher pTau217 associated with greater SUVR only within EXT+ individuals. Baseline EXT outperformed SUVR in predicting MTL tau proliferation. For neocortical tau SUVR and PACC change, EXT was the better predictor in earlier Aβ stages (while Aβ spread) while SUVR was superior later (after Aβ was widespread).

CONCLUSIONS: EXT is a robust, generalizable PET metric that detects Aβ before global positivity and early Aβ-related changes in tau and cognition, supporting its relevance for trial enrichment and early therapeutic monitoring in AD prevention trials.},
}

@article {pmid41830836,
year = {2026},
author = {Xu, G and Gao, P and Li, H and Fang, Y and Yang, Z},
title = {Research progress of PTP1B inhibitors and degraders.},
journal = {European journal of medicinal chemistry},
volume = {309},
number = {},
pages = {118770},
doi = {10.1016/j.ejmech.2026.118770},
pmid = {41830836},
issn = {1768-3254},
abstract = {Protein tyrosine phosphatase 1B (PTP1B), a member of the PTP superfamily, inhibits insulin signaling by dephosphorylating the insulin receptor (IR) and its substrates (IRS), making it an important therapeutic target for diabetes and obesity, with potential applications in treating metabolic syndrome. Furthermore, studies have shown that inhibiting PTP1B may also hold promise in diseases such as Alzheimer's disease and fatty liver disease, and may exert therapeutic effects in cancer by suppressing oncogenic signaling pathways. However, developing inhibitors with selectivity and oral bioavailability remains a major challenge due to the positively charged, highly conserved catalytic site of the PTP superfamily and its strong structural similarity to homologous PTPs. PTP1B degraders represent a novel therapeutic strategy that specifically eliminates intracellular PTP1B protein through targeted degradation mechanisms. This approach aims to overcome the "undruggable" limitations of traditional inhibitors and may offer potential treatment avenues for various PTP1B-related diseases. This review summarizes recently reported PTP1B inhibitors and degraders, including natural products, derivatives of natural products, synthetic small molecules, dual-target inhibitors, as well as advances in PTP1B degraders. It aims to provide a foundation for the rational design and further investigation of PTP1B inhibitors and degraders.},
}

@article {pmid41831271,
year = {2026},
author = {Muralidhar, D and Kumar, P},
title = {Positron emission tomography-based radiopharmaceuticals for imaging the expression and function of multidrug resistance P-glycoprotein.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {393},
number = {4},
pages = {104307},
doi = {10.1016/j.jpet.2026.104307},
pmid = {41831271},
issn = {1521-0103},
abstract = {Multidrug resistance is a major reason for drug resistance in patients undergoing chemotherapy or other drug therapy. The overexpression of efflux proteins, such as multidrug resistance protein or P-glycoprotein (P-gp), has been recognized as a major cause of the drugs' efflux from the brain. P-gp expression is not only responsible for drug resistance, but underactivity leads to the accumulation of amyloid proteins and may become one of the reasons for Alzheimer disease. Hence, measuring the activity of the efflux proteins can indicate whether the candidate is suitable for chemotherapy. Therefore, several radiotracers have been developed to image P-gp activity. Positron emission tomography imaging can assess P-gp function and, therefore, plays a crucial role in informing clinicians' decisions to adjust treatment. This review article discusses advancements in radiopharmaceuticals for imaging P-gp function and expression, particularly at the blood-brain barrier. It highlights the significance of various radiolabeled tracers, including verapamil, metoclopramide, and MC225, in assessing P-gp-mediated drug delivery to the brain and its role in various neurodisorders. This article discusses the outcomes of various radiopharmaceuticals used in imaging P-gp expression and function. SIGNIFICANCE STATEMENT: This review article highlights the evolution of radiopharmaceuticals for imaging P-gp in various disorders, including drug resistance, Alzheimer disease, and epilepsy. P-gp imaging can play a crucial role in drug development and aid in identifying tumors that are responsive or resistant to chemotherapy. It may help clinicians decide whether a patient is suitable for chemotherapy. Positron emission tomography imaging can provide information on P-gp activity, which can be assessed before and during chemotherapy.},
}

@article {pmid41831326,
year = {2026},
author = {Furlan, R and Di Sapio, A and Ferraro, D and Rossi, E and Valentino, P and Terracciano, D},
title = {Translating neurofilament light chain testing into clinical practice: a multidisciplinary implementation roadmap.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {41831326},
issn = {1437-4331},
abstract = {Neurofilament light chain (NfL) has been identified as a sensitive and broadly validated biomarker of neuroaxonal injury across multiple neurological conditions, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and atypical parkinsonian syndromes. This position paper provides a multidisciplinary roadmap for translating circulating NfL testing into routine clinical practice, integrating analytical, interpretative, and organizational dimensions. It summarizes the biological basis and clinical evidence supporting NfL as a diagnostic, prognostic, and monitoring tool, emphasizing its high sensitivity to neuroaxonal injury across both acute inflammatory and chronic degenerative processes. Comparative analysis of immunoassay technologies identifies strengths and critical sources of variability, while operational guidelines highlight the need for pre-analytical standardization, inter-laboratory harmonization, and participation in quality control schemes. Confounders such as age, BMI, renal function, and comorbidities are shown to significantly influence interpretation, supporting the use of age-adjusted Z-scores, percentiles, and longitudinal normalization for accurate patient-level evaluation. From a clinical standpoint, the paper focuses on practical indications for NfL testing in MS, recommending its use for disease activity prediction and monitoring, treatment decisions and treatment response assessment. Integration of blood NfL with magnetic resonance imaging (MRI), glial fibrillary acidic protein (GFAP) and other biomarkers measurement is proposed as a core strategy for biomarker-driven precision neurology. The authors outline an implementation model encompassing laboratory validation, structured reporting and alignment with national neurological care pathways. They conclude that the transition of NfL into clinical use requires harmonized analytical procedures, interdisciplinary education, and sustainable governance frameworks. Priority actions include regulatory qualification, establishment of international reference materials, and development of pragmatic real-world trials to consolidate its clinical utility. When these measures are achieved, NfL will represent a cornerstone biomarker for precision neurology and neurodegeneration monitoring.},
}

@article {pmid41831370,
year = {2026},
author = {Perry, R and Kipps, C and Martín, MES and Bozzali, M and Logroscino, G and Trafford, S and Dhadda, S and Kanekiyo, M and Goodwin, A and Hodgkinson, M and Hersch, S and Irizarry, M and Kramer, L and Froelich, L},
title = {Corrigendum to "Lecanemab for treatment of individuals with early Alzheimer's Disease (AD) who are apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes" [The Journal of Prevention of Alzheimer's Disease (2026) 100507].},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {4},
pages = {100527},
doi = {10.1016/j.tjpad.2026.100527},
pmid = {41831370},
issn = {2426-0266},
}

@article {pmid41831376,
year = {2026},
author = {Jacobson, M and Deuschle, C and Peneva, D and Wang, AN and Roache, C and Walsh, M and Ferrell, PB and Manetas, MA and Raman, R and Aisen, P and Goldman, D},
title = {Evaluating evidence-based recruitment strategies for Alzheimer's disease and related dementias clinical trial research: A literature review.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100532},
doi = {10.1016/j.tjpad.2026.100532},
pmid = {41831376},
issn = {2426-0266},
abstract = {BACKGROUND: With the prevalence of Alzheimer's disease and related dementias (ADRD) rising, prevention and treatment clinical trials are increasingly important. Yet inadequate participant recruitment to ADRD research-a leading cause of trial delays, suspensions, or discontinuations-continues to hinder innovation and increase costs. This literature review aimed to identify ADRD recruitment strategies that are effective and ineffective, based on quantitative outcomes, with the goal of optimizing recruitment and advancing recruitment science.

METHODS: PubMed, Google Scholar, relevant ADRD websites, and references were searched for studies meeting inclusion criteria-those reporting quantitative outcomes aimed at improving recruitment rates, timely recruitment, or representation. Reference lists from relevant systematic reviews and meta-analyses, including publications from leading researchers, were also examined. The Mixed Methods Appraisal Tool (MMAT) was used to assess evidence quality.

RESULTS: The search yielded 965 publications, of which 50 met inclusion criteria. Few studies reported recruitment methods for pharmacological trials, and many lacked sufficient detail or standardized reporting to assess quality using MMAT criteria, making it difficult to determine effectiveness. Recruitment efforts deemed successful by study authors often relied on multi-pronged approaches integrating community engagement, structured outreach, and digital tools. However, evidence for effective and scalable strategies remains limited.

CONCLUSION: Advancing ADRD recruitment science requires progress in two key areas: embedding recruitment evaluation directly into trial protocols and encouraging broader sharing of recruitment data. Routine practices, such as publishing recruitment outcomes and adopting standardized reporting, can help close the evidence gap. These approaches enable comparison, replication, and generalizability of effective strategies, ultimately accelerating progress in ADRD research.},
}

@article {pmid41832672,
year = {2026},
author = {Haddadi, A and Heidari, A and Rezaei, N},
title = {Alzheimer's Disease, Circadian Rhythms, and the Immune System: Potential Interconnections.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128433445251211165723},
pmid = {41832672},
issn = {1873-4286},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, marked by the accumulation of amyloid-β plaques and neurofibrillary tangles. Its incidence is rising as the global population ages. This narrative review explores the emerging interconnections among AD, circadian rhythms, and the immune system. The circadian system, governed by endogenous clocks, regulates key physiological processes and exhibits disruptions in the early stages of AD. Chronodisruption, disturbance of circadian rhythms, has been implicated in AD pathogenesis through its effects on metabolism, sleep, and neuroinflammation. The immune system also plays a central role in AD, with microglia and astrocytes contributing to disease progression. Immune function displays circadian variation, and disruptions in sleep and circadian timing may impair immune responses, promote inflammation, and compromise amyloid-β clearance. Therapeutic strategies targeting circadian regulation, including melatonin agonists and orexin receptor antagonists, may help mitigate cognitive decline. Additionally, the gut microbiome, modulated by circadian and sleep patterns, has emerged as a potential contributor to AD pathophysiology. This review also highlights interventions that support immune health, such as the Mediterranean diet, antiviral therapies, and physical activity, which may collectively attenuate AD risk. Finally, the bidirectional relationship between immune signaling and circadian rhythms, evidenced by immune modulation of clock genes, underscores a complex, integrated regulatory network. Understanding these interrelated systems may uncover novel approaches for prevention and treatment. By elucidating these interconnections, this review aims to shed light on novel therapeutic strategies and interventions that address multiple facets of the disease, offering potential avenues to improve outcomes for individuals with AD.},
}

@article {pmid41832727,
year = {2026},
author = {Sharma, M and Mazumder, R and Padhi, S and Shivangi, },
title = {Target-Based Drug Delivery Approaches against Alzheimer's Disease - Recent Updates.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266421105251206211422},
pmid = {41832727},
issn = {1873-4294},
abstract = {Millions of people worldwide suffer from Alzheimer's disease (AD), a crippling neurological illness. The ongoing rise of AD necessitates the rapid development of effective preventive and therapeutic approaches. Existing pharmacologic treatments for AD are divided into two categories: acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, both of which have numerous adverse effects and are largely ineffective in slowing disease progression. Current treatments for AD face challenges such as limited bioavailability and the difficulty of crossing the brain's protective barriers, known as the Blood-Brain Barrier (BBB). The side effects of these drugs include dizziness, elevated blood pressure, constipation, vomiting, and cramping of abdominal muscles. In this review, we focus on novel targets, including the Tau protein, M1 mAChR, and PDE4s, along with their intricate mechanisms of action in AD, which have shown promising outcomes in numerous studies for successful treatment. Additionally, we discuss synthetic and herbal medications that act on these novel targets, including orthosteric agonists, allosteric compounds, and positive allosteric modulators (PAMs) of M1 mAChR, as well as taubased natural products as AD therapeutics. Examples include the microtubule stabilizer paclitaxel from the Pacific Yew Taxus brevifolia and the anti-amyloid agent curcumin, isolated from turmeric. The role of PDE4 in the coordination of cAMP response element-binding signaling in AD is also covered in this review. We highlight the advantages of specifically targeting PDE4D and discuss the use of herbal medications such as resveratrol, curcumin, 6-gingerol, and capsaicin, which are effective AD therapeutics and potential PDE4D inhibitors.},
}

@article {pmid41833033,
year = {2026},
author = {Mallick, K and Ruwatia, R and Mondal, AC and Banerjee, S},
title = {Neurosteroids in Neurological and Psychiatric Disorders: Therapeutic Implications.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273411580251203115939},
pmid = {41833033},
issn = {1996-3181},
abstract = {Neurosteroids play a significant role in brain functions with substantial implications for mood regulation, seizure susceptibility, stress response, and potential therapeutic applications. However, dysregulation of steroidogenesis and its signalling is associated with various neurological and psychiatric disorders, such as major depressive disorder, schizophrenia, tourette syndrome and post-traumatic stress disorder, with altered levels of neuroactive steroids contributing to these conditions. Neurosteroids can counteract the effects of stress by enhancing GABAergic inhibition, thereby helping to maintain emotional homeostasis. Furthermore, neuroinflammatory processes linked to neurodegenerative diseases, including Alzheimer's and Parkinson's, can disrupt neurosteroid synthesis. The potential for therapeutic modulation of neurosteroid biosynthesis via ligands targeting steroidogenic pathways offers an exciting avenue for treatment. Despite the promise of neuroactive steroids, their rapid metabolism and low oral bioavailability pose significant challenges. Consequently, extensive research is now focused on developing synthetic analogues and modulators that can modulate neuroactive steroid synthesis and metabolism. This review is based on an understanding of neuroactive steroids and their role in neurological disorders.},
}

@article {pmid41833049,
year = {2026},
author = {Yanchao, L and Yuchen, L and Huan, X and Yuyan, G and Junfei, Z and Roumiantsev, S and Mashkin, A and Beylerli, O and Gareev, I and Sibin, Z and Yang, G},
title = {Immune Cell Infiltration and Key Gene Identification in Alzheimer's Disease and Sleep Deprivation.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273402581251127144625},
pmid = {41833049},
issn = {1996-3181},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by Amyloid-β plaques and neurofibrillary tangles. Disrupted circadian rhythms are common in AD and may worsen cognitive decline and psychological symptoms. The link between sleep deprivation and Alzheimer's risk remains unclear. This study aimed to identify potential diagnostic markers for Alzheimer's and sleep deprivation, focusing on the role of immune cell infiltration in disease progression.

MATERIALS AND METHODS: We examined AD expression data from the GEO database and sleep deprivation(SD)-related data from GeneCards. Using LIMMA on the GSE15222 dataset, we found 209 DEGs, analyzed them with four machine learning algorithms, and identified four Hub genes. We validated these findings with the GSE33000 dataset. CIBERSORT was employed to analyze 22 immune cell features, and Spearman correlation was used to assess the link between diagnostic markers and immune cells.

RESULTS: AD and SD were linked to immune microenvironment changes. Initially, 1568 potential key genes were identified, and Venn analysis revealed 209 overlapping regions. Machine learning validated four key genes, confirming their high predictive accuracy. Significant differences in immune cell expression were found in AD samples, and correlation analysis showed CIT, FASN, ELK1, and GFAP were significantly associated with various immune cells.

CONCLUSION: CIT, FASN, ELK1, and GFAP are key genes linked to pathology progression in AD and SD within the immune microenvironment. Identifying molecular subgroups may offer new perspectives for personalized Alzheimer's treatment.},
}

@article {pmid41833051,
year = {2026},
author = {Thorat, DS and Uddin, MJ and Hag Ibrahim, RI and Oladosu, TA and Sahu, KK and Chidrawar, VR and Singh, S and Nagime, PV and Basu, B and Shafi, S},
title = {Reconnoitering the Potential of the Pharmacogenomics Approach in the Management of Alzheimer's Disease: A Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273388245251113054232},
pmid = {41833051},
issn = {1996-3181},
abstract = {Alzheimer's disease (AD) is a neurological disorder that affects adults worldwide. AD is also an essential geriatric disorder because of its significant emotional and economic impact on individuals, their loved ones, and society. Traditional treatments do not account for the genetic heterogeneity among patients, leading to variable therapeutic effects. Pharmacogenomics customizes medicinal therapies based on a person's genetic profile, enhances efficacy, and minimizes side effects. This review examines how genetic variables affect responses to drugs in neurodegenerative illnesses and the potential for pharmacogenomics to improve treatment. This review explores the possibility of pharmacogenomics in clinical practice, including ethical and data integration concerns. Furthermore, this review discusses the hypothesis of the effects of mutant presenilin on AD therapeutics, along with several clinical trial drugs, their effects, and possible treatment opportunities. Additionally, this review provides insights into prospects and potential treatment strategies for AD. The use of pharmacogenetic/pharmacogenomic procedures in AD studies and clinical trials can help generate cost-effective medications while also increasing therapeutic safety and efficacy.},
}

@article {pmid41833245,
year = {2026},
author = {Rajkumar, M and Kirubakaran, D and Govindaraj, P and Shanmugarathinam, A and Deepak, P and Rajkumar, P and Uvarajan, D and Uddandrao, VVS and Manikandan, R and Balamurugan, P},
title = {Recent advances in polymeric nanoparticle-mediated drug delivery system across the blood-brain barrier in Alzheimer's disease.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {263},
number = {},
pages = {115612},
doi = {10.1016/j.colsurfb.2026.115612},
pmid = {41833245},
issn = {1873-4367},
abstract = {Alzheimer's disease (AD) is driven by complex and interrelated pathological processes, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, synaptic loss, and chronic neuroinflammation. These multifactorial mechanisms contribute to progressive cognitive decline and limit the effectiveness of conventional therapeutic strategies. Polymeric nanoparticles (PNPs) have emerged as a promising nanotechnological platform for targeted drug delivery in AD, addressing key challenges such as inadequate blood-brain barrier (BBB) permeability, rapid enzymatic degradation of therapeutic molecules, and poor pharmacokinetics. PNPs improve therapeutic efficacy by enabling controlled and sustained drug release, enhancing molecular stability, and promoting selective accumulation in affected brain regions. PNPs can modulate multiple molecular events that underlie AD pathogenesis. They inhibit Aβ fibrillation, reduce tau phosphorylation, scavenge reactive oxygen species (ROS), suppress neuroinflammatory signalling, activate Nrf2-driven antioxidant defense, and regulate microglial polarization toward a neuroprotective phenotype. Additionally, PNPs provide an efficient delivery system for diverse therapeutic agents, including small molecules, peptides, antioxidants, nucleic acids, and natural compounds, which often face challenges in BBB penetration and systemic stability. Recent innovations in surface engineering, biodegradable polymer chemistry, gene-responsive nanocarriers, and stimuli-responsive release systems have further enhanced the potential of PNPs as disease-modifying interventions. Despite these significant advancements, key limitations remain, including uncertainties regarding long-term biosafety, inconsistent biodistribution, challenges in nanoparticle clearance, and translational gaps between preclinical models and humans with AD. Addressing these issues will require interdisciplinary collaboration among materials science, neurobiology, pharmaceutical technology, and clinical research. Overall, this review highlights recent progress, therapeutic mechanisms, and the growing promise of PNP-based brain-targeted nanomedicine as a transformative approach for AD treatment.},
}

@article {pmid41833767,
year = {2026},
author = {Guo, Y and Li, X and Chen, Y and Li, Y and Cheng, Q and Jiang, Y and Tian, S and Yuan, B and Liu, Y and Hu, H and Li, S},
title = {Sarsasapogenin ameliorates Alzheimer's disease by dual inhibition of RIPK1-mediated necroptosis and pyroptosis.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112481},
doi = {10.1016/j.cellsig.2026.112481},
pmid = {41833767},
issn = {1873-3913},
abstract = {Sarsasapogenin (Sar), a natural bioactive steroidal saponin derived from Anemarrhena asphodeloides, has demonstrated significant neuroprotective effects in preclinical models of Alzheimer's disease (AD). However, its specific mechanism of action, particularly in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis and pyroptosis, remains underexplored. This study aimed to investigate Sar's therapeutic potential in AD by targeting RIPK1, a central regulator of programmed cell death. We employed biolayer interferometry (BLI), cellular thermal shift assays (CETSA), and drug affinity responsive target stability (DARTS) to confirm the binding of Sar to RIPK1. In vitro, we assessed the effects of Sar on RIPK1 activation, necroptosis, and pyroptosis in SH-SY5Y neuroblastoma and BV2 microglial cells using Western blotting, immunofluorescence, and cytokine assays. In vivo, the therapeutic efficacy of Sar was evaluated in the 5 × FAD transgenic mouse model, with behavioral analysis (Morris water maze) and histological assessments of brain tissue pathology. Sar demonstrated robust binding to RIPK1 (KD = 435 nM), enhancing its thermal stability and resistance to proteolytic degradation. Treatment with Sar significantly inhibited RIPK1 phosphorylation and downstream necroptotic and pyroptotic signaling in neurons and microglia. In the 5 × FAD mouse model, Sar markedly improved spatial memory performance, reduced amyloid-beta (Aβ) plaque deposition, and decreased neuroinflammatory and necroptotic markers in both the cortex and hippocampus. Sar is a promising natural RIPK1 inhibitor capable of concurrently mitigating both necroptosis and pyroptosis-two critical pathological processes underlying AD. These findings suggest that Sar may serve as a novel disease-modifying therapeutic for AD by regulating multiple pathways involved in neurodegeneration, offering new insights into the potential of natural products in AD treatment.},
}

@article {pmid41834394,
year = {2026},
author = {Yuan, M and Zhou, HY},
title = {CTAD 2025: Key trends redefining therapeutic and diagnostic strategies in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430764},
doi = {10.1177/13872877261430764},
pmid = {41834394},
issn = {1875-8908},
abstract = {This article synthesizes key themes emerging from the CTAD 2025 meeting, highlighting significant advances in Alzheimer's disease (AD) research and clinical practice. New disease-modifying approaches-ranging from next-generation anti-amyloid-β and anti-tau antibodies to small-molecule aggregation inhibitors and gene-based strategies-underscore a growing shift toward multi-target therapeutic frameworks. Blood-based biomarkers, such as p-tau217, p-tau181, glial fibrillary acidic protein, and neurofilament light, are nearing clinical readiness, while digital biomarkers and wearable technologies are enabling remote, continuous assessment of cognitive and physiological functions. Clinical trial design is increasingly oriented toward earlier disease stages and genetically or biomarker-defined high-risk groups, incorporating adaptive methodologies and real-world data to enhance efficiency and generalizability. Collectively, these developments signal an impending transition over the next two to three years from a centralized, cognitive scale-driven model of AD care to a more decentralized, biomarker-guided precision paradigm. CTAD 2025 thus marks a pivotal inflection point in the evolving structure of AD diagnosis and treatment.},
}

@article {pmid41834402,
year = {2026},
author = {Al-Hammadi, M and Fleyeh, H and Thomas, I},
title = {Gait and movement analysis for discrimination between people with dementia and healthy control persons based on pose estimation and machine learning.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430001},
doi = {10.1177/13872877261430001},
pmid = {41834402},
issn = {1875-8908},
abstract = {BackgroundDementia disorders are affecting millions of people globally, characterized by memory loss, communication difficulties, and motor function decline. Accurate and early dementia detection is crucial for effective management and treatment. Gait analysis offers a non-invasive method for dementia detection by identifying subtle changes in walking patterns that often precede cognitive symptoms.ObjectiveThis study aims to evaluate the clinical utility of video-based gait analysis using the Timed Up and Go (TUG) test under single and dual-task conditions (TUGdt) for distinguishing individuals with dementia disorders from healthy controls (HCs).MethodThe study implemented three machine learning models: Support Vector Machine (SVM), Logistic Regression (LR), and Random Forest (RF), to discriminate between persons with dementia and HCs. The dataset consists of a cohort of 64 people with dementia (47 with Alzheimer's disease) and 67 HCs. The participants performed the TUG test as a single and dual-task (TUGdt). In the TUGdt, participants performed the TUG test while simultaneously completing an additional cognitive task (i.e., animal naming (TUGdt-NA) or reciting months in reverse order (TUGdt-MB)).ResultsThe results showed that dual-task classification outperformed the single-task. The SVM algorithm achieved the highest accuracy in the TUGdt-NA task (accuracy of 87% ± 5.1 and recall of 86.6% ± 3.2) using 5-fold cross-validation and accuracy of 85.5% and recall of 89.5% using Leave-One-Out Cross-Validation (LOOCV) in the TUGdt-MB task.ConclusionsIn summary, video-based gait features effectively distinguish people with dementia from HCs, particularly under dual-tasking, offering cost-effective, automated, and non-invasive pre-screening to complement clinical assessments.},
}

@article {pmid41834411,
year = {2026},
author = {Yue, J and Carriquiriborde, V and Cheng, WH and Yildirim, T and Fan, J and Tok, S and Kelly, ML and Wellington, CL and Kent, BA},
title = {Repetitive Mild Traumatic Brain Injury Causes Neuronal Damage in the APP/PS1 Mouse Model of Alzheimer's Disease Without an Enduring Impact on Amyloid Pathology, Sleep, or Epileptiform Activity.},
journal = {Journal of neurotrauma},
volume = {},
number = {},
pages = {8977151261430301},
doi = {10.1177/08977151261430301},
pmid = {41834411},
issn = {1557-9042},
abstract = {Traumatic brain injury (TBI) is a known risk factor for Alzheimer's disease and related neurodegenerative diseases. Sleep disturbances and epileptiform abnormalities can appear after TBI and may contribute to the development of neuropathology. In this study, we characterized sleep, epileptiform activity, and neuropathology after repetitive mild traumatic brain injury (rmTBI) in a mouse model of Alzheimer's disease. We used the Closed Head Impact Model of Engineered Rotational Acceleration to deliver rmTBI or sham (control) treatment to 6-month-old APP/PS1 mice (N = 19). One month post-injury, we implanted electroencephalogram and electromyographic electrodes, recorded for 72 h, and then collected brain tissue and blood plasma. Our assessment of sleep architecture showed that time spent in vigilance state was not affected by the rmTBI 1 month post-injury; however, power spectra analysis showed a shift toward higher frequencies in the rmTBI group during non-rapid eye movement sleep. Epileptiform activity did not differ between sham and rmTBI. Compared with sham controls, the rmTBI group showed higher neurofilament light (NF-L), but not glial fibrillary acidic protein in blood plasma and no change in Aβ pathology. These results indicate sustained neurological injury in the APP/PS1 mice 1 month after rmTBI without affecting amyloid deposition in the brain. Our study suggests that rmTBI can induce neural injury without causing enduring sleep disruption, seizures, and exacerbation of amyloidosis in the APP/PS1 mouse model.},
}

@article {pmid41834587,
year = {2026},
author = {Shimizu, K and Yasuda, S and Maeshima, H and Ichikawa, T and Baba, H},
title = {Serum Amyloid β Oligomer May Predict Treatment Response in Middle-Aged and Late-Life Patients With Depression.},
journal = {Neuropsychopharmacology reports},
volume = {46},
number = {2},
pages = {e70109},
doi = {10.1002/npr2.70109},
pmid = {41834587},
issn = {2574-173X},
mesh = {Humans ; Male ; Female ; *Amyloid beta-Peptides/blood ; Middle Aged ; Aged ; *Antidepressive Agents/therapeutic use ; *Major Depressive Disorder/drug therapy/blood ; *Peptide Fragments/blood ; Treatment Outcome ; Biomarkers/blood ; Adult ; Aged, 80 and over ; },
abstract = {AIM: Late-life patients with depression are reportedly less responsive to antidepressant treatment than younger patients. Additionally, patients who have depression comorbid with Alzheimer's disease (AD) and those with an amyloid β (Aβ) burden have shown a poor response to antidepressant treatment, suggesting that AD pathology may contribute to treatment resistance. A recent report indicated that Aβ oligomers in blood have increased in patients with AD and are associated with AD pathology. This study was performed to reveal the relationship between blood Aβ oligomers and the response to antidepressant treatment in middle-aged and late-life patients with depression.

METHODS: In this observational study, serum levels of Aβ40, Aβ42, and Aβ oligomers were evaluated in 80 inpatients with major depressive disorder aged ≥ 40 years. Depressive symptoms were assessed at admission (baseline) and after 4 weeks of treatment.

RESULTS: There were significantly fewer treatment responders among patients with than without serum Aβ oligomers (p = 0.016). Serum Aβ oligomers were found to influence the treatment response even after control for age, sex, number of depressive episodes, severity of depression, and Mini-Mental State Examination scores (p = 0.031).

CONCLUSIONS: These results suggest that serum Aβ oligomers may predict a poor response to antidepressant treatment in middle-aged and late-life patients with depression. Our findings also lead us to speculate that elderly patients with a poor treatment response may share AD-related pathophysiological features or neural vulnerability.},
}

Humans
Male
Female
*Amyloid beta-Peptides/blood
Middle Aged
Aged
*Antidepressive Agents/therapeutic use
*Major Depressive Disorder/drug therapy/blood
*Peptide Fragments/blood
Treatment Outcome
Biomarkers/blood
Adult
Aged, 80 and over

@article {pmid41834979,
year = {2026},
author = {Li, Y and Chen, Y and Chen, S and Huang, X},
title = {[Aging-Associated Oral Microbiota Dysbiosis and Hypofunction: Their Role in Alzheimer's Disease Pathogenesis].},
journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition},
volume = {57},
number = {1},
pages = {56-64},
pmid = {41834979},
issn = {1672-173X},
mesh = {Humans ; *Alzheimer Disease/microbiology/etiology/physiopathology ; *Dysbiosis/complications/microbiology ; *Mouth/microbiology/physiopathology ; *Aging/physiology ; *Microbiota ; Amyloid beta-Peptides/metabolism ; Brain ; },
abstract = {Alzheimer's disease (AD), a multifactorial neurodegenerative condition, imposes a major burden on societies with aging populations. Recent research indicates that oral cavity health is a critical factor influencing AD pathology, making proactive investigation of this modifiable risk factor essential. This review proposes that aging-related oral microecological dysbiosis and oral hypofunction may promote AD progression by inducing or exacerbating systemic inflammation and disrupting the homeostasis of the "oral-gut-brain" axis. Moreover, each factor may worsen damage through distinct biological pathways: oral microbiota dysbiosis allows direct invasion of the central nervous system by oral pathogens, promoting amyloid β-protein (Aβ) deposition and Tau hyperphosphorylation, while chronic sensory deprivation from oral dysfunction triggers neuronal degeneration and adverse remodeling in key cognitive brain regions. This review aims to systematically elucidate the roles of oral microbiota dysbiosis and oral hypofunction in AD pathogenesis in the context of aging, clarify their underlying biological mechanisms, and explore the potential value of integrating oral cavity health management into comprehensive AD prevention and treatment strategies.},
}

Humans
*Alzheimer Disease/microbiology/etiology/physiopathology
*Dysbiosis/complications/microbiology
*Mouth/microbiology/physiopathology
*Aging/physiology
*Microbiota
Amyloid beta-Peptides/metabolism
Brain

@article {pmid41835065,
year = {2026},
author = {Xiao, X and Yan, X and Liang, C and Yang, Y},
title = {Metabolic dysfunction and mitochondrial failure in Alzheimer's disease: integrating pathophysiology, clinical evidence and emerging interventions.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1772036},
pmid = {41835065},
issn = {1664-2295},
abstract = {Alzheimer's disease (AD) is a gradual and irreversible decline in the brain's ability to function which is not only signified by amyloid-beta plaques and neurofibrillary tangles but also by and metabolic and mitochondrial changes that have a negative impact on the classical neuropathological hallmarks. It is becoming increasingly clear that the central roles in the process of synaptic dysfunction, neuronal death and cognitive decline are played by the brain's impaired glucose utilization, insulin resistance, lipid metabolism alterations, and energy homeostasis disruption. Mitochondrial dysfunctions in AD comprising of oxidative phosphorylation defects, ATP production decrease, reactive oxygen species generation over and above the normal level, poor mitochondrial dynamics, and vacuolar-type H+-ATPase-mediated cell death are the factors that further worsen the situation and hence speed up the process of neuronal death and eventually, disease progression. The metabolic and mitochondrial disturbances have a two-way relationship with amyloid-beta and tau pathology, neuroinflammation, and oxidative stress, thus creating a self-sustaining cycle of neurodegeneration. Besides, clinical and neuroimaging studies, fluorodeoxyglucose positron emission tomography, cerebrospinal fluid biomarkers, and peripheral metabolic profiling all support the notion that metabolic impairment is an early and clinically relevant feature of AD very convincingly. Thus, the attention of the scientific community has turned more and more toward the approaches that use the metabolic and mitochondrial pathways as their target. The new treatments are coming, including insulin sensitizers, ketogenic and Mediterranean diets, mitochondrial-targeted antioxidants, exercise, metabolic modulators, and new drugs, all aimed at bringing back equilibrium to bioenergetics and letting neurons live longer. In this review, we have considered the current mechanistic insights, clinical evidence, and therapeutic advances related to metabolic dysfunction and mitochondrial failure in AD together and their potential as early biomarkers and modifiable targets for disease prevention and treatment that are highlighted.},
}

@article {pmid41836011,
year = {2026},
author = {Chakif, D and Furrer, J},
title = {The impact of nutritional, environmental, and lifestyle factors on neurological disorders: therapeutic implications and mechanistic insights.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1765786},
doi = {10.3389/fphar.2026.1765786},
pmid = {41836011},
issn = {1663-9812},
abstract = {Neurological disorders like Alzheimer's, Parkinson's, multiple sclerosis, and primary psychiatric conditions are complex, arising from a mix of genetic and modifiable risks. Growing evidence indicates that nutrition, environment, and lifestyle significantly influence disease development, progression, and treatment response. Nutrients such as vitamins, minerals, omega-3 fatty acids, and polyphenols affect neuroinflammation, oxidative stress, mitochondrial health, and neurotransmitter function. Dietary patterns like the Mediterranean and ketogenic diets offer protective benefits in clinical and experimental contexts. Meanwhile, environmental neurotoxicants-air pollution, heavy metals, pesticides, and endocrine disruptors contribute to neurodegeneration via oxidative damage, synaptic impairment, and epigenetic alterations. Lifestyle factors, such as physical activity, sleep, stress, and substance use, affect brain plasticity, neurogenesis, and metabolic health, thereby influencing disease progression over time. These factors often share common pathways such as oxidative stress, inflammation, vascular injury, mitochondrial dysfunction, and protein misfolding, underscoring the need for a comprehensive prevention and treatment strategy. Emerging therapies now incorporate personalized nutrition, lifestyle changes, and environmental risk mitigation alongside traditional drugs, supported by advances in multi-omics, digital health, and systems biology. Public health efforts to reduce neurotoxic exposure and encourage healthy habits further strengthen these approaches. This review summarizes existing mechanistic and clinical knowledge, with a focus on the potential of nutritional, environmental, and lifestyle interventions in neurological diseases. It also outlines the future research required to enhance precision neurology and strategies for brain health prevention.},
}

@article {pmid41836026,
year = {2026},
author = {Zhao, M and Qu, Y and Zhang, S and Zhang, M and Wang, H and Yang, Y and Xue, G and Hou, X and Yan, X},
title = {Multi-target intervention mechanisms and prospects of the traditional Chinese medicine Scutellaria baicalensis georgi in Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1707688},
doi = {10.3389/fphar.2026.1707688},
pmid = {41836026},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is one of the most prevalent central nervous system disorders affecting middle-aged and elderly populations. As a neurodegenerative disease, its primary clinical manifestations include memory impairment, cognitive dysfunction, and behavioral abnormalities. However, there are limited clinically available treatments for AD. Existing medications neither cure the disease nor halt its progression, and are often associated with significant side effects. Scutellaria baicalensis Georgi, with its long history of medicinal use, shows potential for treating central nervous system disorders. Modern pharmacological research has revealed its antioxidant, anti-inflammatory, antiviral, neuroprotective, and immunomodulatory properties. Its active metabolites, such as baicalin and baicalein, exert multi-target effects by simultaneously influencing Aβ production and aggregation, tau phosphorylation, and microglial activation, while also regulating brain-gut axis function. This systematic review examines the mechanisms of action of baicalin and baicalein, the active metabolites of Scutellaria baicalensis Georgi, in treating Alzheimer's disease, offering novel insights and research directions for modern medical approaches to Alzheimer's disease treatment.},
}

@article {pmid41836505,
year = {2026},
author = {Ma, T and Jester, H and Wang, X and Li, T and Suhocki, A and Zhou, X and Proud, C and Rosenblum, K},
title = {Suppression of neuronal eEF2K alleviates cognitive deficits and apathy-like behavior in APP/PS1 AD model mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8970895/v1},
pmid = {41836505},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by synaptic failure, cognitive impairment and neuropsychiatric symptoms (NPS). Apathy is the most common NPS seen in AD patients, and its underlying mechanisms remain unknown. Here, we investigated the roles of neuronal eukaryotic elongation factor 2 (eEF2) phosphorylation (by its kinase eEF2K) in AD-associated cognitive deficits and NPS. We performed a series of experiments using a multidisciplinary approach including genetics, behavioral assays, synaptic electrophysiology, and unbiased proteomics. The results demonstrated that neuron-specific inhibition of eEF2K and eEF2 phosphorylation can alleviate cognitive deficits, synaptic plasticity impairments, and apathy-like behavior in aged APP/PS1 AD model mice. Our findings indicate the therapeutic potential of targeting the eEF2K signaling in the treatment of dementia and NPS in AD and related dementias (ADRDs).},
}

@article {pmid41836522,
year = {2026},
author = {Liu, A and Xing, L and Li, J and Yao, M and Song, J and Guo, W and Duan, P and Li, H},
title = {Traditional Chinese Medicine and Ferroptosis in Alzheimer's Disease: A Potential Therapeutic Approach.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {590868},
doi = {10.2147/DDDT.S590868},
pmid = {41836522},
issn = {1177-8881},
mesh = {*Ferroptosis/drug effects ; Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Medicine, Chinese Traditional ; *Drugs, Chinese Herbal/pharmacology/chemistry/therapeutic use ; Animals ; },
abstract = {Alzheimer's disease (AD) represents a prevalent neurodegenerative disorder associated with considerable morbidity and mortality. Currently, no therapeutic agents exist that can achieve a fundamental reversal or complete cure for this condition. Consequently, the identification of novel molecular targets and the development of innovative treatment modalities aimed at slowing progression and alleviating symptoms represent pressing priorities within AD clinical research. Ferroptosis, a regulated cell death process driven by intracellular iron dysregulation and excessive lipid peroxidation, is now recognized as a critical contributor to AD pathogenesis. Traditional Chinese medicine (TCM) has demonstrated beneficial outcomes in managing AD, and emerging evidence suggests its regulatory effects may extend to modulating ferroptotic pathways. This review summarizes and analyzes the therapeutic efficacy of various TCM strategies against AD, including herbal extracts, monomers (eg, alkaloids, terpenoids, glycosides, phenolic derivatives, quinones), compound formulas, and acupuncture. It highlights how these interventions target key ferroptosis-related axes-such as iron homeostasis, the system Xc-/GSH/GPX4 antioxidant system, and the Keap1/Nrf2/ARE pathway-to collectively address the pathological foundation of the disease. However, current evidence is predominantly preclinical, and the translational potential of TCM is constrained by challenges including blood-brain barrier penetration, pharmacokinetic profiles, standardization, and safety assessments. In conclusion, TCM exhibits substantial potential for both research and clinical application in AD by targeting and attenuating the ferroptosis pathway, offering promising avenues for disease modification and symptomatic relief.},
}

*Ferroptosis/drug effects
Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Medicine, Chinese Traditional
*Drugs, Chinese Herbal/pharmacology/chemistry/therapeutic use
Animals

@article {pmid41837371,
year = {2026},
author = {Ackley, SF and La Joie, R and Caunca, M and Mukherjee, S and Choi, SE and Trittschuh, EH and Crane, PK and Hayes-Larson, E and , },
title = {Substituting Blood-Based Biomarkers for Imaging Measures in Alzheimer's Disease Studies: Implications for Sample Size and Bias.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag068},
pmid = {41837371},
issn = {1758-535X},
abstract = {BACKGROUND: Blood-based biomarkers for Alzheimer's disease (AD) pathology are appealing options in large population-based studies due to their low cost, minimal invasiveness, and feasibility of collection in non-clinical settings. Despite these benefits, blood-based biomarkers have lower test-retest reliability than neuroimaging measures like amyloid positron emission tomography (amyloid-PET) Centiloids; trade-offs in power and bias remain unexplored.

METHODS: We use data from Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) studies, which include both amyloid-PET and blood-based measures, to assess differences in statistical power, required sample size, and bias when replacing a neuroimaging measure with a blood-based measure. We use simulations parameterized based on these studies to show potential implications of using plasma p-tau 181 or p-tau 217, blood-based AD biomarkers, in place of Centiloids from amyloid-PET, when the biomarker is either the exposure or the outcome in an analysis of interest.

RESULTS: We demonstrated that substituting amyloid-PET Centiloids with a blood-based measure of p-tau can substantially reduce power, requiring 1.5 to 6.5 times the sample size to achieve 80% power compared to amyloid-PET. In addition, using a blood-based biomarker as the exposure can introduce significant regression dilution bias, attenuating estimated associations.

CONCLUSIONS: While blood-based biomarkers are lower cost and easier to collect than neuroimaging measures, their use as proxies for AD pathology may introduce substantial methodological challenges, depending on the p-tau isoform. Consideration of the sample sizes they necessitate and their potential for bias is critical for the design and interpretation of studies employing these biomarkers.},
}

@article {pmid41837374,
year = {2026},
author = {Kaufmann, CN and Yang, KH and Tseng, CI and Chang, G and Amjad, H and Albrecht, JS and Spira, AP and Gross, AL and Wickwire, EM and Malhotra, A},
title = {Using Observational Data to Investigate Cognitive Outcomes of Obstructive Sleep Apnea Treatment: A Scoping Review.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag078},
pmid = {41837374},
issn = {1758-535X},
abstract = {BACKGROUND: Prior research indicates a connection between obstructive sleep apnea (OSA) and cognitive deficits, prompting interest in whether OSA treatment can prevent or slow cognitive decline. Past clinical trials on OSA treatment and cognitive impairment have shown inconsistent results. However, observational data might help by examining more diverse populations and larger sample sizes, increasing the ability to detect subtle effects. Therefore, we reviewed literature to characterize studies evaluating cognitive outcomes from OSA treatment using observational study data.

METHODS: We conducted a scoping review of studies retrieved on PubMed and Embase. Studies were screened by title/abstract, and then full text, for inclusion. We extracted data characterizing data source, study design, population, sample size, follow-up time, treatments assessed, cognitive outcome variables, and key associations.

RESULTS: Of 3,655 unique articles obtained from PubMed and Embase, 13 met eligibility criteria. All were retrospective cohort studies. Ten studies evaluated positive airway pressure (PAP) therapies, one examined uvulopalatopharyngoplasty, and two evaluated any type of OSA treatment. No studies evaluated mandibular advancement devices. Cognitive outcomes assessed included dementia diagnosis (8 studies), and changes in cognitive performance (5 studies). Results from studies for most part found OSA treatment was associated with better cognitive outcomes, although effects varied in magnitude and statistical significance based on the data source, outcomes, and sample size.

CONCLUSIONS: Observational data has the potential to help evaluate cognitive outcomes from OSA treatment, but more studies are needed, especially for OSA therapies beyond PAP alone.},
}

@article {pmid41837520,
year = {2026},
author = {Zhao, Y and Lei, J and Wang, Z and Yang, S and Zhao, Z and Xie, Y and Ran, J and Zang, G},
title = {Identification of novel biomarkers for Alzheimer's disease: A deep learning omics-based approach to drug pair discovery and exploration of potential therapeutic targets.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00989},
pmid = {41837520},
issn = {1673-5374},
abstract = {The understanding of Alzheimer's disease is shifting from a traditional focus on Aβ/tau pathology to an emerging consensus that positions immune dysregulation as a central synergistic driver in the early stages of the disease. However, the causal relationships between peripheral immune cells, plasma proteins, and Alzheimer's disease, as well as the mediating effects of plasma proteins on the disease, remain poorly understood. Moreover, there are no effective drug combination therapies targeting plasma proteins for Alzheimer's disease. This study investigated the causal associations between immune cells, plasma proteins, and Alzheimer's disease, with a focus on the role of Fc gamma receptor 3A in disease progression. Using a two-sample Mendelian randomization approach, we identified 59 plasma proteins and 65 immune cell types significantly associated with Alzheimer's disease. We performed data mining of a large Alzheimer's disease cohort and drug databases and established a biofactor-regulated neural network for rapidly screening and optimizing compound drug pairs. Among the immune cells, CD8+ T cells, particularly CD8+CD28+CD45RA. T cells, were found to have a protective effect against Alzheimer's disease. Furthermore, increased expression of Fc gamma receptor 3A (also known as CD16a, an activating receptors of NK cells) in plasma and the hippocampus correlated with enhanced CD8+ T-cell infiltration and accelerated Alzheimer's disease progression in 5×FAD mice. Mediation analysis revealed that Fc gamma receptor 3A mediates the effects of CD8+ T cells on Alzheimer's disease risk. Additionally, Fc gamma receptor 3A gene expression levels were significantly higher in patients with Alzheimer's disease compared with individuals with mild cognitive impairment and cognitively normal participants, as revealed by an analysis of the Alzheimer's Disease Neuroimaging Initiative database. These findings suggest that CD8+ T-cell infiltration and Fcγ receptor 3A expression play critical roles in the pathophysiology of Alzheimer's disease and may serve as therapeutic targets. Molecular docking analysis further identified 19 candidate drugs targeting Fcγ receptor 3A. This study proposes novel immune-based therapeutic strategies and introduces an omics-based intelligent drug discovery framework for repurposing existing drugs for the treatment of complex diseases. The key contributions of this study include the identification of potential immune-based therapeutic targets for Alzheimer's disease and demonstration of the utility of bioinformatics and drug repurposing approaches in addressing complex neurodegenerative diseases.},
}

@article {pmid41837598,
year = {2026},
author = {Ma, J and Liu, T and Liu, FZ and Shi, YJ},
title = {Mechanistic Insights into the Qingge Formula for the Treatment of Alzheimer's Disease: A Network Pharmacology and Molecular Docking Study.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128403988251202073700},
pmid = {41837598},
issn = {1873-4286},
abstract = {INTRODUCTION: Alzheimer's disease (AD) affects millions globally. This study explores the therapeutic mechanisms of Qingge Formula (QGF) against AD using network pharmacology and molecular docking.

METHODS: Active components and targets were identified via TCMSP, Swiss ADME, and GeneCards databases. PPI networks, GO, and KEGG analyses were performed, followed by molecular docking.

RESULTS: Core targets included PTGS2, EGFR, ESR1, STAT3, and SRC. GO identified 222 terms; KEGG revealed 65 pathways. Molecular docking revealed that the six key components bind to the core targets with energetically favorable conformations, among which SRC showed the highest affinity for all the Discussion: QGF likely modulates neuroinflammation, immunity, and synaptic plasticity pathways, with SRC as a crucial target.

CONCLUSION: QGF demonstrates multi-component, multi-target therapeutic potential against AD.},
}

@article {pmid41837602,
year = {2026},
author = {Onuki, K and Nishio, Y},
title = {Assessing professional caregiver burden related to patient agitation in dementia: A systematic review of measurement scales.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430767},
doi = {10.1177/13872877261430767},
pmid = {41837602},
issn = {1875-8908},
abstract = {BackgroundAgitation is a common behavioral and psychological symptom of dementia that places significant burden on caregivers. While its impact on family caregivers is well-documented, its effect on professional caregivers remains underexplored. Additionally, it is unclear whether existing caregiver burden scales adequately capture the International Psychogeriatric Association's (IPA) definition of agitation. Since agitation requires different treatment approaches than cognitive impairment, its distinct burden warrants further investigation.ObjectiveThis systematic review examined scales used to assess professional caregiver burden related to agitation in dementia.MethodsFollowing PRISMA guidelines, we searched MEDLINE, Embase, and ICHUSHI for English and Japanese articles published during January 1980-August 2024. Studies included professional caregivers, either exclusively or alongside informal caregivers. Key outcomes were the number and frequency of scales, target population, and agitation coverage within the scales.ResultsWe identified 52 articles: 22 focused exclusively on professional caregivers, and 30 included both types. Publications involving both caregiver types increased notably in the last decade. Across studies, 39 scales were used. The Zarit Burden Interview (n = 21) and Neuropsychiatric Inventory (n = 15) were most frequent. Sixteen scales targeted the general population; 11 each were designed for professional and informal caregivers, and one for both. Most scales did not fully reflect the IPA's definition of agitation. Scales for professional caregivers also included work-related factors like coworker conflicts and administrative workload.ConclusionsThere is a critical gap in validated scales to measure agitation-related burden in professional dementia caregivers. Specialized tools are urgently needed to assess this burden and guide support strategies.},
}

@article {pmid41837609,
year = {2026},
author = {Hu, S and Ge, J and Wang, G and Zhao, M and Lv, P and Wang, F and Guo, F and Huang, J and Guan, H and Ma, X and Xing, Z},
title = {Plasma biomarker changes following deep cervical lymphatic venous anastomosis: An exploratory study in Alzheimer's disease using single-molecule array technology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431355},
doi = {10.1177/13872877261431355},
pmid = {41837609},
issn = {1875-8908},
abstract = {BackgroundDeep cervical lymphatic venous anastomosis (dcLVA) is a novel surgical approach for patients with Alzheimer's disease (AD). Its theoretical basis lies in the promotion of the clearance of large biomolecular metabolites in the central nervous system by unblocking the deep cervical lymphatic system. Currently, there is a lack of systematic and comprehensive research on biomarkers for monitoring disease progression and therapeutic efficacy in patients with AD after treatment. Single-molecule technology is applied widely in the field of medicine to detect trace amounts of proteins, especially for detecting the biomarkers related to neurodegenerative diseases such as AD.ObjectiveThis study presents the data of 30 AD patients who underwent dcLVA surgery and the results of analyzing AD biomarkers, exploring the efficacy of dcLVA treatment, and explores whether peripheral blood biomarkers could be used to monitor the treatment effects.MethodsUsing single-molecule technology to detect dynamic changes in blood biomarkers, combined with cognitive scores and Clinician's Interview-Based Impression of Change Plus (CIBIC-plus) data, a prognostic prediction model is constructed.ResultsThe results show that dcLVA surgery elevates peripheral blood amyloid-β (Aβ)42 levels which correlate significantly with the CIBIC plus score. The combination of Aβ42 and Aβ42/40 achieved the highest AUC (0.737) at 180 days post-surgery, showing good diagnostic performance and potential as a prognostic biomarker for dcLVA surgery.ConclusionsBy leveraging the dynamic changes of blood biomarkers, it is helpful to adjust the treatment plan in a timely manner, thereby achieving personalized treatment and improving the treatment effectiveness.},
}

@article {pmid41837631,
year = {2026},
author = {Kim, MG and Woo, SH and Kim, GW and Choi, HK and Kim, KK and Koo, BS},
title = {Efficacy and safety of Woohwangchungsimwon in combination with donepezil for behavioral and psychological symptoms of dementia in probable Alzheimer's disease: An assessor-blinded randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431692},
doi = {10.1177/13872877261431692},
pmid = {41837631},
issn = {1875-8908},
abstract = {BackgroundWoohwangchungsimwon (WCW) is a traditional Korean herbal formula commonly used to treat anxiety and restlessness. However, its potential role in managing behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD) is unclear.ObjectiveThis study evaluated the efficacy and safety of WCW as an adjunctive treatment for BPSD in patients with mild probable AD already receiving donepezil.MethodsSeventy-four patients receiving donepezil 5 mg daily were randomized 1:1 into an intervention group (WCW add-on, n = 37) or a control group (no additional treatment, n = 37) for 24 weeks. The primary outcome was the change in BPSD measured using the Neuropsychiatric Inventory (NPI). Secondary outcomes were cognitive function and emotional and physical well-being, including depression, anxiety, insomnia, quality of life, and severity of dementia. Safety was assessed via adverse events and laboratory results.ResultsSixty-three participants were included. The WCW group demonstrated significantly improved total NPI scores versus controls, particularly in the irritability/lability subdomain. Analysis of covariance (ANCOVA) confirmed these findings in both the full analysis set (FAS) and per-protocol set (PPS). T-test and rank ANCOVA showed significance in the PPS and a trend in the FAS. The general quality of life dementia scale showed a trend toward improvement. No significant differences in adverse events or laboratory results were observed.ConclusionsWCW may be a safe and effective adjunctive therapy for BPSD in patients with mild probable AD. Future studies should adopt more rigorous designs and include patients with broader disease severity to enhance clinical applicability.Trial registrationThe trial was registered with the Clinical Research Information Service (CRIS) on December 10, 2020 (KCT0005669).},
}

@article {pmid41837772,
year = {2026},
author = {Yilmaz, A and Ashrafi, N and Guerra, Z and Goniwiecha, D and Saiyed, N and Gordevičius, J and Krinickis, K and Gabrielaite, M and Osentoski, T and Schumacher, N and Khan, S and Pai, A and Ruff, S and Maddens, ME and Imam, K and Monastero, R and Graham, SF},
title = {Salivary metabolomics for early detection of vascular contributions to cognitive impairment and dementia: Exploring microbiome dysbiosis and sex differences.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261423158},
doi = {10.1177/13872877261423158},
pmid = {41837772},
issn = {1875-8908},
abstract = {BackgroundVascular factors contribute to dementia in approximately 20 million individuals, notably in vascular contributions to cognitive impairment and dementia (VCI). However, the lack of specific molecular biomarkers to differentiate VCI from normal aging and Alzheimer's disease (AD) impedes early diagnosis and treatment.ObjectiveTo date the use of saliva for VCI diagnosis has not been previously reported. In this small proof-of-concept study, we aim to explore the feasibility of screening novel salivary diagnostic biomarkers for VCI.MethodsUsing both proton nuclear magnetic resonance ([1]H NMR) spectroscopy and liquid chromatography coupled with mass spectrometry (LC-MS) we biochemically profiled saliva samples collected from individuals with VCI (n = 26) and compared them with cognitively healthy controls (n = 37).ResultsOf the 167 salivary metabolites 56 of them are found to be at significantly different concentrations in the saliva of individuals with VCI as compared to controls. Subsequently, we developed predictive models capable of distinguishing VCI from controls with 0.92 accuracy. Moreover, sex-stratified analysis revealed the perturbation of different metabolic pathways in the saliva of individuals with VCI.ConclusionsThis study underscores the promising role of salivary metabolomics as a non-invasive tool for the early detection of VCI. Our findings suggest that oral microbiome dysbiosis may contribute to VCI pathogenesis, offering novel mechanistic insights. Given the accessibility of saliva, further validation of these robust salivary biomarkers could facilitate scalable, cost-effective screening for VCI, aiding in timely intervention strategies.},
}

@article {pmid41838033,
year = {2026},
author = {Ali, N and Alotaibi, FT and Babu, MA and Singh, TG and Tyagi, Y and Alotaibi, AN and Bansal, N and Puri, S},
title = {Developments on BACE 1 Inhibitors as Anti-Alzheimer Agents: A Perspective on Medicinal Chemistry-Based Advances.},
journal = {Archiv der Pharmazie},
volume = {359},
number = {3},
pages = {e70220},
doi = {10.1002/ardp.70220},
pmid = {41838033},
issn = {1521-4184},
support = {IMSIU-DDRSP2601//Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU)/ ; },
mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Humans ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Structure-Activity Relationship ; Drug Development ; Molecular Structure ; },
abstract = {Alzheimer's disease (AD) is a progressive and complicated neurodegenerative disorder that mostly affects the elderly and is characterized by memory loss, cognitive dysfunction, accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, and cholinergic deficits. Current therapies used for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonist memantine, can only provide temporary or symptomatic relief, but they do not stop or reverse the progression of the disease. Numerous pathogenic hypotheses have been proposed to explain this mechanism; however, the amyloid cascade hypothesis remains the most widely accepted theory, as it suggests that β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays a critical role in the generation of Aβ peptides. Therefore, BACE1 may be a key therapeutic target. This review primarily focuses on the key role of BACE1 in AD pathogenesis and describes the development of its inhibitors over three generations, explaining their structure, design, and pharmacological properties. While the first generation lacked brain penetration, the second-generation improved potency but encountered clinical trial failures due to adverse effects. The third generation of these drugs was designed to achieve a balance between efficacy, selectivity, and safety. Additionally, we review the promising molecules currently under clinical investigation, highlighting both their therapeutic potential and the challenges that remain in developing effective disease-modifying therapies for AD treatment.},
}

*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
Humans
*Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism
*Alzheimer Disease/drug therapy/metabolism
Animals
Structure-Activity Relationship
Drug Development
Molecular Structure

@article {pmid41830123,
year = {2026},
author = {Aldahish, A and Vasudevan, R and Qasim, SYA and Alshahrani, MS and Almohsen, LK and Alghanoom, SM and AlQahtani, AA and Alshahrani, WK},
title = {Exploring the Epigenetic Mechanisms Underlying Chronic Diseases: A Comprehensive Review.},
journal = {Current gene therapy},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115665232443611260121063601},
pmid = {41830123},
issn = {1875-5631},
abstract = {Epigenetics, the study of heritable changes in gene expression without changes to the DNA sequence, has emerged as an important regulator of disease risk and development. Epigenetic alterations, such as DNA methylation, histone modifications, and non-coding RNAs, act as molecular bridges between genetic predisposition and environmental factors. Understanding these changes is critical for determining the pathophysiology of chronic illnesses. This article looks at the involvement of epigenetic mechanisms in chronic diseases such as cardiovascular disease, obesity, depression, Alzheimer's disease, and diabetes mellitus. The emphasis is on recent epigenetic discoveries, their implications for disease risk assessment, and the prospect of epigenetic-based therapeutics in precision medicine. Epigenome-Wide Association Studies (EWAS) and next-generation sequencing technologies have revealed disease-specific epigenetic patterns, underlining their potential as biomarkers for early detection and risk stratification. Epigenetic changes affect important molecular pathways that control metabolic regulation, neuroplasticity, inflammatory response, and cellular homeostasis. Epigenetic modification-targeting therapies, such as DNA methylation inhibitors, histone deacetylase inhibitors, and RNA-based treatments, have shown promise in preclinical and early clinical trials. Epigenetic research offers a transformational framework for understanding the intricate interplay of genetic and environmental variables in chronic illness etiology. Epigenetic alterations are reversible, which opens up new possibilities for therapeutic intervention and individualized therapy. Future research should concentrate on improving epigenetic biomarkers, determining causal links in disease progression, and incorporating epigenetic findings into clinical practice. The advancement of epigenetic medicines has the potential to transform disease prevention, treatment, and global health policies.},
}

@article {pmid41829110,
year = {2026},
author = {Zhang, J and Wu, S and Meng, N and Li, C and Zhao, Y and An, L},
title = {The Mechanism of GABA in Attenuating Neuroinflammation in Alzheimer's Disease: CP/CEBPα/miR-34a-Mediated Suppression of HDAC2/3 in Astrocytes.},
journal = {Foods (Basel, Switzerland)},
volume = {15},
number = {5},
pages = {},
doi = {10.3390/foods15050837},
pmid = {41829110},
issn = {2304-8158},
support = {81903308//National Natural Science Foundation of China/ ; },
abstract = {As a widely available dietary supplement, γ-Aminobutyric acid (GABA) exhibits potential for early intervention against Alzheimer's disease (AD). This study demonstrates that GABA alleviates AD neuroinflammation, and its suppression of astrocytic pro-inflammatory cytokine expression through histone deacetylase (HDAC2/3) inhibition contributes to this effect. Here, in both the cerebral cortex of AD mice and Aβ-exposed U251 cells, pro-inflammatory cytokines and HDAC2/3 expression levels were elevated, whereas the levels of creatine phosphate (CP), CCAAT/enhancer-binding protein α (CEBPα) and microRNA34a (miR-34a) were decreased. GABA treatment counteracted these alterations. Silencing HDAC2 or HDAC3 suppressed pro-inflammatory cytokines. Transfection with miR-34a mimics suppressed pro-inflammatory cytokines and HDAC2/3 expression in U251 cells, while miR-34a inhibitors had the opposite effect. A luciferase reporter assay confirmed HDAC2 as a direct miR-34a target via 3'UTR binding. Knockdown of CEBPα suppressed miR-34a expression, thereby elevating HDAC2/3 and pro-inflammatory cytokine expression in U251 cells. In CP-treated U251 cells, CEBPα and miR-34a expression was elevated, while pro-inflammatory cytokine and HDAC2/3 expression was down-regulated. In conclusion, GABA alleviates neuroinflammation in AD model mice. This effect may be partially attributed to its suppression of astrocyte-derived pro-inflammatory cytokine expression via HDAC2/3 inhibition. The CP/CEBPα/miR-34a pathway mediates the inhibitory effect of GABA on HDAC2/3 expression.},
}

@article {pmid41828536,
year = {2026},
author = {Semyachkina-Glushkovskaya, O and Sursaev, V and Poluektov, M and Diduk, S and Rychkova, L and Madaeva, I and Yakubova, L and Kurths, J},
title = {New Strategies for the Prevention and Therapy of Alzheimer's Disease Based on Stimulation of Brain Drainage and Lymphatic Clearance.},
journal = {International journal of molecular sciences},
volume = {27},
number = {5},
pages = {},
doi = {10.3390/ijms27052312},
pmid = {41828536},
issn = {1422-0067},
support = {23-75-30001//Russian Science Foundation/ ; },
mesh = {*Alzheimer Disease/therapy/prevention & control/metabolism ; Humans ; *Brain/metabolism/pathology ; *Lymphatic Vessels/metabolism ; Amyloid beta-Peptides/metabolism ; COVID-19 ; Low-Level Light Therapy/methods ; Animals ; },
abstract = {Alzheimer's disease (AD) is a serious medical challenge, representing an incurable and insidious disease. Current treatments can slow AD progression but cannot cure it. Promising new methods for AD therapy are essential for addressing the growing number of people with dementia, especially after the COVID-19 pandemic. The review highlights pioneering approaches to AD treatment based on innovative methods for the stimulation of brain drainage and clearance, in which the meningeal lymphatic vessels (MLVs) play a key role. Clinically promising noninvasive technologies using photobiomodulation for the effective clearance of metabolites, including amyloid beta (Aβ), and for the improvement of cognitive impairment during AD progression are discussed. An interesting part of the review is its analysis of innovative methods of improving the efficacy of anti-Aβ immunotherapy by stimulating MLV growth. The review is also focused on lifestyle, including sleep and physical exercises, discussing their support for the efficient lymphatic removal of waste products from the brain. Overall, the review provides an important, informative platform to excite the interest of a wide range of readers in the development of promising and clinically significant strategies for the treatment of AD, based on new strategies for the stimulation of brain drainage and clearance.},
}

*Alzheimer Disease/therapy/prevention & control/metabolism
Humans
*Brain/metabolism/pathology
*Lymphatic Vessels/metabolism
Amyloid beta-Peptides/metabolism
COVID-19
Low-Level Light Therapy/methods
Animals

@article {pmid41828511,
year = {2026},
author = {Zhao, H and Zhang, Z and Wang, C and Lin, F and Cao, H},
title = {Can IVIG Intervene in AD? Insights from Animal Experiments and Clinical Trials-A Systematic Review and Synthesis Without Meta-Analysis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {5},
pages = {},
doi = {10.3390/ijms27052275},
pmid = {41828511},
issn = {1422-0067},
support = {CSBT-SX-2024-04//Shengxiang Blood Transfusion Medicine Development Fund Project of the Chinese Association of Blood Transfusion/ ; Grant No. 2019YFS0105//Science and Technology Project of Sichuan/ ; Grant No. CIFMS, 2021-I2M-1-060//CAMS Innovation Fund for Medical Sciences/ ; },
mesh = {*Immunoglobulins, Intravenous/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism/therapy ; Animals ; Humans ; Clinical Trials as Topic ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Mice ; },
abstract = {The clinical safety of intravenous immunoglobulin (IVIG) is well-established, offering potential as a "one-drug, multi-target" intervention for Alzheimer's disease (AD). However, its efficacy remains inconclusive and appears closely related to specific functional properties. Therefore, we conducted a systematic review based on the analysis of prior animal and clinical trials to provide insights for future IVIG-based therapeutic development. A systematic search was conducted across PubMed, Embase, the Cochrane Library, Web of Science, PsycInfo, ClinicalTrials.gov, SinoMed, and Wanfang databases for the relevant literature published up to 30 October 2025, using terms related to Alzheimer's, IVIG, and β-amyloid protein. Consequently, IVIG demonstrated clinical safety, though methodologies-including dosages, models, and manufacturers-varied significantly across studies. In most cases, IVIG treatment delayed cognitive degradation in both AD mice and patients. Biologically, Aβ and tau levels increased in plasma while decreasing in the brain or cerebrospinal fluid (CSF), suggesting a peripheral clearance mechanism distinct from that of monoclonal antibody interventions. Additionally, brain atrophy was alleviated, and pathological plaques were reduced. In the context of plasma exchange (PE) combination therapy, the administration of IVIG further contributed to improvements in language, memory, and praxis. IVIG possesses a favorable safety profile and can ameliorate AD symptoms, yet efficacy varies considerably between trials. To advance treatment, future research should investigate the reasons for these variances and establish a standardized system for evaluating preclinical IVIG interventions, thereby facilitating the development of specific IVIG products for AD.},
}

*Immunoglobulins, Intravenous/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism/therapy
Animals
Humans
Clinical Trials as Topic
Amyloid beta-Peptides/metabolism
Disease Models, Animal
Mice

@article {pmid41827870,
year = {2026},
author = {Amrutha, S and Prasad, TSK and Modi, PK},
title = {Glycyrrhizic Acid Attenuates Aβ42-Induced Neurodegeneration Through Coordinated Regulation of Oxidative Stress, Synaptic Markers, and Key Alzheimer's Signaling Pathways.},
journal = {Cells},
volume = {15},
number = {5},
pages = {},
doi = {10.3390/cells15050436},
pmid = {41827870},
issn = {2073-4409},
support = {YU/Seed grant/134-2022//Yenepoya (Deemed to be University)/ ; },
mesh = {*Glycyrrhizic Acid/pharmacology/therapeutic use ; *Amyloid beta-Peptides/toxicity/metabolism ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Oxidative Stress/drug effects ; Humans ; *Signal Transduction/drug effects ; Mitochondria/drug effects/metabolism ; *Peptide Fragments/toxicity ; *Synapses/metabolism/drug effects ; Apoptosis/drug effects ; Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology ; Biomarkers/metabolism ; Cell Line ; },
abstract = {Alzheimer's disease (AD) is a catastrophic neurodegenerative disorder marked by progressive decline of cognitive function, memory loss, and neuronal death. Its pathology is characterized by the formation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles from tau hyperphosphorylation. Despite extensive research, current treatments are limited to symptomatic relief and are associated with significant side effects. This accentuates the critical need for alternative therapeutic strategies with potent neuroprotective effects and minimal toxicity. This study investigates the neuroprotective potential of glycyrrhizic acid, as the precise molecular mechanisms by which it might improve AD pathology remain poorly understood. Using an Aβ42-induced IMR-32 cell model of AD, our research revealed that Aβ42 treatment caused significant protein alterations associated with AD pathology, mitochondrial dysfunction, cell cycle re-entry, and synaptic activity. Co-treatment with glycyrrhizic acid not only restored these protein levels, but also mitigated the hyperactivation of several key signaling pathways and rescued neurons from apoptosis. These findings suggest that glycyrrhizic acid exerts neuroprotective effects by preventing mitochondrial dysfunction and apoptosis via modulation of critical signaling pathways. This study provides strong evidence for glycyrrhizic acid's neuroprotective properties in AD, paving the way for further research into its potential as a promising therapeutic agent for Alzheimer's disease.},
}

*Glycyrrhizic Acid/pharmacology/therapeutic use
*Amyloid beta-Peptides/toxicity/metabolism
*Alzheimer Disease/metabolism/drug therapy/pathology
*Oxidative Stress/drug effects
Humans
*Signal Transduction/drug effects
Mitochondria/drug effects/metabolism
*Peptide Fragments/toxicity
*Synapses/metabolism/drug effects
Apoptosis/drug effects
Neurons/drug effects/metabolism/pathology
Neuroprotective Agents/pharmacology
Biomarkers/metabolism
Cell Line

@article {pmid41827316,
year = {2026},
author = {Hasanein, D and Lighezan, DF and Țunea, OE and Ciobotaru, VG and Bașa, NS},
title = {Atrial Fibrillation and Cognitive Decline: Mechanisms, Evidence, and Preventive Strategies-A Narrative Review.},
journal = {Journal of clinical medicine},
volume = {15},
number = {5},
pages = {},
doi = {10.3390/jcm15051899},
pmid = {41827316},
issn = {2077-0383},
support = {Not applicable//Victor Babeș University of Medicine and Pharmacy Timișoara/ ; },
abstract = {Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is increasingly recognized as a risk factor for cognitive decline and dementia, independent of clinically apparent stroke. This narrative review synthesizes current evidence on pathophysiological mechanisms linking AF to cognitive decline, including cerebral hypoperfusion, silent cerebral infarction, microembolism, systemic inflammation, and shared vascular risk factors. A structured literature search was conducted in PubMed and ScienceDirect from January 2000 to October 2025, with evidence quality assessed using adapted Newcastle-Ottawa Scale criteria. Observational evidence suggests that oral anticoagulation, particularly with direct oral anticoagulants (DOACs), may be associated with reduced dementia risk compared to no treatment or vitamin K antagonists. However, most intervention studies were not designed with cognitive endpoints as primary outcomes, limiting causal inference. Current evidence supports comprehensive AF management, including guideline-directed anticoagulation, appropriate rhythm or rate control, and aggressive modification of shared risk factors. Atrial fibrillation is consistently associated with increased risk of cognitive decline and dementia through multiple interrelated mechanisms; however, randomized trials with cognitive endpoints are needed to establish causality.},
}

@article {pmid41825656,
year = {2026},
author = {Dong, M and Guo, ZG and Zhang, Y and Luo, J and Zhang, J},
title = {Optimal control of Alzheimer's disease model via multi-target combination therapy.},
journal = {Journal of theoretical biology},
volume = {},
number = {},
pages = {112425},
doi = {10.1016/j.jtbi.2026.112425},
pmid = {41825656},
issn = {1095-8541},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of toxic protein plaques in the brain. Abundant evidence indicates that β-amyloid (Aβ) serves as an important pathological hallmark in AD, with Aβ oligomers (Aβo) exhibiting critical neurotoxicity. The imbalance of Ca[2+] homeostasis has also been demonstrated to exhibit complex interplay with abnormal Aβ accumulation. Several Aβ-targeting drugs are currently employed in the treatment of AD. However, the multifactorial mechanisms driving AD contribute to the suboptimal efficacy of existing clinical therapies. Motivated by these factors, multi-target combination therapies emerge as the prominent trend in AD research. In this paper, we propose an optimal control model to describe Aβo dynamics under multi-target combined therapy. Also, the basic reproduction number R0 is derived as a threshold parameter to characterize the AD process. We find that Aβo can be maintained at a low steady state when R0 < 1, indicating the potential for disease control. The results of parameter sensitivity analysis based on R0 further confirm the significant impact of control variables on the system evolution. Subsequently, we investigate the theoretical results of the optimality system, proving the existence and uniqueness of the optimal solution. Numerical simulations are conducted to demonstrate the control efficacy of different strategies, revealing that drug combination therapy exhibits superior control over Aβo steady-state compared to mono therapy. Moreover, cost-effectiveness analysis is employed to compare different control strategies, with the objective of identifying the optimal approach that balances drug costs with therapeutic efficacy. Notably, appropriately lowering the drug dosage in triple therapy retains the potential for maintaining therapeutic effects, thereby improving drug cost control. In summary, this work provides important insights into multi-target combination therapy for early treatment of AD.},
}

@article {pmid41825614,
year = {2026},
author = {Yang, H and Zhou, H and Zhao, K and Shi, L and Li, Y and Zhao, Q and Ya, J and Wu, C},
title = {PDGF-BB mitigates pericyte injury by activating the PHF19-PRC2 complex via the miR-221/BRCA1 signaling axis in Alzheimer's disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111819},
doi = {10.1016/j.brainresbull.2026.111819},
pmid = {41825614},
issn = {1873-2747},
abstract = {BACKGROUND: Platelet-derived growth factor-BB (PDGF-BB) is a critical factor in maintaining pericyte function. Damage to pericytes has been shown to accelerate the progression of Alzheimer's disease (AD). This study aimed to investigate the role of PDGF-BB in the pathogenesis of AD.

METHODS: Pericytes were treated with Aβ1-42 alone or in combination with PDGF-BB. Cell viability, proliferation, and apoptosis were assessed using the CCK-8 assay, EdU assay, and flow cytometry, respectively. Co-immunoprecipitation was performed to investigate the interactions among BRCA1, PHF19, EZH2, EED, SUZ12, and RbAp46/48. The relationships among BRCA1, miR-221-3p, and miR-222-3p were evaluated using a luciferase reporter assay. APP/PS1 transgenic mice were administered PDGF-BB, and behavioral performance was assessed via the Morris water maze test. Immunofluorescence staining and Evans Blue assay were employed to examine pericyte coverage and blood-brain barrier (BBB) integrity.

RESULTS: PDGF-BB enhanced cell viability and proliferation while inhibiting apoptosis in Aβ1-42-treated pericytes; these effects were reversed by BRCA1 overexpression. BRCA1 expression was upregulated in pericytes exposed to Aβ1-42. Furthermore, PDGF-BB treatment resulted in the downregulation of BRCA1 and the upregulation of members of the PHF19-PRC2 complex, including PHF19, EZH2, EED, SUZ12, and RbAp46/48. BRCA1 was found to interact with these PHF19-PRC2 complex components. Additionally, miR-221 suppressed BRCA1 expression by directly targeting BRCA1, whereas miR-222 interacted with BRCA1 without affecting its expression. In vivo, PDGF-BB administration improved learning and memory abilities, increased pericyte coverage, and enhanced blood-brain barrier integrity in an Alzheimer's disease mouse model.

CONCLUSION: PDGF-BB activated PHF19-PRC2 complex through the regulation of the miR-221/BRCA1 axis, thereby decreasing blood-brain barrier permeability and improving learning and memory abilities in AD mouse models. Consequently, PDGF-BB may have a therapeutic potential in the progression of AD.},
}

@article {pmid41825555,
year = {2026},
author = {Li, W and Chen, S and Liu, Z and Lei, B and Lin, X and Ying, J and Lin, Z and Chen, L and Rowan, MJ and Hu, N and Wang, Q and Li, L},
title = {Differential effects and underlying mechanisms of voluntary, forced, and combined exercise on ameliorating Alzheimer's disease pathophenotypes.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115731},
doi = {10.1016/j.expneurol.2026.115731},
pmid = {41825555},
issn = {1090-2430},
abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disorder characterized by extracellular Aβ accumulation and intracellular tau hyperphosphorylation. Currently, there are no effective therapeutic drugs available for AD. Regular exercise training has emerged as a promising physical intervention strategy for mitigating both the risk and progression of AD, but different types of exercise interventions show varied and conflicting results in AD treatment, with their differential effects and mechanisms still unelucidated.

METHODS: Using an Aβ oligomer-induced AD mouse model, we investigated therapeutic effects of voluntary wheel running, forced treadmill running, and combined exercise (voluntary combined with forced running) on AD pathologies. For depressive-like behavior, we conducted forced swimming test and tail suspension test; for cognition, Novel object recognition test (object recognition ability) and Morris water maze test (spatial learning and memory) was used respectively. We applied BrdU-DCX/NeuN/GFAP immunofluorescence co-staining to measure neurogenesis, Western blot to examine proteins associated with synapses, neurons, astrocytes, apoptosis, and BDNF signaling key components, serum metabolomics to identify exercise-induced metabolites. Furthermore, a clinical trial involving healthy subjects and patients with AD implemented an acute exercise intervention and utilized portable functional near-infrared spectroscopy to assess cortical activation and functional connectivity under conditions of both voluntary and forced exercise.

RESULTS: Voluntary, forced, and combined exercise alleviated depressive-like phenotypes and short-term cognitive deficits in AD mice, while only forced exercise conferred sustained long-term memory benefit. All exercises boosted hippocampal neurogenesis by enhancing newborn cell (BrdU[+] cells) proliferation, promoting differentiation into immature neurons (BrdU[+]DCX[+] cells), and maintaining newborn astrocytes (BrdU[+]GFAP[+] cells). Forced/combined exercise sustained immature neurons (DCX[+] cells), and forced exercise alone significantly elevated mature newborn neurons (BrdU[+]NeuN[+] cells). Neuroprotective mechanisms may involve the modality-specific BDNF-TrkB signaling and BAX-dependent apoptosis regulation. Exercise-induced metabolites (amino acid homeostasis, energy provision, oxidative defense) strongly correlated with neurogenesis and neural function. In AD patients, acute voluntary exercise was associated with enhanced left prefrontal cortex activity, whereas acute forced exercise increased bilateral motor cortex activation.

CONCLUSIONS: Our findings reveal distinct neuroprotective profiles of long-term voluntary, forced, and combined exercise interventions against Aβ oligomer neurotoxicity in an AD mouse model, and different acute exercise modalities also demonstrate distinct effects on cortical activation and functional connectivity in patients with AD. Our study provides novel insights into exercise modalities' therapeutic effects in ameliorating AD neuropathology.},
}

@article {pmid41825224,
year = {2026},
author = {Soria-Tobar, L and Ouro-Corredera, D and Roman-Valero, L and Hernández, F and Millán, JL and Álvarez-Castelao, B and Sebastián-Serrano, Á and Aivar, P and Díaz-Hernández, M},
title = {Neuronal alkaline phosphatase promotes the spread of Tau-induced pathology, and its blockade prevents neurodegeneration and memory loss.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {2},
pages = {e00869},
doi = {10.1016/j.neurot.2026.e00869},
pmid = {41825224},
issn = {1878-7479},
abstract = {Tauopathies, such as Alzheimer's disease (AD), are neurodegenerative disorders marked by abnormal intraneuronal aggregates of phosphorylated Tau protein. Unfortunately, no effective treatment is currently available. Since extracellular Tau (eTau) is essential for the spread of cerebral tauopathy, immunotherapy approaches using specific antibodies against Tau have been investigated. However, these strategies have shown limited applicability and benefit. Because previous in vitro studies reported that dephosphorylation of eTau by tissue-nonspecific alkaline phosphatase (TNAP) enhances its neurotoxicity, here we evaluate how neuronal TNAP contributes to Tau-induced neurotoxicity in vivo. To address this, we generated new transgenic mouse lines using Cre-lox technology to i) specifically delete TNAP in excitatory neurons of P301S mice, a well-characterized tauopathy model, or ii) induce neuronal TNAP overexpression in WT mice. Moreover, we compare the in vivo spreading capacity of phospho-eTau and dephospho-eTau-induced neurotoxicity. Our findings show that neuronal TNAP deletion in P301S mice reduces i) neuronal and synaptic loss, ii) the number of neurons with neurofibrillary tangles (NFTs), iii) reactive astrogliosis and microgliosis, and iv) brain calcifications; collectively, these changes lead to v) improved memory function in these mice. Conversely, overexpression of neuronal TNAP in WT mice alone is sufficient to cause i) loss of thalamic neurons and synaptic contacts, ii) formation of intracellular NFTs, iii) reactive gliosis, iv) brain calcifications, and v) memory impairment. These results demonstrate that neuronal TNAP promotes Tau-induced neurotoxicity spreading by facilitating eTau dephosphorylation, which confirms this ectoenzyme as a promising therapeutic target for tauopathies.},
}