@article {pmid41981490,
year = {2026},
author = {Akbiyik Az, ZA and Majidov, S and Saruhanoglu, A and Ak, G},
title = {Oral mucosal lesions and oral health-related quality of life (GOHAI) in nursing home residents and community-dwelling older adults in Türkiye: a comparative cross-sectional study.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {41981490},
issn = {1471-2318},
abstract = {BACKGROUND: To compare the prevalence of oral mucosal lesions and oral health-related quality of life between nursing home residents (NHR) and community-dwelling older adults (CDA) in Türkiye.

METHODS: This observational cross-sectional study included 639 individuals aged ≥ 65 years: 329 NHR from seven state-authorized nursing homes and 310 CDA attending a university dental clinic between July 2024 and January 2025. Demographics, systemic conditions, denture use, and dental visit history were recorded. Oral mucosal lesions were identified through standardized examinations by a blinded oral medicine specialist. Oral health-related quality of life was assessed using the validated Turkish version of the Geriatric Oral Health Assessment Index (GOHAI-TR). Group comparisons employed Chi-squared, Fisher’s exact, and Mann–Whitney U tests (p < 0.05).

RESULTS: NHR had higher denture use (p = 0.001) and more Alzheimer’s and cerebrovascular disease, whereas CDA had more ischemic heart disease, smoking, and xerostomia (p < 0.05). Candidiasis and angular cheilitis were more common in NHR, while oral lichen planus, ulcerative lesions, and fissured tongue predominated in CDA. Red–blue lesions, particularly sublingual varicosities, were more frequent in CDA (41.6% vs. 31.6%, p = 0.009). CDA had higher GOHAI functional limitation scores (p = 0.001), indicating better self-perceived oral function, while NHR scored higher in pain/discomfort (p = 0.006). No significant differences were observed in psychological impact or total GOHAI scores.

CONCLUSION: NHR exhibited greater functional limitations and higher rates of infectious oral diseases. Personalized oral care strategies, including specialist-led assessments, targeted infection prevention, and structured caregiver training, are needed in long-term care to preserve oral function and quality of life in older adults.},
}

@article {pmid42185039,
year = {2026},
author = {Maestri Tassoni, M and Chiusolo, S and Hoxhaj, D and Fabbrini, M and Gargani, L and Faraguna, U and Bonanni, E and De Caterina, R},
title = {Sleep breathing disorders and cardioneurological complications: from pathophysiology to endotype-driven precision management.},
journal = {Heart (British Cardiac Society)},
volume = {},
number = {},
pages = {},
doi = {10.1136/heartjnl-2025-325833},
pmid = {42185039},
issn = {1468-201X},
abstract = {Sleep breathing disorders (SBDs)-including obstructive sleep apnoea, central sleep apnoea and sleep-related hypoventilation syndromes-represent a major yet under-recognised contributor to global cardiovascular and neurological morbidity. Through recurrent hypoxia, sympathetic overactivation, oxidative stress and systemic inflammation, these disorders promote hypertension, heart failure, arrhythmias, stroke and cognitive decline. Accumulating evidence also implicates SBDs in the progression of neurodegenerative diseases such as Alzheimer's, highlighting their role as a pathophysiological bridge between cardiometabolic and neurological dysfunction. Despite this growing recognition, diagnosis and management remain suboptimal, constrained by limited screening, underuse of polysomnography and an excessive reliance on uniform therapeutic models. Recent advances underscore the need for a precision medicine framework that integrates clinical phenotyping, physiological endotyping and technological innovation. This review synthesises current evidence on the cardiovascular and neurological implications of SBDs and explores evolving strategies for personalised, endotype-driven management.},
}

@article {pmid42185061,
year = {2026},
author = {Huang, JY and Dong, WG and Guo, WQ and Yang, SM and Huang, ST and Huang, Y and Zhan, SJ and Lin, L and Wang, F and Liu, LL},
title = {[Effect of electroacupuncture on hippocampal myelin and Rac1/PAK1/LIMK1/cofilin signaling pathway in Alzheimer's disease mice].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {51},
number = {5},
pages = {614-621},
doi = {10.13702/j.1000-0607.20250434},
pmid = {42185061},
issn = {1000-0607},
mesh = {Animals ; *p21-Activated Kinases/metabolism/genetics ; *Lim Kinases/metabolism/genetics ; *rac1 GTP-Binding Protein/metabolism/genetics ; *Alzheimer Disease/therapy/genetics/metabolism/psychology ; *Hippocampus/metabolism ; Male ; Mice ; Signal Transduction ; *Electroacupuncture ; Humans ; *Actin Depolymerizing Factors/metabolism/genetics ; *Cofilin 1/metabolism/genetics ; *Myelin Sheath/metabolism/genetics ; Neuropeptides ; },
abstract = {OBJECTIVES: To observe the effect of electroacupuncture (EA) on learning-memory ability, hippocampal myelin and RAS-associated C3 botulinum toxin substrate 1 (Rac1)/ P21-activated kinase 1 (PAK1)/ LIM kinase 1 (LIMK1)/ cofilin signaling pathway in senescence-accelerated mouse prone 8 (SAMP8) mice, so as to explore its mechanisms underlying improvement of Alzheimer's disease (AD) from the perspective of the cytoskeleton.

METHODS: Male SAMP8 (AD) mice were randomly divided into model group and EA group, with 9 mice in each group, and 9 male SAMR1 mice of the same age were used as the control group. The mice in the EA group received EA at "Dazhui" (GV14) and "Shenshu" (BL23) and punctured at "Baihui" (GV20) for 20 min, once per day, for 24 d, rest for 2 d after every 8 d of treatment. The Morris water maze test was used to observe the learning-memory ability. The Luxol fast blue (LFB) staining was used to observe the myelin sheath, and the phalloidin staining was used to observe the cytoskeleton in the hippocampus tissue. The mRNA expression levels of Rac1, PAK1, LIMK1, and cofilin were detected using real-time fluorescence quantitative PCR, and the protein expression levels of myelin basic protein (MBP), Rac1, PAK1, phosphorylated (p)-PAK1, LIMK1, p-LIMK1, cofilin, and p-cofilin in the hippocampal tissue were detected using Western blot.

RESULTS: Compared with the control group, the model group showed an obvious increase in the escape latency (P<0.01), and a significant decrease in the number of the original platform-crossing, the swimming time in the original platform quadrant, cytoskeleton fluorescence intensity, mRNA expression levels of Rac1, PAK1, LIMK1, and cofilin, and protein expression levels of MBP and Rac1, and the ratios of p-PAK1/PAK1, p-LIMK1/LIMK1, and p-cofilin/cofilin in the hippocampus tissue (P<0.01). Following EA intervention, the increased level of escape latency and the decreased levels of the number of the original platform-crossing, the swimming time in the original platform quadrant, cytoskeleton fluorescence intensity, and the expression levels of Rac1, PAK1, LIMK1, and cofilin mRNAs, and the expression levels of MBP and Rac1 proteins, and the ratios of p-PAK1/PAK1, p-LIMK1/LIMK1, and p-cofilin/cofilin were reversed (P<0.01, P<0.05). LFB staining showed disordered and loose arrangement of the fibers with vacuoles in the model group. Compared with the model group, the number of myelin fibers was increased with the fibers arranged in relatively regular order in the EA group, suggesting a reduction of the degree of demyelination.

CONCLUSIONS: EA can improve the learning-memory ability of SAMP8 mice, which may be related to its functions in up-regulating the activity of Rac1/PAK1/LIMK1/cofilin signaling, and promoting the cytoskeletal reorganization to improve myelin function.},
}

Animals
*p21-Activated Kinases/metabolism/genetics
*Lim Kinases/metabolism/genetics
*rac1 GTP-Binding Protein/metabolism/genetics
*Alzheimer Disease/therapy/genetics/metabolism/psychology
*Hippocampus/metabolism
Male
Mice
Signal Transduction
*Electroacupuncture
Humans
*Actin Depolymerizing Factors/metabolism/genetics
*Cofilin 1/metabolism/genetics
*Myelin Sheath/metabolism/genetics
Neuropeptides

@article {pmid42185171,
year = {2026},
author = {Yang, A and Xu, H and Yang, J and Wang, T},
title = {Bridging genetic-environmental features and intelligent exercise rehabilitation in Alzheimer's disease classification.},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2026.05.075},
pmid = {42185171},
issn = {0929-6646},
}

@article {pmid42185186,
year = {2026},
author = {Harrison, JR and Robertson, A and Tang, SL and Kaur, L and Poole, M and Mullin, D and Robertson, E and De Silva, P and Collis, T and Huang, L and Blackburn, D and Meinert, E and Liang, H and Taylor, JP},
title = {Automating collateral histories in dementia: Development and proof‑of‑concept evaluation of the LUMEN conversational AI.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100221},
doi = {10.1016/j.inpsyc.2026.100221},
pmid = {42185186},
issn = {1741-203X},
abstract = {BACKGROUND: Collateral histories from carers are central to dementia diagnosis but are often collected inconsistently and variably documented. With rising demand on memory services and the emergence of disease-modifying therapies requiring timely diagnosis, there is increasing need for structured and efficient assessment approaches. Conversational AI powered by large language models (LLMs) may support standardised collateral history acquisition while maintaining clinician oversight. We developed LUMEN, a stakeholder-informed prototype designed to generate structured collateral summaries for clinical review.

METHODS: A five-stage patient, public and professional involvement programme (approximately 232 participants) co-designed the question set, interface and outputs. Seven open-source LLMs were benchmarked; Qwen3-30B-A3B was selected to generate structured summaries from interview transcripts. Six clinician-authored vignettes representing Alzheimer's disease, dementia with Lewy bodies, vascular dementia, frontotemporal dementia, mild cognitive impairment and normal cognition were used to generate 54 synthetic dialogues (27 clinician role-played, 27 GPT-4 generated). Diagnostic categories were assigned using a deterministic rule-based rubric applied to structured summaries. Two clinicians independently rated each dialogue. Outcomes included exploratory evaluation of alignment with diagnostic categories measured by area under the receiver operating characteristic curve (AUROC) and Cohen's κ, and System Usability Scale (SUS) scores.

RESULTS: In this small synthetic vignette-based dataset, macro-average AUROC was 0.95; these values reflect performance under closed-loop proof-of-concept conditions rather than real-world diagnostic accuracy. Discrimination was highest for Alzheimer's disease and vascular dementia (AUROC = 1.00 in this synthetic dataset) and lowest for mild cognitive impairment (AUROC = 0.77). Agreement between categories assigned by the rule-based rubric and averaged clinician ratings was κ = 0.88 (95% CI 0.83-0.93). Mean SUS score was 78.1/100.

CONCLUSIONS: In a small, closed-loop synthetic proof-of-concept dataset, this LLM-assisted, rubric-based pipeline showed that structured summaries could be processed reproducibly by the rubric and separated diagnostic categories under controlled conditions. These findings do not show real-world diagnostic performance. Further evaluation is required to determine clinical usefulness, robustness and workflow impact.},
}

@article {pmid42185226,
year = {2026},
author = {Speckmann, T and Saurenbach, J and Schürmann, A},
title = {Golgi-associated membrane scaffolds: roles in health and disease.},
journal = {Biological chemistry},
volume = {},
number = {},
pages = {},
pmid = {42185226},
issn = {1437-4315},
abstract = {Golgi-associated membrane scaffolds, or tethers, have broad roles in membrane-bound protein and lipid trafficking and in maintaining Golgi architecture. Accordingly, they exert strong influence over cellular development, signalling, cargo modification and transport. An ever-expanding group of Golgins and multi-subunit tethering complexes assumes distinct functions in specific Golgi subcompartments in close partnership with Rab and ARL family GTPases. Their dysregulation or mutation impairs glycosylation, vesicle trafficking, and cytoskeletal dynamics, thereby contributing to a spectrum of human pathologies ranging from neurodegenerative disorders (e.g. Alzheimer's and Parkinson's disease) to cancers (e.g. lung, breast, colon) and metabolic defects (impaired insulin secretion and lipid droplet formation). Here, we review these diverse roles across molecular, cellular and organismal physiology.},
}

@article {pmid42185268,
year = {2026},
author = {Li, Z and Wu, W and Han, C and Cui, Y and Lu, T and Ke, R and Sun, J and Yuan, Z},
title = {SOFisher: reinforcement learning-guided experiment designs for spatial omics.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-73404-6},
pmid = {42185268},
issn = {2041-1723},
support = {32470706//National Natural Science Foundation of China (National Science Foundation of China)/ ; 62303119//National Natural Science Foundation of China (National Science Foundation of China)/ ; 62303054//National Natural Science Foundation of China (National Science Foundation of China)/ ; 62495090//National Natural Science Foundation of China (National Science Foundation of China)/ ; 62495095//National Natural Science Foundation of China (National Science Foundation of China)/ ; 25JS2850200//Science and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)/ ; 24FCA10//Fudan University/ ; },
abstract = {Spatial omics technologies enable the precise detection of proteins and RNAs at high spatial resolution. Designing spatial omics experiments requires careful consideration of "what" targets to measure and "where" to position the field of views (FOVs). Current FOV sampling strategies often involve acquiring densely sampled FOVs and stitching them together, which is time-consuming, resource-intensive, and sometimes impossible. To optimize FOV sampling strategies, we propose SOFisher, a reinforcement learning-based framework that harnesses the knowledge gained from the sequence of previously sampled FOVs to guide the selection of the next FOV position, to improve the efficiency of capturing more regions of interest. We rigorously evaluated SOFisher's performance using comprehensive simulations based on real spatial datasets, and our results clearly demonstrated that SOFisher consistently outperformed the conventional approach across various metrics. SOFisher's robustness and generalizability were further validated through cross-domain generalization tests and its adaptability to varying FOV sizes. On a real Alzheimer's Disease (AD) dataset, SOFisher successfully guided the selection of FOVs containing neurofibrillary tangles and amyloid-β plaques in both single and dual target tissue landmark scenarios. Remarkably, with the trained SOFisher policy, the guided experiment design of spatial single-omics on small number of FOVs yielded insights into AD-related cell states, subtypes, and gene programs previously obtained through spatial multi-omics experiments on large tissue slices. We further showcased SOFisher's applications on a colorectal cancer dataset with complex tissue structures and high heterogeneity. Beyond cell type based targeting, we extended SOFisher's reward function to maximize gene expression levels across diverse spatial patterns and enhanced its exploration capacity through SOFisherWR (SOFisher With Restart) to comprehensively capture discontinuous target enriched regions. SOFisher has the potential to revolutionize the experiment design of spatial biology.},
}

@article {pmid42185568,
year = {2026},
author = {Guo, Y and Wang, X and Zhang, L and Liu, X and Lu, P and Liang, F and Wu, J and Zhao, J and Hai, Y},
title = {Ghrelin Ameliorates Alzheimer's Disease-Associated Astrocyte Dysfunction via UCP2-Mediated Inhibition of FOXO1 Nuclear Translocation.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42185568},
issn = {1559-1182},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Astrocytes/drug effects/metabolism/pathology ; *Uncoupling Protein 2/metabolism ; *Ghrelin/pharmacology/therapeutic use ; *Forkhead Box Protein O1/metabolism ; Mitochondria/metabolism/drug effects ; Amyloid beta-Peptides/toxicity ; *Cell Nucleus/metabolism/drug effects ; Mice, Inbred C57BL ; Mice ; Protein Transport/drug effects ; Male ; Membrane Potential, Mitochondrial/drug effects ; Glycolysis/drug effects ; },
abstract = {Alzheimer's disease (AD) is associated with mitochondrial dysfunction and impaired energy metabolism in astrocytes. Although ghrelin is known to exert neuroprotective effects, the mechanisms through which it modulates astrocyte bioenergetics under AD-like conditions remain incompletely defined. In primary astrocytes treated with Aβ25-35 oligomers, ghrelin attenuated mitochondrial damage, reducing ROS and enhancing mitochondrial membrane potential (ΔΨm) and respiratory complex activities. Glycolytic function was partially restored, as evidenced by upregulation of key enzymes, increased glucose uptake, lactate release, and NAD[+]/NADH ratio. Ghrelin inhibited autophagosome formation while enhancing mitophagy (increased LC3II/I and Parkin) and suppressed inflammation. In co-culture models, these metabolic improvements enhanced astrocytic support for neurons, reducing apoptosis and promoting neurite growth, an effect abolished by the glycolytic inhibitor 2-DG. Mechanistically, ghrelin upregulated uncoupling protein 2 (UCP2), which inhibited forkhead box protein O1 (FOXO1) nuclear translocation. In Aβ25-35-injected mice with UCP2 or FOXO1 modulation, ghrelin improved cognitive performance and reduced pathology, effects that were negated by UCP2 knockdown and partially rescued by FOXO1 knockdown. In conclusion, ghrelin ameliorates Aβ-induced astrocyte dysfunction involving the UCP2-FOXO1 pathway, partially restoring mitochondrial integrity, glycolytic metabolism, and neurotrophic support, suggesting its therapeutic potential.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/pathology
*Astrocytes/drug effects/metabolism/pathology
*Uncoupling Protein 2/metabolism
*Ghrelin/pharmacology/therapeutic use
*Forkhead Box Protein O1/metabolism
Mitochondria/metabolism/drug effects
Amyloid beta-Peptides/toxicity
*Cell Nucleus/metabolism/drug effects
Mice, Inbred C57BL
Mice
Protein Transport/drug effects
Male
Membrane Potential, Mitochondrial/drug effects
Glycolysis/drug effects

@article {pmid42185591,
year = {2026},
author = {Hiruthyaswamy, SP and Rao, D and Balakrishna, S and Macarius, NMN and Sakthivel, YK and Deepankumar, K and Vijayan, M},
title = {Transglutaminase and its role in Alzheimer's disease: focus on mitochondria, aging, defective mitophagy, synaptic degeneration, and metabolomics.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42185591},
issn = {2509-2723},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline driven by amyloid-β plaques, tau neurofibrillary tangles, and extensive neuronal loss. Emerging evidence highlights mitochondrial dysfunction, defective mitophagy, and disrupted proteostasis as pivotal events in disease progression. Transglutaminase TG2, a multifunctional calcium-dependent enzyme, has gained attention for its capacity to link these pathological processes. Beyond catalyzing ε-(γ-glutamyl)-lysine crosslinks that stabilize amyloid and tau aggregates, TG2 interacts with mitochondrial membranes, altering permeability and bioenergetic efficiency. In neurons, aberrant TG2 activity promotes oxidative stress, impairs mitophagy through crosslinking of PINK1 and Parkin, and exacerbates calcium dyshomeostasis via modification of VDAC and ANT1, culminating in energy failure and apoptosis. Aging-related increases in ROS and inflammatory cytokines further amplify TG2 activation, reinforcing proteostatic collapse and synaptic degeneration. Recent metabolomic studies reveal that TG2-mediated dysregulation extends to lipid and amino acid metabolism, affecting mitochondrial respiration and neuronal signaling. Therapeutically, selective TG2 inhibition restores autophagic flux, mitigates mitochondrial damage, and reduces aggregate burden in preclinical models. This integrative review underscores TG2 as a central orchestrator connecting mitochondrial dysfunction, aging, mitophagy failure, and metabolic imbalance in AD. Targeting TG2's transamidase activity while preserving its regulatory roles may offer a promising strategy for neuroprotection and disease modification.},
}

@article {pmid42185646,
year = {2026},
author = {Zhang, X and Liu, W and Guo, N and Gao, X and Pu, S and Yang, Y and Zha, X and Ding, K and Shi, D and Zhao, J and Cheng, D and Luo, Z},
title = {TREM2-Targeting peptide tracer for neuroinflammation PET imaging.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42185646},
issn = {1619-7089},
support = {2021F0209-000-04//Faculty Start-up Foundation of ShanghaiTech University/ ; 18DZ2260400//Shanghai Key Laboratory of Molecular Imaging/ ; },
abstract = {PURPOSE: Triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as an important target in neurodegenerative diseases. However, noninvasive visualization of TREM2 expression in the central nervous system (CNS) remains challenging. This study aimed to develop and evaluate a novel peptide-based positron emission tomography (PET) tracer for imaging TREM2 in CNS.

METHODS: A TREM2-targeting peptide was conjugated with DOTA and radiolabeled with gallium-68 to generate [[68]Ga]Ga-STZL730. Binding affinity, tracer stability, lipophilicity, and cellular uptake were evaluated. Dynamic PET imaging and blocking studies were performed in wild-type mice, TREM2 knockout mice, lipopolysaccharide (LPS)-induced neuroinflammation mice, and APP/PS1 Alzheimer's disease (AD) model mice. Autoradiography and immunofluorescence staining were conducted to validate tracer specificity and target expression.

RESULTS: [[68]Ga]Ga-STZL730 was synthesized with high radiochemical purity (> 99%) and demonstrated excellent stability in vitro. The tracer exhibited specific binding to TREM2 with an affinity (KD) of 274 nM. In vivo PET imaging demonstrated that [[68]Ga]Ga-STZL730 could cross the blood-brain barrier, displaying moderate and sustained brain uptake. Notably, at 20-35 min post-injection, compared to wild-type controls, brain uptake was significantly reduced in TREM2 knockout mice (41.6% lower), whereas it was markedly increased in both LPS-treated mice (113.8% higher) and AD mice (86.0% higher). Blocking studies in AD mice demonstrated the specific binding of [[68]Ga]Ga-STZL730. In vitro autoradiography and immunohistochemical analyses further confirmed that elevated PET signals corresponded to increased TREM2 expression, which was spatially localized to activated microglia in APP/PS1 mice brain sections.

CONCLUSION: [[68]Ga]Ga-STZL730 is a novel peptide-based PET tracer that enables specific, noninvasive imaging of TREM2 expression in the CNS. It provides a promising tool for investigating neuroinflammation and TREM2-associated pathology in neurodegenerative diseases.},
}

@article {pmid42185674,
year = {2026},
author = {Gerasimov, KA and Ignasheva, YE and Dobryakova, YV and Korotkova, TA and Koryagina, AA and Markevich, VA and Bolshakov, AP},
title = {Overexpression of WNT3a in the Hippocampus Can Partly Alleviate Deficits in Animal Models of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42185674},
issn = {1573-6903},
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics ; *Wnt3A Protein/genetics/metabolism/biosynthesis ; Mice, Transgenic ; Disease Models, Animal ; *Hippocampus/metabolism ; Male ; Rats ; Mice ; Long-Term Potentiation/physiology ; Wnt Signaling Pathway/physiology ; Neuronal Plasticity/physiology ; },
abstract = {Dysregulation of the WNT signaling pathway is implicated in the synaptic dysfunction underlying Alzheimer's disease (AD). This study investigates whether enhancing WNT signaling through hippocampal overexpression of the WNT3a ligand can mitigate functional deficits in two distinct animal models of AD pathology. We used a rat model of cholinergic deficit, induced by intraseptal 192IgG-saporin injections, and a transgenic 5XFAD mouse model of amyloidosis. Adeno-associated viruses were used to overexpress WNT3a in the hippocampal CA1 region. We assessed cognitive and sensorimotor behavior, synaptic plasticity (long-term potentiation, LTP) in vivo (rats) and in vitro (mice), and analyzed key proteins of the WNT signaling pathway. In rats with cholinergic deficit, WNT3a overexpression ameliorated sensorimotor coordination deficits and restored the initial phase of hippocampal LTP in vivo, without preventing the loss of cholinergic neurons or the decrease in acetylcholinesterase activity. In 5XFAD mice, which exhibited impaired LTP in vitro, WNT3a overexpression significantly enhanced the early phase of potentiation. This functional rescue was associated with a recovery of elevated phospho-β-catenin levels in the 5XFAD hippocampus. WNT3a did not affect behavior in the 5XFAD model and its benefits were independent of changes in cholinergic markers in both models. Our findings demonstrate that targeted WNT3a overexpression in the hippocampus can partially alleviate synaptic and functional deficits in AD models by directly modulating synaptic plasticity, primarily through the restoration of the Wnt/β-catenin pathway. This positions WNT3a gene therapy as a promising strategy for counteracting synaptic failure in Alzheimer's disease.},
}

Animals
*Alzheimer Disease/metabolism/genetics
*Wnt3A Protein/genetics/metabolism/biosynthesis
Mice, Transgenic
Disease Models, Animal
*Hippocampus/metabolism
Male
Rats
Mice
Long-Term Potentiation/physiology
Wnt Signaling Pathway/physiology
Neuronal Plasticity/physiology

@article {pmid42185748,
year = {2026},
author = {Zarkali, A and Dobreva, I and Hannaway, N and Bhome, R and Thomas, GEC and Carrera, S and Heslegrave, AJ and Veleva, E and Zetterberg, H and Weil, RS},
title = {Gray Matter Microstructure Measured Using Diffusion Imaging as a Biomarker of Severity in Lewy Body Diseases.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70355},
pmid = {42185748},
issn = {1531-8257},
support = {UKRI2343//UK Research and Innovation/ ; 225263/Z/22/WT_/Wellcome Trust/United Kingdom ; //Rosetrees Trust/ ; /AMS_/Academy of Medical Sciences/United Kingdom ; /PUK_/Parkinson's UK/United Kingdom ; },
abstract = {BACKGROUND: Despite widespread cortical involvement in Lewy body diseases, conventional gray matter magnetic resonance imaging (MRI) shows limited sensitivity. Diffusion-weighted MRI-derived microstructural measures have shown utility in Alzheimer's disease, but their application across the Lewy body disease spectrum remains limited.

OBJECTIVES: The goal was to examine gray matter microstructure in 197 participants across the Lewy body disease spectrum (88 Lewy body dementia [LBD], 109 Parkinson's disease, and normal cognition [PD-NC]) and 46 controls.

METHODS: Tissue-weighted neurite density index, tissue-weighted orientation dispersion index, and free water fraction were examined across 200 cortical and 32 subcortical regions. We compared these cross-sectionally between LBD, PD-NC and controls, and longitudinally over 3 years in a subset of 100 patients with Parkinson's disease cognitively intact at baseline. We assess associations with disease severity and plasma p-tau217 levels.

RESULTS: LBD showed widespread cortical and subcortical increases in free water fraction and, to lesser extent, orientation dispersion compared to controls and PD-NC, despite minimal atrophy and no neurite density differences. In temporoparietal regions, increases in free water fraction and orientation dispersion correlated with cognitive, but not motor, severity, and with plasma p-tau217. Longitudinally, Parkinson's disease patients who developed cognitive impairment showed greater free water fraction increases within bilateral temporal regions, right thalamus, and right caudate.

CONCLUSIONS: Diffusion-derived microstructural measures, particularly free water fraction are sensitive to early and progressive gray matter changes associated with cognitive decline in Lewy body diseases. Findings suggest microstructural disruption without overt neuronal loss and support free water fraction as a potential biomarker for disease staging and progression. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
}

@article {pmid42185915,
year = {2026},
author = {Singh, B and Youssef, SH and Uddin, AHMM and Song, Y and Garg, S},
title = {Simultaneous quantification of donepezil and memantine by HPLC-refractive index detection for novel drug delivery systems.},
journal = {BMC chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13065-026-01835-9},
pmid = {42185915},
issn = {2661-801X},
abstract = {Alzheimer's dementia is often treated with a combination of memantine and donepezil, which is more effective than monotherapy. Despite its clinical relevance, simultaneous determination is challenging due to the absence of a chromophore in memantine. Herein, a simple, accurate, and sensitive High-Performance Liquid Chromatography-refractive index method is reported for the first time for the simultaneous quantification of memantine and donepezil for routine analysis. The method employed a C18 column with a mobile phase of 1% diethylamine in water: methanol (50:50, v/v), adjusted to pH 6.0 using dilute glacial acetic acid. Optimized conditions (flow rate 0.8 mL/min, injection volume 20 µL at 40 °C) yielded a linearity ranging between 2.5 and 30 µg/mL (R[2] = 1) for both the drugs. Limits of detection and quantification were 0.194 and 0.589 µg/mL for Dnp and 0.237 and 0.718 µg/mL for Mem. Validation confirmed precision, robustness, and stability. The method was successfully applied to determine the amount of drug release from the intranasal nano-colloidal preparations, along with optimized sample preparations giving analyte recoveries within range without any interference from the formulation excipients. The derivatization exhibited acceptable selectivity with no interfering peaks from excipients, demonstrating its suitability for routine analysis. The sustainability of the developed method was assessed using different metrics, namely the Analytical GREEnness Metric Approach and Software, Green Analytical Procedure Index, and Blue Applicability Grade Index.},
}

@article {pmid42186042,
year = {2026},
author = {Salgueiro, AM and Ferreira-Marques, M and Ribeiro, RFN and Lopes, SM and Pereira, D and Costa, DG and Santana, MM and de Almeida, LP and Cavadas, C},
title = {Ketogenic diet as a therapeutic strategy for neurodegenerative diseases: from mechanisms to translational challenges.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42186042},
issn = {2047-9158},
support = {UIDB/04539/2020//Fundação para a Ciência e a Tecnologia/ ; UIDP/04539/2020//Fundação para a Ciência e a Tecnologia/ ; LA/P/0058/2020(JPND/ 0001/2022//Fundação para a Ciência e a Tecnologia/ ; DOI: 10.54499/JPND/0001/2022; JPND/0002/2022//Fundação para a Ciência e a Tecnologia/ ; DOI: 10.54499/JPND/0002/2022//Fundação para a Ciência e a Tecnologia/ ; SFRH/BD/120023/2016; 2020.04850.BD//Fundação para a Ciência e a Tecnologia/ ; 2022.11293.BD//Fundação para a Ciência e a Tecnologia/ ; GeneT project-The Gene Therapy CoE at the Center of Portugal (Project ID: 101059981//HORIZON EUROPE Widening participation and spreading excellence/ ; DOI: 10.3030/101059981); GCure - From Gene to Cure//HORIZON EUROPE Widening participation and spreading excellence/ ; ID: 101186929//HORIZON EUROPE Widening participation and spreading excellence/ ; DOI:10.3030/101186929; GeneH - Excellence Hub for Advancing Innovation in Gene Therapy//HORIZON EUROPE Widening participation and spreading excellence/ ; ID: 101186939//HORIZON EUROPE Widening participation and spreading excellence/ ; DOI: 10.3030/101186939//HORIZON EUROPE Widening participation and spreading excellence/ ; },
mesh = {Humans ; *Diet, Ketogenic/methods ; *Neurodegenerative Diseases/diet therapy/metabolism ; Animals ; *Translational Research, Biomedical/methods ; Gastrointestinal Microbiome/physiology ; Oxidative Stress/physiology ; },
abstract = {The ketogenic diet (KD) is increasingly recognized as a promising therapeutic strategy for neurodegenerative disorders because of its multifaceted impacts on key pathophysiological mechanisms. This review explores the molecular pathways through which KD may protect against neurodegeneration, including the use of ketone bodies as alternative energy substrates, reduction of oxidative stress and inflammation, modulation of autophagy and protein aggregation, and impact on the gut microbiome. The potential benefits of KD are explored across neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, based on both preclinical and clinical evidence that supports its feasibility. However, challenges in long-term safety, patient adherence, and clinical practicality limit its widespread adoption. This review underscores the potential of KD for treating neurodegeneration on the basis of current scientific evidence while highlighting the need for further research to optimize its application and address existing gaps.},
}

Humans
*Diet, Ketogenic/methods
*Neurodegenerative Diseases/diet therapy/metabolism
Animals
*Translational Research, Biomedical/methods
Gastrointestinal Microbiome/physiology
Oxidative Stress/physiology

@article {pmid42186115,
year = {2026},
author = {Iqbal, S and Olivares, CB and Rizzo, L and Parker, TD and Wong, C and Underwood, BR and Carpenter, J and Dunne, R and Raymont, V and Reith, A and Mummery, CJ and Karran, EH and Ducotterd, F and Wilcock, G and Cummings, JL and O'Brien, JT and Mursaleen, L and Schneider, LS and Vandenberghe, R and Macleod, M and Khan, Z and Malhotra, P and Reeves, S},
title = {Repurposed drug prioritization pipeline for a multi-arm platform trial in clinical Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71495},
doi = {10.1002/alz.71495},
pmid = {42186115},
issn = {1552-5279},
support = {//Alzheimer's Research UK/ ; //UK National Institute for Health and Care Research (NIHR)/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Drug Repositioning/methods ; Clinical Trials as Topic ; Atomoxetine Hydrochloride/therapeutic use ; Metformin/therapeutic use ; },
abstract = {INTRODUCTION: There is an urgent need to identify effective, safe, and affordable treatments for Alzheimer's disease (AD). Funded by the UK National Institute for Health and Care Research (NIHR), we developed a systematic drug prioritization pipeline to identify repurposed drug candidates for inclusion in a planned platform trial for clinical AD.

METHODS: The wider AD community was invited to propose compounds using a standardized proposal template. Fourteen proposals were presented to an international expert panel, who independently ranked compounds based on biological plausibility, preclinical efficacy, safety, and trial feasibility. Extended drug summaries were compiled for shortlisted compounds, supported by ReLiSyR, a machine learning-supported systematic review tool.

RESULTS: Following review in a second panel meeting, independent re-ranking identified the following compounds: atomoxetine (1st), metformin (2nd), isosorbide mononitrate and levetiracetam (joint 3rd).

DISCUSSION: This robust drug prioritization pipeline will speed the identification and progression of promising candidates for therapeutic evaluation.},
}

*Alzheimer Disease/drug therapy
Humans
*Drug Repositioning/methods
Clinical Trials as Topic
Atomoxetine Hydrochloride/therapeutic use
Metformin/therapeutic use

@article {pmid42186244,
year = {2026},
author = {Xu, G and Xu, P and Lei, Y and Zhou, Z and Chen, Y and Zhan, J and Feng, F and Cai, Z and Chen, F},
title = {Association of peripheral blood NLRP3, sTREM2, and p-tau217 levels with cognitive outcomes in patients with chronic alcohol-related brain damage.},
journal = {Alcohol and alcoholism (Oxford, Oxfordshire)},
volume = {61},
number = {4},
pages = {},
doi = {10.1093/alcalc/agag036},
pmid = {42186244},
issn = {1464-3502},
support = {(2025)030//Key Laboratory of Brain Function and Brain Disease Prevention and Treatment of Guizhou Province/ ; GZWJWPF2025008//Guizhou Provincial Health Commission Clinical Key Specialty Construction 'Climbing Peak Plan' Project/ ; [2024]145//Young Scientific and Technological Talent Growth Project of Guizhou Provincial Department of Education/ ; [2025]41//Zunyi Municipal Science and Technology Support Program/ ; //Future Renowned Clinicians/ ; gzwkj2026-176//the 2026 Science and Technology Fund Project of Guizhou Provincial Health Commission/ ; [2026] 993//Guizhou Science and Technology Cooperation Foundation/ ; },
mesh = {Humans ; Male ; Female ; *NLR Family, Pyrin Domain-Containing 3 Protein/blood ; *tau Proteins/blood ; Cross-Sectional Studies ; Middle Aged ; Biomarkers/blood ; *Alcoholism/blood/psychology/complications ; Aged ; *Membrane Glycoproteins/blood ; Alzheimer Disease/blood/psychology ; *Receptors, Immunologic/blood ; *Cognition/physiology ; Mental Status and Dementia Tests ; Cognitive Dysfunction/blood ; },
abstract = {OBJECTIVES: Although NLRP3, sTREM2, and p-tau217 are important in Alzheimer's disease (AD), their relevance in alcohol-related brain damage (ARBD) is unclear. This study aimed to compare these biomarkers in patients with ARBD, non-alcoholic AD, and alcohol dependence without encephalopathy, and to examine their links to cognitive function.

METHODS: This cross-sectional study included 45 ARBD patients, 41 non-alcoholic AD patients, and 39 alcohol-dependent patients without encephalopathy. We measured peripheral serum levels of NLRP3, sTREM2, and p-tau217 by enzyme-linked immunosorbent assay and assessed cognitive function using the Montreal Cognitive Assessment and Mini-Mental State Examination. Statistical analyses were performed to evaluate group differences and associations with ARBD. ARBD patients exhibited higher levels of inflammatory markers and more severe anxiety and depression than other groups.

RESULTS: Serum sTREM2 was significantly highest in the ARBD group compared to both non-alcoholic AD and alcohol-dependent groups (P < .05). NLRP3 was also elevated in ARBD patients compared to the alcohol-dependent group (P = .005). No significant group differences were found for p-tau217. After adjusting for confounders, sTREM2 was significantly associated with cognitive, alcohol use, and mood scores, whereas NLRP3 was associated only with alcohol use and cognitive scores. Both sTREM2 and NLRP3 were independent predictors of ARBD. ROC analysis demonstrated that sTREM2 had the highest diagnostic accuracy for ARBD (AUC = 0.814), significantly outperforming NLRP3 (AUC = 0.671) and p-tau217 (AUC = 0.590).

CONCLUSIONS: Serum sTREM2 and NLRP3 are promising peripheral biomarkers for ARBD. sTREM2, in particular, shows a strong association with clinical severity and demonstrates robust diagnostic potential, supporting its utility in the diagnosis and pathophysiological understanding of ARBD.},
}

Humans
Male
Female
*NLR Family, Pyrin Domain-Containing 3 Protein/blood
*tau Proteins/blood
Cross-Sectional Studies
Middle Aged
Biomarkers/blood
*Alcoholism/blood/psychology/complications
Aged
*Membrane Glycoproteins/blood
Alzheimer Disease/blood/psychology
*Receptors, Immunologic/blood
*Cognition/physiology
Mental Status and Dementia Tests
Cognitive Dysfunction/blood

@article {pmid42186247,
year = {2026},
author = {Kay, DF and Brooks, NJ and Caulton, SG and Jayasekera, HS and Lovering, AL and Leney, AC},
title = {Mapping Phosphorylation-Specific Pin1-CRMP2 Interactions Using an Integrated Mass Spectrometry Approach.},
journal = {ACS chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschembio.6c00227},
pmid = {42186247},
issn = {1554-8937},
abstract = {Abnormal protein phosphorylation is a fundamental trigger in the pathogenesis of Alzheimer's Disease, leading to the formation of neurofibrillary tangles. Thus, molecular determination of the critical factors in controlling phosphorylation is desirable. Pin1, a cis-trans prolyl isomerase has recently been implicated in Alzheimer's Disease progression. Moreover, Pin1 specifically targets phosphoproteins, regulating their function. Here, we reveal a novel interaction interface between Pin1 and the Collapsin Response Mediator Protein-2 (CRMP2), a protein found hyperphosphorylated alongside Tau within neurofibrillary tangles. Using native mass spectrometry, we show that Pin1 binds to the disordered C-terminus of CRMP2 in a phosphorylation-dependent manner with residues Thr509 and Thr514 on CRMP2 important for enhanced binding affinity. Hydrogen-deuterium exchange mass spectrometry experiments further localized this binding site to the WW domain of Pin1. Together, these findings provide novel insight into a putative regulatory role of Pin1 in modulating hyperphosphorylation of CRMP2.},
}

@article {pmid42186374,
year = {2026},
author = {Tseng, WI and Hsieh, YC and Hsu, YC and Huang, LK and Fu, CK and Chen, DY and Chen, JH and Hong, CT and Lu, YH and Chan, L and Chiou, HY},
title = {Gray matter brain age predicts cognitive outcome one year after ischemic stroke.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450602},
doi = {10.1177/13872877261450602},
pmid = {42186374},
issn = {1875-8908},
abstract = {BackgroundPredicting post-stroke cognitive impairment (PSCI) remains challenging.ObjectiveThis study validated two brain age metrics-Gray Matter Brain Age (GMBA) and Predicted Age Difference (PAD)-as independent predictors of 12-month cognitive decline following ischemic stroke.MethodsWe analyzed 39 patients with ischemic stroke. Brain age was estimated using a machine learning model trained on healthy controls (n = 362). Baseline assessments, including demographics, clinical severity, and thick-sliced (7 mm) 2D T1- and T2-weighted MRI, were performed during acute hospitalization (median 5 days post-stroke). Change in Clinical Dementia Rating-Sum of Boxes (ΔCDR-SB) was measured between baseline and 12 months. Multiple linear regression (MLR) and receiver operating characteristic (ROC) analysis identified predictors of ΔCDR-SB.ResultsMLR identified two significant models. In Model 1, PAD (β = 0.109, p = 0.035) and chronological age (β = 0.082, p = 0.038) were independent predictors (Adjusted R[2] = 0.183). In Model 2, GMBA emerged as the sole robust predictor (β = 0.092, p = 0.002; Adjusted R[2] = 0.201). ROC analysis showed GMBA possessed the highest discriminative ability (AUC = 0.717, p = 0.026), followed by PAD (AUC = 0.691, p = 0.050), while chronological age was not significant (AUC = 0.629, p = 0.188).ConclusionsBoth GMBA and PAD are independent predictors of PSCI. Notably, these metrics maintained high predictive utility even when derived from real-world, thick-sliced MRI protocols. Integrating brain age estimation into routine clinical workflows can potentially facilitate early identification of patients at high risk for PSCI.},
}

@article {pmid42186541,
year = {2026},
author = {Clemens, SG and Hobbs, DA and McKay, NS and Millar, PR and Morris, JC and Hassenstab, J and Zacks, JM and Balota, DA and Gordon, BA},
title = {Elevated functional magnetic resonance imaging activity in cognitively normal participants predicts future dementia.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag167},
pmid = {42186541},
issn = {2632-1297},
abstract = {As individuals age, they are more likely to show increased functional MRI (fMRI) activity, particularly in frontal regions. This has been interpreted as a compensatory mechanism, yet the very need to draw upon such resources indicates increasing failures of brain systems. Almost all work addressing theoretical models explaining these patterns has been cross-sectional, with minimal work testing how elevated fMRI activity predicts future cognitive trajectories. Further, although often viewed as ageing, there is increasing evidence that subtle fMRI changes may represent the earliest manifestation of neurodegenerative conditions such as Alzheimer's disease. One hundred nine individuals completed a Stroop colour/word task during fMRI data acquisition. Analyses focused on differences between trials where the colour and word were incongruent (the word red written in blue) relative to congruent trials (the word blue written in blue). At baseline, participants also underwent amyloid positron emission tomography imaging and APOE genotyping. Individuals had longitudinal clinical follow-up (mean 6.8 years) with 15 individuals reaching the threshold of clinically defined cognitive impairment. Across the entire cohort, several brain regions, including dorsolateral prefrontal cortex, anterior cingulate cortex, and lateral temporal and parietal regions, were more active on conflict trials. At the individual level, increases in activity were related to changes in reaction time, with those experiencing greater conflict having greater evoked activity. Further, individuals who later developed dementia had greater activity at baseline than their peers who remained cognitively normal despite there being no differences in accuracy (t = 0.23, P = 0.82) or reaction time (t = 0.94, P = 0.35) in the Stroop task nor differences in mini-mental state examination (t = 0.06, P = 0.95) or a neuropsychological composite (t = -0.99, P = 0.32). Individuals who progressed were more likely to be amyloid positive (χ [2] = 26.71, P = 0.000002) and carriers of the APOE ε4 allele (χ [2] = 4.81, P = 0.03). The current work suggests that, although compensatory in nature in the short term, increased activation of frontal and parietal control regions during attentional control tasks is indicative of underlying declines in brain health. The larger implications are 2-fold. Undetected neurodegenerative disease pathology biases our understanding of what constitutes healthy ageing. Further, alterations in brain function occur well in advance of clinically detectable cognitive change, emphasizing the need to intervene with disease modifying therapies early in the disease course.},
}

@article {pmid42186774,
year = {2026},
author = {DeAngelis, R and Burnside, L and Donnell, DO and Hicken, M and Umberson, D and Perry, B},
title = {Social connection and cognitive health: A review of concepts, measures, and research priorities.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71517},
doi = {10.1002/alz.71517},
pmid = {42186774},
issn = {1552-5279},
support = {U24AG088894/AG/NIA NIH HHS/United States ; P30AG066614/AG/NIA NIH HHS/United States ; R37AG076057/AG/NIA NIH HHS/United States ; R37AG57739/AG/NIA NIH HHS/United States ; R01AG076032/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Cognition/physiology ; Alzheimer Disease/psychology ; *Social Interaction ; },
abstract = {Lack of social connection is a major risk factor for Alzheimer's disease and related dementias, on a par with other common risk factors like physical inactivity and smoking. Yet we still know surprisingly little about how social connection affects cognitive health. Our review provides updated guidance for researchers interested in testing new mechanistic models of social connection and cognitive health over the life course. First, we conceptualize social connection and its various components. Second, we provide readers with a supplemental compendium of social connection measures and discuss how to tailor different types of measures to specific research goals. Third, we advance a conceptual model linking social connection to cognitive health across different social, spatial, and temporal contexts, while also considering potential sources of confounding and reciprocal causation. Finally, we outline five priority areas for future research into social connection and cognitive health across the life course.},
}

Humans
*Cognition/physiology
Alzheimer Disease/psychology
*Social Interaction

@article {pmid42186792,
year = {2026},
author = {Ma, F and Akolkar, H and Benosman, R and Herrup, K},
title = {Behavior of neural networks in culture suggest that sporadic and genetic forms of Alzheimer's disease may not be equivalent.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71493},
doi = {10.1002/alz.71493},
pmid = {42186792},
issn = {1552-5279},
support = {//University of Pittsburgh Momentum Fund/ ; //University of Pittsburgh School of Medicine/ ; NS120922//National Institute of Neurological Diseases and Stroke (NINDS)/ ; 4100087331//Pennsylvania Department of Health/ ; AG005133/AG/NIA NIH HHS/United States ; AG069912/AG/NIA NIH HHS/United States ; //University of Pittsburgh Start Up Fund/ ; },
mesh = {*Alzheimer Disease/genetics/pathology/physiopathology ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Neurons/physiology/drug effects ; Animals ; Amyloid beta-Peptides/metabolism/pharmacology ; Cells, Cultured ; *Nerve Net ; Humans ; Action Potentials/physiology/drug effects ; Rats ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) research often assumes that familial and sporadic forms share a common pathogenesis. However, the cellular impacts of amyloid precursor protein (APP) mutations compared with age-related overexpression of APP or the deposition of amyloid beta (Aβ) are likely different.

METHODS: Using high-density multi-electrode arrays, we compared neural activity in cultured neurons subjected to Aβ exposure or APP overexpression (via lentiviral delivery or genetic models). Effects on neuronal firing, synaptogenesis, axonal branching, and network connectivity were assessed in both developing and mature cultures.

RESULTS: APP overexpression reduced individual neuron firing probability and impaired synaptogenesis and axonal branching during development. In contrast, Aβ disrupted synaptic connections in mature cultures and impaired network-level communication without blocking early structural development.

DISCUSSION: These findings indicate that APP mis-regulation and Aβ toxicity contribute differently to neuronal behavior. These differences raise questions about the assumptions that familial and sporadic AD are similar if not identical conditions.},
}

*Alzheimer Disease/genetics/pathology/physiopathology
*Amyloid beta-Protein Precursor/genetics/metabolism
*Neurons/physiology/drug effects
Animals
Amyloid beta-Peptides/metabolism/pharmacology
Cells, Cultured
*Nerve Net
Humans
Action Potentials/physiology/drug effects
Rats

@article {pmid42186854,
year = {2026},
author = {Khani, M and Yeboah, SN and Cerquera-Cleves, C and Kedmi, A and Bustos, BI and Grant, SM and Can Akerman, S and Akçimen, F and Lee, PS and Reyes-Pérez, P and Lange, LM and Leonard, H and Koretsky, MJ and Makarious, MB and Schneider, Z and Jonson, C and Chen, PS and Tay, YW and Rothstein, JD and Lin, CH and Lim, SY and Klein, C and Merchant, K and Mencacci, NE and Krainc, D and Cookson, MR and Singleton, A and Bandres-Ciga, S},
title = {Is SORL1 a common genetic target across neurodegenerative diseases? A multi-ancestry biobank study.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag187},
pmid = {42186854},
issn = {1460-2156},
abstract = {SORL1, the gene encoding the SORLA protein, has arisen as a potential therapeutic target for Alzheimer's disease (AD). Studies suggest that restoring SORLA function or its trafficking pathways, particularly the SORLA-retromer recycling system, may offer a promising strategy to slow or halt AD progression. While both rare and common SORL1 variants have been associated with increased AD risk, recent evidence suggests a potential involvement of SORL1 in other neurodegenerative conditions. This study assessed the contribution of SORL1 genetic variation to the risk of AD, related dementias (RD), and Parkinson's disease (PD) using data from six large-scale biobanks, comprising 15,043 AD, 9,943 RD, and 42,763 PD cases, along with 111,969 controls across 11 ancestries. We identified 53 potentially disease-related SORL1 variants (CADD score > 20, MAC ≥ 2, annotated as protein-altering or splicing, and with the mutated allele present only in cases), including 41 novel and 12 previously reported variants. Three were found across multiple ancestries. Overall, 13 variants were found in AD-related cohorts, 5 in RD cohorts, and 35 in PD cohorts. Association analysis identified 10 nominally significant variants associated with AD and 5 with PD. The replication of multiple SORL1 variants across neurodegenerative diseases and ancestrally diverse populations underscores its potential broad genetic contribution to neurodegeneration and reinforces its relevance across distinct clinical phenotypes. Burden analysis identified a nominal association of SORL1 variants in PD in the South Asian population (P = 0.048). A family-based analysis identified a rare predicted-damaging variant in two East Asian families (11:121478242:G:A, p.R176Q) and two variants in two families of European ancestry (11:121514222:A:C, p.N371T; 11:121545392:G:A, p.V672M) that show some evidence of segregation in PD families. Although these variants were slightly more frequent in unrelated PD cases vs. controls, none of them showed statistically significant enrichment in PD, likely due to their very low frequency. Overall, our results extend the understanding of SORL1 beyond AD, suggesting a broader role in neurodegeneration and emphasizing the need for diverse population studies when evaluating genetic risk.},
}

@article {pmid42186917,
year = {2026},
author = {Piehl, NC and Halle, AW and Rodriguez, G and Locci, A and Kujawa, S and Haywood, C and Coon, J and McNally, RP and Karim, ZA and You, T and Dong, H and Bulun, SE and Zhao, H},
title = {Loss of Brain-Derived Estrogen Is Associated With Sex- and Age-Dependent Alterations in Memory, Affective Behavior, and Hippocampal Extracellular Matrix Gene Expression.},
journal = {Aging cell},
volume = {25},
number = {6},
pages = {e70551},
doi = {10.1111/acel.70551},
pmid = {42186917},
issn = {1474-9726},
support = {RF1-AG079419/NH/NIH HHS/United States ; },
mesh = {Animals ; *Hippocampus/metabolism ; Female ; Male ; *Estrogens/metabolism/deficiency ; Mice ; Aromatase/deficiency/metabolism/genetics ; *Extracellular Matrix/metabolism/genetics ; Mice, Knockout ; *Aging ; *Memory ; *Brain/metabolism ; Mice, Inbred C57BL ; },
abstract = {Nearly two-thirds of Americans with Alzheimer's disease (AD) are women. Prior research suggested that women with AD have lower brain estrogen levels than those without AD. However, how estrogen deficiency modulates this sex-based difference in AD vulnerability is not well understood. Aromatase, the key enzyme for estrogen biosynthesis, is expressed in both neurons and astrocytes of the brain, including the hippocampus. This study aims to assess the mechanistic link between brain-selective aromatase deficiency and sex-specific AD vulnerability. To achieve this goal, we used brain-specific aromatase knockout (bArKO) and whole-body total aromatase knockout (tArKO) mice of both sexes at young (6- to 8-month-old) and old (> 19-month-old) ages. We found that aromatase deletion decreased brain estrogen levels in bArKO mice and circulating and brain estrogen levels in tArKO mice. Impairment in spatial working memory and social interaction behavior was observed only in old female bArKO and tArKO mice. Both young and old female, but not male, tArKO mice displayed depression-like behavior. Bulk RNA-seq analysis of hippocampal tissues from young and old bArKO mice of both sexes revealed enrichment of extracellular matrix-related pathways and upregulated mRNA and/or protein expression of extracellular matrix-associated genes (e.g., Col1a1, Ccn2, Dcn, and Ogn) in old female bArKO mice compared to littermate control mice. These findings point to a novel link between local brain estrogen deficiency and sex- and age-specific extracellular matrix changes in the hippocampus of old bArKO female mice accompanied by AD-related memory and behavioral impairments.},
}

Animals
*Hippocampus/metabolism
Female
Male
*Estrogens/metabolism/deficiency
Mice
Aromatase/deficiency/metabolism/genetics
*Extracellular Matrix/metabolism/genetics
Mice, Knockout
*Aging
*Memory
*Brain/metabolism
Mice, Inbred C57BL

@article {pmid42187024,
year = {2026},
author = {Wang, D and Ta, V and Wang, H and Ju, J and Wang, C and Chehadeh, C and Torreblanca-Zanca, A and Magaña, Y and Castle, MJ and Wang, S and Head, BP},
title = {Systemic delivery of synapsin-promoted caveolin-1 overexpression ameliorates pathological TDP-43-induced cognitive decline and neurodegenerative changes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71450},
doi = {10.1002/alz.71450},
pmid = {42187024},
issn = {1552-5279},
support = {2039592//University of California-San Diego/ ; AL230115//U.S. Department of Defense/ ; BX006318//U.S. Department of Veterans Affairs/ ; //National Institute of health/ ; UM1TR005449/NH/NIH HHS/United States ; },
mesh = {Animals ; *Caveolin 1/metabolism/genetics ; *Synapsins/metabolism/administration & dosage ; Mice ; *DNA-Binding Proteins/metabolism/genetics ; Disease Models, Animal ; *Cognitive Dysfunction/pathology/metabolism/genetics ; *TDP-43 Proteinopathies/pathology/metabolism/genetics ; Mice, Transgenic ; Brain/metabolism/pathology ; Neurons/metabolism/ultrastructure ; Receptors, N-Methyl-D-Aspartate/metabolism ; },
abstract = {INTRODUCTION: Transactive response DNA-binding protein 43 (TDP-43) proteinopathy is associated with frontotemporal dementia and Alzheimer's disease (AD). We previously demonstrated that synapsin-promoted caveolin-1 (SynCav1) preserves cognitive function in the mouse model of AD. This study investigated the therapeutic potential of SynCav1 in a mouse model of TDP-43 proteinopathy.

METHODS: AAV-PhP.eB-SynCav1 was delivered systemically to the TDP-43[A315T] mouse, followed by cognitive evaluation and biochemical and ultrastructural analysis of brain tissue.

RESULTS: SynCav1 exerted robust neuroprotective effects on cognition. Mechanistically, pathological TDP-43 mislocalized to membrane lipid rafts (MLRs), resulting in decreased MLR-associated GluN2A expression and degenerative changes in neuronal ultrastructure. In contrast, SynCav1 delivery alleviated TDP-43 mislocalization on MLRs, stabilized MLR-associated GluN2A expression, and preserved synaptic ultrastructure. Furthermore, SynCav1 mitigated TDP-43-induced mitochondrial hyper-fragmentation and excessive mitochondrial fission signaling.

DISCUSSION: These findings establish a novel link between TDP-43 proteinopathy and MLR instability, supporting SynCav1 as a "neuron-centric" candidate for treating TDP-43-related neurodegeneration.},
}

Animals
*Caveolin 1/metabolism/genetics
*Synapsins/metabolism/administration & dosage
Mice
*DNA-Binding Proteins/metabolism/genetics
Disease Models, Animal
*Cognitive Dysfunction/pathology/metabolism/genetics
*TDP-43 Proteinopathies/pathology/metabolism/genetics
Mice, Transgenic
Brain/metabolism/pathology
Neurons/metabolism/ultrastructure
Receptors, N-Methyl-D-Aspartate/metabolism

@article {pmid42187040,
year = {2026},
author = {Hardy, CJD and Levett, BA and Jiang, J and Core, LB and Froud, S and Bishop, L and Lim, D and Durrani, F and Volkmer, A and Koohi, N and Bamiou, DE and Marshall, CR and Warren, JD},
title = {Non-verbal dichotic listening: A new cognitive hearing test for dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71358},
doi = {10.1002/alz.71358},
pmid = {42187040},
issn = {1552-5279},
support = {//Brain Research Trust/ ; //Wolfson Foundation/ ; 627/ALZS_/Alzheimer's Society/United Kingdom ; AS-PG-16-007/ALZS_/Alzheimer's Society/United Kingdom ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; //National Brain Appeal/ ; ARUK-RF2024-19//Alzheimer's Research UK/ ; //UCL Research Excellence Scholarship/ ; G105//Royal National Institute for Deaf People/ ; //Bart's Charity/ ; NIHR204280//National Institute for Health and Care Research/ ; NIHR302240//National Institute for Health and Care Research/ ; },
mesh = {Humans ; Male ; Female ; Aged ; *Dichotic Listening Tests/methods ; *Alzheimer Disease/diagnosis/complications ; Aphasia, Primary Progressive/diagnosis ; Middle Aged ; Aged, 80 and over ; *Dementia/diagnosis/complications ; *Frontotemporal Dementia/diagnosis/complications ; Neuropsychological Tests ; Prohibitins ; },
abstract = {INTRODUCTION: Central hearing difficulties are a feature of Alzheimer's disease (AD) but not well captured by standard speech perception tests.

METHODS: We developed a non-verbal dichotic listening test (NVDLT) based on everyday sounds, and compared this with a standard verbal dichotic listening test (VDLT) in 36 people with primary progressive aphasia (PPA), 18 with typical AD (tAD), 6 with right temporal-variant frontotemporal dementia (rtvFTD), and 29 cognitively-healthy controls. Daily-life hearing function was assessed using the modified Amsterdam Inventory for Auditory Disability and Handicap (mAIAD).

RESULTS: On NVDLT, all dementia groups except rtvFTD performed worse than controls; tAD, logopenic-variant PPA and nonfluent/agrammatic-variant PPA performed worse than rtvFTD. NVDLT performance predicted atrophy in the retrosplenial cortex and hippocampus. NVDLT score discriminated tAD patients from controls with near-perfect accuracy (area under the curve [AUC] = 0.99) and predicted daily-life hearing function (r = 0.57).

DISCUSSION: NVDLT performance indexes daily-life hearing function and may aid dementia diagnosis, potentially in culturally-diverse populations.},
}

Humans
Male
Female
Aged
*Dichotic Listening Tests/methods
*Alzheimer Disease/diagnosis/complications
Aphasia, Primary Progressive/diagnosis
Middle Aged
Aged, 80 and over
*Dementia/diagnosis/complications
*Frontotemporal Dementia/diagnosis/complications
Neuropsychological Tests
Prohibitins

@article {pmid42187062,
year = {2026},
author = {Zainuddin, MS and Pamidi, N and Azman, AS and Bai Magalingam, K and Bhuvanendran, S},
title = {Oxidative stress biomarkers and flavonoids in Alzheimer's disease: current clinical evidence and therapeutic perspectives.},
journal = {Redox report : communications in free radical research},
volume = {31},
number = {1},
pages = {2677396},
doi = {10.1080/13510002.2026.2677396},
pmid = {42187062},
issn = {1743-2928},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Oxidative Stress/drug effects ; Humans ; *Flavonoids/therapeutic use/pharmacology ; *Biomarkers/metabolism ; Antioxidants/therapeutic use ; Animals ; Neuroprotective Agents/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a major global neurodegenerative disorder associated with high morbidity and mortality, yet current treatments remain largely symptomatic and ineffective in halting neurodegeneration. Growing evidence links oxidative stress potentially being an early event in AD progression. Consequently, therapeutic strategies targeting oxidative stress-mediated cellular damage are increasingly attractive. This review summarizes clinical evidence of oxidative stress biomarkers in AD and examines the neuroprotective mechanisms of flavonoids against oxidative stress in vivo, together with current clinical findings. Despite inconsistencies among studies due to variations in detection methods, a consistent trend of elevated oxidative stress in AD is evident, correlating with disease severity. Although in vivo studies have demonstrated that flavonoids restore antioxidant defences and suppress neuroinflammation, convincing clinical evidence of their efficacy in AD patients remains limited. Overall, these findings emphasize oxidative stress as a therapeutic target requiring further validation efforts.},
}

*Alzheimer Disease/drug therapy/metabolism
*Oxidative Stress/drug effects
Humans
*Flavonoids/therapeutic use/pharmacology
*Biomarkers/metabolism
Antioxidants/therapeutic use
Animals
Neuroprotective Agents/therapeutic use

@article {pmid42187102,
year = {2026},
author = {Thakkar, A and Alavala, RR and Kaur, G and Gadade, A and Dighe, V and Vora, A},
title = {Design, synthesis, and in vitro evaluation of novel longifolene derivatives for Alzheimer's disease.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/17568919.2026.2676784},
pmid = {42187102},
issn = {1756-8927},
abstract = {AIM: The study combines computational and experimental approaches to provide structural and functional features of novel ligands, emphasizing their promising role as canditates for Alzheimer's disease (AD) drug development.

MATERIALS AND METHODS: The research focused on developing molecules capable of targeting acetylcholinesterase (AChE) enzyme as potential treatments for AD. Starting with longifolene, a natural compound known for its anti-inflammatory properties, 198 derivatives were designed. Structure-guided molecular docking, MD simulations, and MM/GBSA free energy calculations identified four compounds that exhibited favorable interactions on AChE. These compounds were synthesized and characterized, followed by series of biological evaluation. Donepezil hydrochloride was used as the standard reference drug.

RESULTS: Cytotoxicity assay conducted established its safety on SH-SY5Y cells with IC50 exceeding 90 µM. In the in vitro model developed for AD using Aβ1-42, the ligands demonstrated anti-inflammatory and neuroprotective effects with compound 4f showing promising effect. At 0.1 and 0.3 µM, compound 4f significantly decreased intracellular reactive oxygen species, preserved mitochondrial membrane potential, and reduced cellular apoptosis.

CONCLUSIONS: The results identify compound 4f as a promising lead candidate for AD management. The molecular hybridization strategy successfully enhances biological activity, supporting further preclinical development of longifolene-derived scaffolds as potential anti-Alzheimer's therapeutics.},
}

@article {pmid42187146,
year = {2026},
author = {Wharton, SB and Richardson, CD and Ashford, B and Brooke, H and Ahamed, SU and Fillingham, DJ and Simpson, JE and Francis, S and Brayne, C and Matthews, FE and , },
title = {VCING Scoring and White Matter Arteriolosclerosis Show Relationships to Dementia Status and White Matter Damage in an Unselected Ageing Brain Cohort.},
journal = {Neuropathology and applied neurobiology},
volume = {52},
number = {3},
pages = {e70081},
doi = {10.1111/nan.70081},
pmid = {42187146},
issn = {1365-2990},
support = {PG22/11008/BHF_/British Heart Foundation/United Kingdom ; MRC/G9901400/MRC_/Medical Research Council/United Kingdom ; U.1052.00.0013/MRC_/Medical Research Council/United Kingdom ; G0900582/MRC_/Medical Research Council/United Kingdom ; AS-PhD-21-006/ALZS_/Alzheimer's Society/United Kingdom ; //National Institute for Health and Care Research/ ; },
mesh = {Humans ; Female ; Male ; *White Matter/pathology ; *Arteriolosclerosis/pathology ; *Aging/pathology ; *Brain/pathology ; *Dementia/pathology ; Aged, 80 and over ; Aged ; Cohort Studies ; *Dementia, Vascular/pathology ; },
abstract = {INTRODUCTION: Vascular disease is associated with late-life dementia and other morbidities during life and commonly coexists with neurodegenerative pathologies. A complex variety of lesions can be documented, which has made development of standardised operationalised criteria difficult. A semiquantitative approach, vascular cognitive impairment neuropathology guidelines (VCING), has been developed that provides a score based on assessment of occipital white matter arteriolosclerosis, occipital leptomeningeal cerebral amyloid angiopathy (CAA) and the presence of any macroscopic infarct.

METHODS: We applied VCING assessment to an ageing population-derived neuropathology cohort derived from two subcentres of the cognitive function and ageing study (n = 158, 63.7% female and 36.3% male).

RESULTS: Vascular pathology using this method was common in this UK ageing population sample with 75% of individuals having a score of 1 or more. VCING score was associated with the presence of dementia at death, even accounting for Alzheimer's disease neuropathological change (ADNC). Of the VCING components, white matter arteriolosclerosis, but not CAA or infarcts, was associated with dementia (after adjustment for ADNC). VCING score was not associated with vascular risk factors during life, but males were at greater risk of a higher VCING score than females. VCING and arteriolosclerosis were associated with white matter pallor and perivascular space widening as markers of white matter damage. Venous collagenosis was also associated with white matter pallor. There was an association between VCING score and ADNC in regression analysis, and the association was particularly strong for the CAA component.

CONCLUSIONS: VCING is a straightforward method to assess vascular pathology in neuropathology cohorts and retains its association with dementia. The arteriolosclerosis component, in particular, is related to dementia and to white matter damage, whereas venous-side effects may also be important for the latter. The strong association of the CAA component with ADNC measures, however, raises the question of whether the VCING approach may have some confounding effects with ADNC.},
}

Humans
Female
Male
*White Matter/pathology
*Arteriolosclerosis/pathology
*Aging/pathology
*Brain/pathology
*Dementia/pathology
Aged, 80 and over
Aged
Cohort Studies
*Dementia, Vascular/pathology

@article {pmid42187415,
year = {2026},
author = {Prabhakar, SK and Won, DO},
title = {A Consolidated Framework for the Detection of Alzheimer's Disease Using EEG Signals and Hybrid Models.},
journal = {Biomimetics (Basel, Switzerland)},
volume = {11},
number = {5},
pages = {},
doi = {10.3390/biomimetics11050348},
pmid = {42187415},
issn = {2313-7673},
support = {2026//Hallym University/ ; },
abstract = {Alzheimer's disease (AD) is a serious neurodegenerative disorder that can severely affect behavior and thinking patterns, and is accompanied by frequent memory loss. The early diagnosis of AD is essential, as this can benefit the patient, but detecting AD is a complex process due to the nature of its associated clinical data. Electroencephalography (EEG) serves as a promising and cost-effective technique for analyzing AD-related brain activity patterns. In this work, a consolidated framework for detecting AD using EEG signals and hybrid models is proposed that uses a dataset that is available online. For the feature extraction module, five efficient techniques-Principal Component Analysis (PCA), Kernel Partial Least Squares (KPLS), Kriging Model, Isomap, and K-means clustering-are used. For feature selection, with the help of biomimetics-based concepts, three efficient algorithms are used: hybrid Cuckoo Search Optimization-Rat Swarm Optimization (CSO-RSO), Zebra Optimization (ZOA), and hybrid Gravitational Search Algorithm-Particle Swarm Optimization (GSA-PSO). Four interesting hybrid classifiers are utilized here to detect AD using EEG signals-hybrid Extreme Learning Machine-Adaboost (ELM-Adaboost), hybrid Classification and Regression Trees-Adaboost (CART-Adaboost), and hybrid weighted broad learning system-based Adaboost (HWBLSA), followed by a hybrid machine learning classification model with a soft voting technique-and, finally, these are compared with other standard machine learning classifiers. The highest classification accuracy of 98.71% is found when the Kriging Model feature extraction concept is combined with the hybrid GSA-PSO feature selection method and classified with the ELM-Adaboost classifier.},
}

@article {pmid42187454,
year = {2026},
author = {Jiang, L and Chen, Y and He, Y and Liang, J and Zhao, X and Guo, X},
title = {A Two-Stage EEG Microstate Fusion Framework for Dementia Screening and Alzheimer's Disease/Frontotemporal Dementia Differentiation.},
journal = {Biosensors},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/bios16050258},
pmid = {42187454},
issn = {2079-6374},
support = {2024M750518//China Postdoctoral Science Foundation/ ; 12304513//National Natural Science Foundation of China/ ; 2024J235//Natural Science Foundation of Ningbo/ ; 20251JCGY010476//Natural Science Foundation of Ningbo/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Electroencephalography ; *Frontotemporal Dementia/diagnosis ; Convolutional Neural Networks ; },
abstract = {Differentiating Alzheimer's disease (AD) from frontotemporal dementia (FTD) using resting-state electroencephalography (EEG) remains clinically challenging because of their overlapping electrophysiological characteristics. Although EEG suits large-scale dementia screening, current method often overestimates performance because of epoch-level data leakage and multiclass feature competition in unified models. We propose a task-decoupled, two-stage hierarchical deep learning framework utilizing multiband EEG microstate dynamics. Continuous microstate sequences, modeled via Hungarian matching to preserve fine-grained temporal information, are processed using a normalizer-free 1D convolutional neural network (1D-CNN-NFNet) integrated with multi-head attention. By decoupling the workflow, Stage 1 performs generalized dementia screening using alpha and delta microstates, achieving an area under the curve (AUC) of 0.851. Stage 2 disentangles AD from FTD using delta and theta dynamics, yielding an AD-locking specificity of 86.1%. Evaluated under a strict subject-level leave-one-subject-out (LOSO) cross-validation protocol, the two-stage framework achieved 63.9% balanced accuracy, outperforming the single-stage baseline (55.4%) with a negligible inference latency of 0.733 ms. Furthermore, attention-based interpretability analysis links frequency-specific microstate alterations to underlying cortical disconnection syndromes. These results demonstrate that the framework provides a reproducible and interpretable auxiliary reference for dementia screening and subtyping in clinical neurology.},
}

Humans
*Alzheimer Disease/diagnosis
*Electroencephalography
*Frontotemporal Dementia/diagnosis
Convolutional Neural Networks

@article {pmid42187467,
year = {2026},
author = {Lv, Y and Zhou, Y and Liu, Z and Dong, H and Zheng, H and Cheng, S and Wang, X and Lv, C and Xu, M},
title = {Fabrication of Co-Doped Covalent Organic Framework Nanosheets with Mild Interlayer Stress for Quantitative Detection of Alzheimer's Disease Biomarkers.},
journal = {Biosensors},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/bios16050271},
pmid = {42187467},
issn = {2079-6374},
support = {22474072//National Natural Science Foundation of China/ ; 242300421208//Henan Academy of Sciences/ ; },
mesh = {*Alzheimer Disease/diagnosis ; Humans ; *Biosensing Techniques ; NAD ; Biomarkers/analysis ; *Metal-Organic Frameworks/chemistry ; Cobalt ; Electrodes ; Glutamic Acid ; Electrochemical Techniques ; Nanostructures ; Metal Nanoparticles ; },
abstract = {Alzheimer's disease (AD) seriously affects human health worldwide. Nicotinamide adenine dinucleotide (NADH) and glutamate are important biomarkers of AD, which play an indispensable role in the pathogenesis of AD. Herein, two ligands were used to synthesize a layered covalent organic framework (TPCOF) via amide bond formation, which was loaded with cobalt to obtain Co-TPCOF. TPCOF has a twisted 2D layered structure, along with large interlayer spacing and porosity, enabling precise Co coordination and stable loading of metal nanoparticles/enzymes to support electrocatalysis. A Co-TPCOF was immobilized on a screen-printed electrode (SPE) to catalyze the oxidation of NADH. After that, the oxidation product NAD[+] of NADH and the NAD[+]-dependent dehydrogenase immobilized on the electrode jointly catalyzed the glutamate in the solution. COFs' unique structures endow Co-TPCOFs with excellent NADH catalytic activity. The Co-TPCOF/SPE showed good linearity for NADH (10 nM-5 mM, LOD 7.07 nM) and GDH/Co-TPCOF/SPE for glutamate (50 μM-5 mM, LOD 3.74 μM). The biosensor can sensitively detect trace NADH and glutamate in human serum, providing an adequate technical means and theoretical reference for the pathological research of AD.},
}

*Alzheimer Disease/diagnosis
Humans
*Biosensing Techniques
NAD
Biomarkers/analysis
*Metal-Organic Frameworks/chemistry
Cobalt
Electrodes
Glutamic Acid
Electrochemical Techniques
Nanostructures
Metal Nanoparticles

@article {pmid42187517,
year = {2026},
author = {Atanasova, B and Tokmakova, M and Dzhambov, AM and Chitak, R and Atanassova, P},
title = {Exploring Associations Between Early Cognitive Impairment and Echocardiographic Markers in Middle-Aged Patients with Atrial Fibrillation and Cardiometabolic Comorbidities: A Pilot Study.},
journal = {Clinics and practice},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/clinpract16050082},
pmid = {42187517},
issn = {2039-7275},
abstract = {Objectives: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, and cardiometabolic comorbidity, have been increasingly associated with cognitive impairment and dementia. These associations, however, remain underexplored and underappreciated in middle-aged individuals with AF. This study aimed to explore the associations of early cognitive impairment with the presence of cardiometabolic comorbidities and potential associations with echocardiographic markers in middle-aged patients with and without AF. Methods: Between 2023-2024, fifty-six consecutive outpatients with a diagnosis of AF aged 45-65 years underwent clinical evaluation, transthoracic echocardiography, and comprehensive neuropsychological assessment using the Montreal Cognitive Assessment (MoCA) and the Consortium to Establish a Registry for Alzheimer's Disease battery (CERAD). A control group of 58 age group-matched individuals without known cardiometabolic disease was included in comparative cognitive analyses. Results: Patients with AF and cardiometabolic comorbidities demonstrated early cognitive deficits, particularly in episodic memory and visuospatial functions, detectable even in individuals with normal MoCA scores, compared with the control group. However, no associations were observed between cognitive performance and conventional echocardiographic parameters in the group with AF. Conclusions: This study corroborated prior evidence of an association between cardiometabolic impairment and subtle cognitive impairment, but did not identify a specific contribution of echocardiography markers. More extensive and sensitive biomarkers of left atrial structure and function may be required to detect harmful associations with subtle cognitive impairment in middle-aged individuals. Further prospective studies, with a more balanced control for comorbidities, are warranted to clarify the clinical relevance of atrial structural remodeling in this context.},
}

@article {pmid42188046,
year = {2026},
author = {Tang, G and Guo, L and Liu, Z and Quan, Y},
title = {Hypothesis of the Causal Mechanisms Between Gut Microbiota and Neurodegenerative Diseases: An Elucidation from Evolutionary Perspective and Metabolic Consideration.},
journal = {Metabolites},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/metabo16050337},
pmid = {42188046},
issn = {2218-1989},
support = {Grant 32570777 and Grant 32300545//National Natural Science Foundation of China/ ; Grant 2662025XXPY004//Fundamental Research Funds for the Central Universities/ ; },
abstract = {Growing evidence links gut microbiota dysbiosis to neurodegenerative diseases (NDs) such as Alzheimer's disease and Parkinson's disease, yet the field remains dominated by correlational observations rather than experimentally validated causal mechanisms. In this hypothesis-generating Perspective, we propose that causal inference in microbiota-associated neurodegeneration may be strengthened by combining two complementary lenses: evolutionary biomedicine and microbial metabolism. Because evolutionary information carries intrinsic temporal and causal structure, it can provide biological prior knowledge for inferring causal mechanisms of diseases. Human Accelerated Regions (HARs), genomic loci conserved across mammals but rapidly divergent in the human lineage, offer an anchor for identifying human-specific host-microbe co-evolutionary units relevant to NDs. We further hypothesize that microbial metabolites represent one class of mechanistically testable intermediates linking host genetic background, gut microbial ecology, and neurodegenerative phenotypes. This integrated evolutionary-metabolic perspective offers a tractable path from correlation toward mechanism in gut microbiota-ND research.},
}

@article {pmid42188341,
year = {2026},
author = {Buccarello, L and Montagna, C and Di Matteo, S and Mangione, R and Carota, G and Sibbitts, J and Jarosova, R and Lunte, SM and Lazzarino, G and Caruso, G},
title = {The Bright and Dark Sides of Nitric Oxide in Neurodegenerative Diseases.},
journal = {Journal of personalized medicine},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/jpm16050246},
pmid = {42188341},
issn = {2075-4426},
abstract = {Nitric oxide (NO) plays an important role in neuronal communication, synaptic plasticity and vascular regulation. Due to its important function in neuronal homeostasis, NO imbalance is associated with neurodegeneration. Specifically, in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and frontotemporal lobar degeneration (FTLD), an excessive amount of NO, mostly produced by inducible NO synthase (iNOS), reacts with superoxide to form peroxynitrite, driving oxidative/nitrosative stress, mitochondrial dysfunction, and aberrant protein modifications. In AD, NO dysregulation promotes amyloid-β (Aβ) accumulation, tau hyperphosphorylation and synaptic loss, creating a self-perpetuating cycle of neuronal damage. NO's dual role, protective at physiological levels but harmful if overproduced, underscores the therapeutic potential of antioxidant compounds that restore the balance of NO/NOS (especially iNOS) while preserving physiological functions. However, despite the emerging role of antioxidant-based therapeutic approaches, clinical translation is limited by the complexity of NO signaling and the absence of safe, specific NOS inhibitors. By targeting the molecular switch from protective to toxic, NO activity may offer new personalized treatment avenues for neurodegenerative diseases.},
}

@article {pmid42188679,
year = {2026},
author = {Agavriloaei, LM and Iliescu, BF and Stanciu, GD and Costachescu, I and Szilagyi, A and Gogu, MR and Tamba, BI and Turliuc, MD},
title = {Cognitive and Histological Methodological Framework for an Intrahippocampal Aβ1-42 Rat Model of Alzheimer's Disease.},
journal = {Neurology international},
volume = {18},
number = {5},
pages = {},
doi = {10.3390/neurolint18050079},
pmid = {42188679},
issn = {2035-8385},
support = {10060/15.05.2025//Grigore T. Popa University of Medicine and Pharmacy/ ; },
abstract = {BACKGROUND: Standardized and ethically compliant animal models remain essential for improving translational research in Alzheimer's disease. Although Aβ1-42-induced rodent models are widely used, methodological variability continues to limit reproducibility.

METHODS: We explored the feasibility of a stereotactic intrahippocampal Aβ1-42 rat model established by bilaterally injecting pre-aggregated peptide into the hippocampus of adult Sprague Dawley rats. Model feasibility and targeting accuracy were assessed intraoperatively. Cognitive performance was evaluated using the Y-maze for spatial recognition memory and the novel object recognition (NOR) test. Histological examination was performed using hematoxylin-eosin (H&E) and Congo red staining to assess cytoarchitecture and to provide supportive evidence of amyloid-like deposits.

RESULTS: The surgical procedure was well-tolerated, and the injected animals showed reduced performance in behavioural testing, including reduced spatial recognition memory in the Y-maze and decreased discrimination indices in the NOR test. The animals also showed histological changes, including Congo red-positive birefringent structures consistent with amyloid-like congophilic material.

CONCLUSIONS: This study presents a feasible experimental framework for intrahippocampal Aβ1-42 administration, showing behavioural and histological changes under the present experimental conditions. However, further validation, including sham-operated controls and molecular characterization, will be required before these findings can be interpreted as specific to Aβ-driven pathology.},
}

@article {pmid42188684,
year = {2026},
author = {Aljuhani, M and Ashraf, A and Alqarni, A and Alshuhri, MS and Alkhybari, EM and Alharbi, A and Almudayni, A and Alablani, FJ and Alhulail, AA},
title = {CSF Levels of Baseline VCAM-1 and ICAM-1 Are Associated with Tau Pathology in Patients Demonstrating Cognitive Impairment.},
journal = {Neurology international},
volume = {18},
number = {5},
pages = {},
doi = {10.3390/neurolint18050084},
pmid = {42188684},
issn = {2035-8385},
support = {PSAU/2025/3/37092//Prince Sattam Bin Abdulaziz University/ ; },
abstract = {BACKGROUND: Vascular dysfunction and neurovascular inflammation are increasingly recognized as contributors to Alzheimer's disease (AD) pathophysiology, particularly through interactions with tau-related neurodegeneration. Endothelial adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), play key roles in blood-brain barrier regulation and immune-vascular crosstalk, yet their relevance to long-term disease progression and established AD biomarkers remains incompletely understood.

METHODS: Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we examined associations between baseline cerebrospinal fluid (CSF) levels of VCAM-1 and ICAM-1 and clinical progression, CSF biomarkers, neuroimaging measures, and cognitive outcomes over up to 10 years of follow-up. This study included 294 participants (87 cognitively normal, 129 with mild cognitive impairment, and 78 with AD). Multivariable logistic regression was used to assess associations with diagnostic progression, and linear regression models examined relationships with baseline and longitudinal measures of tau, amyloid-β, hippocampal volume, Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) metabolism, and cognition. Models were adjusted for age, sex, apolipoprotein E epsilon 4 (APOE ε4) status, baseline diagnosis, and baseline CSF amyloid-β, with false discovery rate correction applied for multiple comparisons.

RESULTS: Baseline CSF VCAM-1 and ICAM-1 levels did not differ across diagnostic groups. However, higher baseline levels of both markers were nominally associated with increased odds of disease progression. Notably, ICAM-1 showed a strong and robust association with baseline CSF phosphorylated tau, which remained significant after multiple-comparison correction. VCAM-1 was also associated with tau pathology, though this did not survive correction. Neither marker was associated with baseline or longitudinal changes in hippocampal volume, FDG-PET metabolism, or cognitive performance.

CONCLUSION: CSF VCAM-1 and ICAM-1 appear to reflect neurovascular inflammatory processes linked to tau pathology rather than markers of clinical stage or longitudinal neurodegeneration. These findings support a role for endothelial activation in AD pathophysiology and highlight vascular-immune mechanisms as potential contributors to tau-related disease vulnerability.},
}

@article {pmid42188696,
year = {2026},
author = {Devadoss, D and Akkaoui, J and Vashist, A and Arias, AY and Nefzi, A and Lakshmana, MK},
title = {YAP1 Upregulates Cytoskeleton Regulator ARHGEF1 and Tissue Regeneration Factor NEDD9 in a Multiplex Proteomic Study.},
journal = {Neurology international},
volume = {18},
number = {5},
pages = {},
doi = {10.3390/neurolint18050096},
pmid = {42188696},
issn = {2035-8385},
support = {1R61AG086971//National Institute of Health/ ; 1R21DA060111//National Institute of Health/ ; 5R01DA052271//National Institute of Health/ ; },
abstract = {Background/Objectives: Yes-associated protein 1 (YAP1) is a transcriptional cofactor that coordinates the complex interplay between cell proliferation, survival, differentiation, metabolism, biomechanics, and tissue regeneration. Previous studies have shown that YAP1 activity is reduced during aging, and replacing YAP1 function has been shown to rejuvenate old cells by mitigating senescence and its associated inflammation. Methods: As YAP1 is now confirmed to exert a profound regenerative influence on multiple organs, we wanted to gain more insight into the molecular signature of YAP1 expression relevant to brain cells. Since proteomics is a very powerful tool for discoveries, we generated SH-SY5Y cells stably expressing GFP-YAP1 and screened 8000 human proteins using multiplex arrays that utilize biotin-label-based antibody arrays. Results: We found YAP1 expression in astrocytes, microglia, neuronal and neuroblastoma cell lines, as well as human neurons. Importantly, YAP1 protein levels were significantly reduced selectively in the nuclear fractions of the brains of patients with Alzheimer's disease (AD) relative to normal control (NC) subjects. The screen resulted in the identification of 283 differentially expressed proteins. In line with YAP1's known role in the regulation of actin and cytoskeleton, we found a 2.53-fold upregulated level of Rho guanine nucleotide exchange factor 1 (ARHGEF1), a guanine nucleotide exchange factor (GEF) for the RhoA GTPase, which is crucial for dendritic spine regulation. A 6.19-fold upregulated level of NECAP endocytosis-associated 2 (NECAP2), the highest known increase for any protein in this screen, plays an essential role in clathrin-mediated endocytosis. Most importantly, another upregulated protein was Neudesin Neurotrophic Factor (NENF) (3.07-fold increase), also known as Neudesin, which primarily acts as a neurotrophic factor, and it promotes neuronal survival, enhances cell proliferation, and neurogenesis in neural progenitor cells. Neural Precursor Cell Expressed, Developmentally Down-Regulated 9(NEDD9) levels were also upregulated by 2.46-fold, and it affects neuronal cell number and synaptic connections through its role in neurite formation. However, it should be noted that these proteomic results are preliminary in nature as they are derived from single-sample data. The upregulated levels of ARHGEF1 and NEDD9 were confirmed by immunoblots. We also found a drastic reduction in the levels of p16INK4a, a marker of senescence. Conclusions: Thus, the anti-senescence effect of YAP1 may be mediated through p16INK4a, which in turn may be crucial for YAP1's regenerative functions through NENF and NEDD9.},
}

@article {pmid42189000,
year = {2026},
author = {Bevan, RJ and Minett, JF and Smith, AL and Figueras, AC and Taylor, PR},
title = {Early Regional Microglial Remodelling in the Hippocampus of the App[NL-G-F] Alzheimer's Model.},
journal = {Neuropathology and applied neurobiology},
volume = {52},
number = {3},
pages = {e70082},
doi = {10.1111/nan.70082},
pmid = {42189000},
issn = {1365-2990},
support = {UK DRI-3203//UK Dementia Research Institute/ ; //Moondance Foundation/ ; },
mesh = {Animals ; *Microglia/pathology ; *Alzheimer Disease/pathology ; *Hippocampus/pathology ; Mice, Transgenic ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics ; Mice ; Male ; Female ; Plaque, Amyloid/pathology ; },
abstract = {AIMS: Microglia undergo profound structural and functional changes during Alzheimer's disease, yet the earliest stages of morphological remodelling that occur prior to amyloid deposition remain poorly defined. We hypothesised that microglia in the hippocampus of App[NL-G-F] mice would exhibit early, region-specific structural adaptations before local plaque formation, reflecting an initial phase of disease-associated structural remodelling.

METHODS: Two-month-old App[NL-G-F] and wildtype mice were examined using high-resolution confocal microscopy of Iba1-labelled microglia in the dorsal CA1 apical field. Automated three-dimensional reconstructions were generated in Imaris, and quantitative morphometric analyses quantified cell density, Iba1 coverage, process topology and Sholl-based arbor complexity. Statistical analyses were performed using linear mixed-effects models incorporating sex as a fixed factor in all analyses.

RESULTS: Microglial density and total Iba1 coverage were unaffected in App[NL-G-F] mice at this age. In contrast, Sholl analysis revealed significant genotype-dependent reductions in process intersections and total process length, accompanied by reduced individual-cell territorial coverage, indicating an early contraction of the surveillance arbor independent of cell number.

CONCLUSIONS: These findings demonstrate that hippocampal microglia in App[NL-G-F] mice undergo an early, coordinated structural remodelling before local amyloid deposition becomes apparent. This preplaque adaptation defines an early structural remodelling of hippocampal microglia prior to evident local amyloid deposition, providing new insight into the earliest structural adaptations associated with neuroimmune engagement in AD pathogenesis.},
}

Animals
*Microglia/pathology
*Alzheimer Disease/pathology
*Hippocampus/pathology
Mice, Transgenic
Disease Models, Animal
Amyloid beta-Protein Precursor/genetics
Mice
Male
Female
Plaque, Amyloid/pathology

@article {pmid42189237,
year = {2026},
author = {Morbelli, SD and Bozzali, M and Cagnin, A and Cecchin, D and Chiti, A and Filippi, M},
title = {Precision pathways: optimising amyloid PET for sustainable Alzheimer's disease care.},
journal = {Journal of neurology},
volume = {273},
number = {6},
pages = {},
pmid = {42189237},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/therapy/drug therapy ; *Positron-Emission Tomography/methods/standards ; *Amyloid beta-Peptides/metabolism ; *Precision Medicine/methods ; Biomarkers/metabolism ; },
abstract = {The approval of anti-amyloid therapies has reshaped Alzheimer's disease from a clinically defined syndrome to a biologically confirmed and treatment-oriented condition. This transition places biomarkers, particularly amyloid positron emission tomography (Aβ-PET), at the centre of diagnostic precision, patient selection, safety governance, and therapeutic monitoring. Aβ-PET provides high specificity for confirming cerebral amyloid pathology, especially in cases with discordant or inconclusive fluid biomarkers, and supports staging through semi-quantitative assessment using standardised Centiloid metrics. In patients considered for anti-amyloid therapies, baseline Aβ-PET refines eligibility and risk-benefit profiling when integrated with MRI and APOE genotyping. During treatment, longitudinal Aβ-PET enables objective assessment of pharmacodynamic target engagement and treatment-related amyloid clearance, supporting response-adapted strategies and, in selected cases, therapy discontinuation. Beyond its clinical role, Aβ-PET has strategic organisational and economic implications. Its value is maximised when embedded within structured, stepwise diagnostic pathways that use scalable fluid biomarkers for triage and reserve Aβ-PET for high-impact decisions. However, implementation is challenged by regional heterogeneity, capacity constraints, and limited harmonisation across centres. Coordinated hub-and-spoke models, quantitative standardisation, and prospective registry-based data collection are essential to ensure the equitable and sustainable integration of anti-amyloid therapies into clinical practice. Aβ-PET has evolved from a confirmatory diagnostic tool to a strategic instrument that enables biologically driven, outcome-oriented care for patients with Alzheimer's disease.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/therapy/drug therapy
*Positron-Emission Tomography/methods/standards
*Amyloid beta-Peptides/metabolism
*Precision Medicine/methods
Biomarkers/metabolism

@article {pmid42189322,
year = {2026},
author = {Shyam, M and Veronica, A and Wadhwa, J and Sharma, V and B M, O and Srirangan, P and Venkatesh, R and Evan Prince, S},
title = {FOXO transcription factors in Alzheimer's Disease: balancing neuroprotection and neuronal degeneration.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42189322},
issn = {1573-4978},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/genetics ; *Forkhead Transcription Factors/metabolism/genetics ; *Neuroprotection ; Oxidative Stress ; Animals ; Signal Transduction ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; *Nerve Degeneration/metabolism/pathology ; Forkhead Box Protein O1/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by the accumulation of amyloid-β, hyperphosphorylation of tau, oxidative stress, synaptic dysfunction, and neuroinflammation. Recent research underscores the Forkhead box O (FOXO) family of transcription factors (FOXO1, FOXO3, FOXO4, FOXO6) as crucial regulators of these pathogenic processes. FOXOs regulate antioxidant defenses, autophagy, mitochondrial quality control, and apoptosis by functioning downstream of insulin/PI3K-Akt and stress-responsive pathways. This context-dependent activity enables FOXOs to act as dual regulators: brief activation improves proteostasis, oxidative stress tolerance, and synaptic resilience, whereas dysregulated signaling triggers pro-apoptotic and neurodegenerative pathways. Genetic and pharmacological studies targeting FOXO signaling highlight its potential as a therapeutic target; nonetheless, obstacles persist, including isoform specificity, compensatory feedback mechanisms, and transport across the blood-brain barrier. This review consolidates contemporary understanding of the structural and functional functions of FOXO isoforms in AD, their participation in amyloid and tau pathology, oxidative stress, and neuroinflammation, and assesses options for therapeutic control. A deeper understanding of FOXO signaling could lead to novel therapies that utilize its neuroprotective properties specifically, while minimizing adverse effects.},
}

Humans
*Alzheimer Disease/metabolism/pathology/genetics
*Forkhead Transcription Factors/metabolism/genetics
*Neuroprotection
Oxidative Stress
Animals
Signal Transduction
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
*Nerve Degeneration/metabolism/pathology
Forkhead Box Protein O1/metabolism

@article {pmid42189396,
year = {2026},
author = {Li, F and Zhao, S and Liang, Z and Xu, Z and Bai, S and Zhou, W and Zheng, Q and Yan, W and Wang, L and Sun, K and Zhang, H and Shen, D},
title = {Brain-body interactions in systemic diseases: a survey from an imaging perspective.},
journal = {MedScience},
volume = {},
number = {},
pages = {},
pmid = {42189396},
issn = {3091-4981},
abstract = {Many diseases are now recognized as systemic, involving extensive crosstalk between brain and body. Although existing reviews have elucidated the biochemical basis of these brain-body connections, their dynamic interactions remain largely unexplored by imaging approaches. To fill this gap, this review investigates brainbody axes from an imaging perspective across three research paradigms: (1) the impact of brain diseases on the body, including Alzheimer's disease, Parkinson's disease, psychiatric disorders, and cerebral small vessel disease; (2) the influence of body diseases on the brain, particularly those originating in the eye, heart, liver, and gut; and (3) the new frontier encompassing multi-organ data acquisition and integrative modeling methods for brain-body interactions. Spanning from biological hypotheses and inter-organ crosstalk to recent technical advances, this review not only summarizes the systemic manifestations of diseases across organs but also offers perspectives toward improved diagnostics and therapies. The integration of whole-body networks from an imaging perspective holds promise for advancing precision medicine and provides a new paradigm for investigating and diagnosing complex systemic diseases.},
}

@article {pmid42189519,
year = {2026},
author = {Salvadó, G and Horie, K and Barthélemy, NR and Schindler, SE and Janelidze, S and Orduña Dolado, A and Bali, D and Perrin, RJ and Morris, JC and Benzinger, TLS and Gordon, BA and Stomrud, E and Mattsson-Carlgren, N and Palmqvist, S and Vogel, JW and Bateman, RJ and Ossenkoppele, R and Hansson, O},
title = {Plasma eMTBR-tau243 and %p-tau217 for Biological Staging of Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.1405},
pmid = {42189519},
issn = {2168-6157},
abstract = {IMPORTANCE: Biological staging of Alzheimer disease (AD) can improve diagnostic accuracy and prognostic assessment. However, existing approaches often require invasive procedures and specialized infrastructure, limiting their routine clinical use.

OBJECTIVE: To develop and validate a plasma-based biological staging model that closely mirrors an amyloid and tau positron emission tomography (PET)-based staging system.

This observational longitudinal study included the research BioFINDER-2 cohort as the main cohort and the Knight Alzheimer Disease Research Center (ADRC) cohort as an independent validation cohort, with data acquired from November 2019 to January 2025 and from September 2007 to March 2020, respectively. Participants ranged from cognitively unimpaired (CU) to experiencing mild cognitive impairment (MCI) and dementia with AD or other neurodegenerative diseases. All individuals had both plasma biomarkers available. A Knight ADRC subsample had neuropathological data available. Data were analyzed from December 2024 to July 2025.

EXPOSURES: Plasma endogenously cleaved microtubule-binding region tau containing residue 243 (eMTBR-tau243) and phosphorylated tau at threonine 217 expressed as a percentage of its unphosphorylated form (%p-tau217).

MAIN OUTCOME AND MEASURES: The primary outcomes were PET-based biological staging according to the revised Alzheimer's Association criteria, clinical criteria, and biomarker levels assessed cross-sectionally and longitudinally.

RESULTS: The BioFINDER-2 main cohort included 872 participants, with an additional 156 participants in the Knight ADRC cohort for independent validation. In the BioFINDER-2 cohort, participants included 383 CU participants, 182 participants with MCI, 151 with AD dementia, and 156 participants with non-AD neurogenerative diseases (mean [SD] age, 72.8 [9.2] years; 438 women [50.2%]; 516 [59.2%] apolipoprotein E [APOE-E4] carriers). A plasma-based model with %p-tau217 and eMTBR-tau243 was derived, which demonstrated high concordance with established PET-based stages (C index, 0.91; 95% CI, 0.90-0.92) and was associated with clinical stage within the AD continuum (C index, 0.84; 95% CI, 0.82-0.86). In the validation cohort, concordance with PET-based stages was high (C index, 0.91; 95% CI, 0.87-0.94), as was concordance with clinical stage (C index, 0.86; 95% CI, 0.82-0.89). Concordance between fluid- and PET-based staging models was higher with this study's %p-tau217 and eMTBR-tau243 model than with a staging model using %p-tau217 alone, especially improving the intermediate or C stage (A+TMOD+) classification. In the neuropathology subsample, plasma staging was strongly aligned with autopsy-confirmed AD pathology using the Alzheimer Disease Neuropathologic Change scale (area under the curve, 0.96; 95% CI, 0.91-1.00).

CONCLUSIONS AND RELEVANCE: In this longitudinal study, a plasma-based biological staging model incorporating %p-tau217 and eMTBR-tau243 showed strong concordance with PET-based staging, correlated with clinical severity and biomarker progression, and aligned with neuropathological categorization. This scalable, minimally invasive approach could facilitate broader implementation of biological staging in clinical practice and could enhance participant selection for disease-modifying treatments and clinical trials.},
}

@article {pmid42189715,
year = {2026},
author = {Saraç, M and Kaffy, J and Peqini, K and Vanoni, C and Wetjen, A and Singh, L and Brandt, R and Campanacci, V and Gigant, B and Giraud, F and Crousse, B and Ongeri, S and Gelmi, ML and Milcent, T},
title = {A β-hairpin mimic built on a fluorinated isoxazoline-β[2,2]-amino acid as a modulator of Tau protein aggregation.},
journal = {Organic & biomolecular chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ob00187d},
pmid = {42189715},
issn = {1477-0539},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is a tauopathy characterized by the intraneuronal accumulation of misfolded Tau into neurofibrillary tangles that drive synaptic dysfunction and neuronal loss. Molecular chaperones such as Hsp90 regulate Tau folding, degradation, and aggregation, but full-length chaperones are not viable drugs, prompting the development of peptidomimetics that reproduce protective Hsp90-Tau contacts. We previously reported two β-hairpin peptidomimetics derived from Hsp90, based on a piperidine-pyrrolidine (β-HM1) or on an isoxazoline amino acid (β-HM2) incorporating key hot-spot sequences, that inhibit the aggregation of wild-type and ΔK280 Tau and restore Tau-microtubule interactions in cells. Here, we describe the design and characterization of fluorinated β-HM2 analogues (β-FH1 and β-FH2) as molecular tools to investigate the mechanism of Tau misfolding. β-FH1 and β-FH2 contain a fluorinated isoxazoline-β[2,2]-amino acid scaffold whose S or R stereochemistry biases the peptidomimetic toward either a fully extended β-strand-like conformation or a β-hairpin fold, respectively. The replacement of the phenyl group of the Isox-β[2,2]-AA core by a trifluoromethyl substituent was intended to refine Tau anti-aggregation activity, enhance metabolic stability toward proteolysis, and introduce a sensitive [19]F NMR probe to monitor Tau-peptidomimetic interactions at the molecular level. The fluorinated analogues completely lost their ability to prevent Tau aggregation in model neurons but caused increased dynamics of the Tau-microtubule interaction. This suggests that subtle changes in β-hairpin preorganization and flexibility impair optimal Tau recognition and affect Tau function in neuronal cell processes. These findings underline the need for finely tuned hairpin architectures in the design of chaperone-mimetic peptides.},
}

@article {pmid42189736,
year = {2026},
author = {Jacobsen, E and Zhang, Y and Ganguli, M and Chang, CH and Kamboh, ML and Karikari, TK and Berman, SB and Snitz, BE},
title = {Olfaction, Cognition, and Early Signs of Neurodegenerative Disease in a Community-Based Sample of Older Adults.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000730},
pmid = {42189736},
issn = {1546-4156},
abstract = {INTRODUCTION: We investigated associations of impaired odor identification with signs of early Alzheimer disease (AD) and Lewy Body disease (LBD).

METHODS: In 787 community-sampled adults aged ≥65 without dementia or Parkinson disease, we evaluated cross-sectional associations of olfaction (Brief Smell Identification Test, BSIT) with 5 cognitive domain scores, gait, tone, tremor, REM sleep behavior disorder (RBD) symptoms, and plasma biomarkers of neurodegeneration.

RESULTS: In adjusted regression models, worse BSIT scores were associated with lower cognitive scores in all domains, slowed gait, resting tremor, and RBD-like symptoms. The association between BSIT and memory was stronger in APOE4 carriers. In cognitively unimpaired participants (Clinical Dementia Rating=0), most associations remained significant. BSIT scores were associated with plasma p-tau217 and NfL in exploratory analyses.

CONCLUSION: Odor identification is associated with cognition in an undifferentiated pattern and with Parkinsonian signs in older adults, even among those with normal cognition. The stronger association in APOE4 carriers potentially suggests an emerging AD-like pathway, consistent with exploratory plasma biomarker analyses. In sum, evidence points to olfactory dysfunction as relevant for both AD and LBD-associated future risk.},
}

@article {pmid42190148,
year = {2026},
author = {Urso, D and Giannoni-Luza, S and Gnoni, V and Giugno, A and Rollo, E and Mauro, A and Sambati, R and De Santis, G and Alessandria, M and Coluccia, B and Panico, NR and Cacciatore, F and Vilella, D and Zecca, C and Ray, N and Logroscino, G and , },
title = {Incidence of Dementia With Lewy Bodies in Salento, Italy: A Population-Based Study.},
journal = {Neurology},
volume = {106},
number = {12},
pages = {e218150},
doi = {10.1212/WNL.0000000000218150},
pmid = {42190148},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Italy/epidemiology ; Aged ; *Lewy Body Disease/epidemiology ; Incidence ; Aged, 80 and over ; Prospective Studies ; Middle Aged ; Alzheimer Disease/epidemiology ; },
abstract = {BACKGROUND AND OBJECTIVES: Population-based incidence data for dementia with Lewy bodies (DLB) remain limited, particularly using contemporary diagnostic criteria and across the full adult age range. We aimed to estimate age-specific and sex-specific incidence of DLB in a defined population and to characterize clinical features, sex-related phenotypic differences, and Alzheimer disease (AD) copathology.

METHODS: We conducted a prospective, population-based incidence study in the Salento region of Southern Italy (767,356 residents) from March 1, 2023, to February 28, 2025. Incident DLB cases were identified through a multisource surveillance network and centrally adjudicated. DLB was diagnosed using the 2017 DLB Consortium criteria, with standardized assessment of all core features; AD biomarkers (CSF or amyloid PET) were incorporated when available. Incidence rates per 100,000 person-years were calculated using population denominators with Poisson 95% CIs and were directly standardized to the 2013 European Standard Population.

RESULTS: Sixty-two incident DLB cases were identified over 1,534,712 person-years (mean age at diagnosis 77.4 years; 42% female). The crude incidence was 4.04 per 100,000 person-years (95% CI 3.10-5.18), and the age-standardized incidence was 3.77 (95% CI 2.89-4.83). Incidence was higher in men than women (crude 4.87 vs 3.27; standardized 4.55 vs 3.04), increased steeply with age, and peaked at 80-84 years (30.83; 95% CI 18.56-48.14). Men had greater motor severity (Movement Disorder Society-Unified Parkinson's Disease Rating Scale, part III 23.7 vs 14.4; p = 0.002), whereas women had higher neuropsychiatric burden (Neuropsychiatric Inventory total 24.0 vs 13.0; p = 0.041). Young-onset DLB (<65 years) accounted for 6.5% of cases. AD biomarkers were available in 45.2% of patients, of whom 75% were positive.

DISCUSSION: In this prospective population-based study, DLB incidence increased sharply with age, peaked in the early 80s and was higher in men, with a substantial proportion of cases showing AD copathology. We also observed sex-related differences in motor and neuropsychiatric profiles. Limitations include the single-region design, incomplete biomarker testing, and lack of neuropathologic confirmation. These contemporary incidence data help quantify the burden of DLB and can inform service provision, resource allocation, and care planning in aging populations.},
}

Humans
Female
Male
Italy/epidemiology
Aged
*Lewy Body Disease/epidemiology
Incidence
Aged, 80 and over
Prospective Studies
Middle Aged
Alzheimer Disease/epidemiology

@article {pmid42190582,
year = {2026},
author = {Rastrygina, VA and Vologzhannikova, AA and Chaplygina, AV and Bobrova, LA and Zemskova, MY and Deryusheva, EI and Sokolov, AS and Permyakova, ME and Litus, EA and Uversky, VN and Permyakov, EA and Permyakov, SE},
title = {Activity of epidermal growth factor is directly affected by S100 proteins.},
journal = {Cell calcium},
volume = {136},
number = {},
pages = {103153},
doi = {10.1016/j.ceca.2026.103153},
pmid = {42190582},
issn = {1532-1991},
abstract = {Epidermal growth factor (EGF) is a therapeutically important member of a family of the growth factors that activate EGF receptors, triggering several signaling pathways vital for development, homeostasis and regeneration of many organs. Previous studies have shown the ability of S100A4, a small calcium-binding protein of the S100 family, to directly affect functional activity of EGF receptors and its ligands, including EGF. However, selectivity and functional significance of EGF-S100 interactions remain unexplored. To address this, we examined specificity of EGF for twenty-one S100 proteins using surface plasmon resonance spectroscopy. The impact of the revealed interactions on EGF-induced cellular effects was assessed using cell proliferation and metabolic activity assays. S100A2/A4/A6/A11/A12/A13/A16/P and S100A8-S100A9 heterodimer bind EGF strictly in the presence of calcium with lowest estimates of the equilibrium dissociation constant ranging from 13 nM to 1.0 μM. Structural modelling indicates involvement of α-helix IV and "hinge" region of the EGF-specific S100 proteins in the EGF binding, which was confirmed for S100P by mutagenesis. The complexation of EGF with S100A2/A6/A12/A16/P exerts distinct S100-dependent effects on viability and metabolic activity of lung adenocarcinoma A549 cells. Bioinformatics analysis showed that dysregulation of EGF and the EGF-specific S100 proteins is associated with many oncological diseases, Alzheimer's and Parkinson's diseases, psoriasis, etc. Overall, specific S100 proteins have been shown to directly modulate various aspects of EGF functioning, which may be important for ensuring efficacy of the EGFR-targeted cancer therapies, as well as for use of EGF in regenerative medicine.},
}

@article {pmid42190614,
year = {2026},
author = {Kumar, SN and Abdul Hamid, NAW and Dafik, D and Sunder, R and S, SS and S, A and Kannadhasan, S},
title = {A Voyage on Computer Aided Intelligent Algorithms for the Segmentation of Brain Tissues for Neurodisorder Diagnosis.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/00207454.2026.2680936},
pmid = {42190614},
issn = {1563-5279},
abstract = {Neurodisorders pose a considerable burden to global health, frequently requiring early treatment and diagnosis to avoid irreversible cognitive and motor impairments. Segmentation of brain tissue is an essential task in neurodiagnostics due to its inability to accurately separate grey matter, white matter, and cerebrospinal fluid within imaging modalities like MRI and CT. This article reviews the progress of brain tissue segmentation techniques from manual and semi-automated approaches to sophisticated machine learning and deep learning algorithms. It discusses how these contemporary methodologies enhance segmentation quality, address difficult anatomical variation, and optimize diagnostic accuracy in diseases like Alzheimer's, multiple sclerosis, traumatic brain injury, and stroke. This research work compares supervised, unsupervised, and deep learning paradigms on the basis of their advantages, disadvantages, and potential use in clinical settings. In addition, it presents hybrid and ensemble methods that blend conventional and AI-based approaches to mitigate obstacles such as data heterogeneity, annotation limitations, and interpretability. This survey details the revolutionizing potential of machine learning in neuroimaging and ultimately seeks to facilitate early diagnosis, treatment planning, and individualized healthcare provision for neurological diseases.},
}

@article {pmid42190655,
year = {2026},
author = {Laub, S and Tulina, N and Hoffman, M and Faryean, JB and Ramachandran, S and Trang, K and Lewkiewicz, SM and Chesi, A},
title = {Integrative genomics and single-cell CRISPRi screening dissect Alzheimer GWAS non-coding variants regulating TSPAN14.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2026.04.011},
pmid = {42190655},
issn = {1537-6605},
abstract = {Genome-wide association studies (GWASs) have uncovered many associations for human complex diseases, but functional dissection of the discovered loci has lagged behind. We present a variant-to-gene (V2G) mapping effort for Alzheimer disease (AD) leveraging the most recent AD GWAS meta-analyses. In this study, we integrated ten brain-relevant genomics datasets-including promoter Capture C, ATAC-seq, and RNA-seq from microglia, neurons, and astrocytes-to fine-map AD GWAS variants and identify effector genes. We then performed a single-cell CRISPRi Perturb-seq screen targeting 74 candidate regulatory regions in the human microglial cell line HMC3. Our V2G mapping effort identified 93 candidate causal variants and 94 effector genes (72 coding) for 35 AD loci. Our CRISPRi screen across ∼97,000 cells validated 21 variant-gene pairs. We showed that an intronic region at the TSPAN14 locus containing rs7080009, rs1870138, and rs1870137 is a microglial-specific enhancer activated by the AD-risk haplotype. CRISPR-mediated deletion of this region reduced TSPAN14 expression, disrupted cell-adhesion pathways, and lowered secretion of pro-inflammatory cytokines interleukin 6 (IL-6) and IL-8. Our study provides a systematic framework for mapping GWAS signals to effector genes in a cell-type-specific manner and identifies robust leads for in-depth functional investigations.},
}

@article {pmid42190774,
year = {2026},
author = {Hnin, HM and Tun, T and Chongcharoen, W and Nalinratana, N and Rodsiri, R and Loftsson, T and Parekh, HS and Jansook, P},
title = {Chitosan-coated cyclodextrin-based niosomes enable enhanced nose-to-brain delivery of rivastigmine and asiaticoside for Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {152709},
doi = {10.1016/j.ijbiomac.2026.152709},
pmid = {42190774},
issn = {1879-0003},
abstract = {The co-delivery of rivastigmine hydrogen tartrate (RHT) and asiaticoside (AS) offers a promising strategy for enhancing acetylcholinesterase (AChE) inhibition in Alzheimer's disease (AD) by targeting both cholinergic deficits and neurodegeneration. However, formulating a combined delivery system is challenging due to the hydrophilic nature of RHT and poor solubility of AS. Accordingly, we developed a scalable intranasal delivery system using cyclodextrin-enabled niosomes. Inclusion complexes of RHT, AS, and 2-hydroxypropyl-β-cyclodextrin were prepared and encapsulated into niosomes via thin-film hydration, followed by surface modification with chitosan (CS) to produce CS-coated RA@N. Characterization confirmed the successful complexation and nanoscale encapsulation. CS-coated RA@N exhibited a biphasic release pattern for RHT and sustained release for AS. Compared to uncoated niosomes, CS-coated RA@N showed a 3.1-fold increase in mucoadhesion and enhanced ex vivo permeation across porcine nasal mucosa (2.1-fold for RHT, 1.8-fold for AS). The formulation exhibited excellent biocompatibility, efficient uptake by RPMI 2650 and SH-SY5Y cells, and improved epithelial-to-neuronal transport. In vivo mouse studies demonstrated significantly higher brain-to-plasma ratios and a more sustained reduction in brain AChE activity following intranasal administration of the formulation. Importantly, co-administration of RHT and AS produced an enhanced pharmacodynamic response, surpassing the effects of single-drug formulations. These findings support CS-coated RA@N as a robust nanocarrier for enhanced nose-to-brain delivery, with strong potential for effective AD symptom management.},
}

@article {pmid42190844,
year = {2026},
author = {Ma, X and Koppelmans, V and Akcicek, H and Akcicek, EY and Shen, J and Chen, L and Balu, N and Yuan, C and King, JB},
title = {SNAP MRI reveals association between distal cerebral arterial flow and cognitive function in an aging population.},
journal = {Magnetic resonance imaging},
volume = {},
number = {},
pages = {110702},
doi = {10.1016/j.mri.2026.110702},
pmid = {42190844},
issn = {1873-5894},
abstract = {OBJECTIVE: Impaired blood flow has recently been recognized as a critical contributor to cognitive impairment and dementia. It was reported that cerebral distal arterial flow measured from Simultaneous Non-contrast Angiography and Intraplaque Hemorrhage (SNAP) MRI is associated with post-treatment cognitive function improvement in carotid atherosclerosis patients. In this study, we aim to evaluate the value of SNAP-based measurements in assessing cerebrovascular function in an aging population.

MATERIALS AND METHODS: Neurovascular MRI data were collected on 36 aging participants (22 cognitively unimpaired and 14 impaired; 9 mild cognitive impairment (MCI) and 5 Alzheimer's Disease (AD)). Neurovascular MRI measurements, including white matter hyperintensities (WMH) volumes, cerebral blood flow (CBF), and SNAP-based distal cerebral arterial flow (dCAF) index, were quantified. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

RESULTS: Significant differences in the dCAF index were observed between cognitively unimpaired and impaired groups, and the dCAF index was significantly correlated with the RBANS total score. While CBF was significantly associated with dCAF index, there is no significant correlation of CBF or WMH with the RBANS score in this population.

CONCLUSION: Our findings suggest that the dCAF measured with SNAP MRI is valuable for evaluating the cognition-related cerebrovascular condition in an aging population.},
}

@article {pmid42190894,
year = {2026},
author = {Oriquat, G and Abdulqader, AF and Farid, H and Ashurov, Z and Sottarov, A and Ghafl, NY and Bainsal, N and Singh, R},
title = {From Protector to Perpetrator: The cGAS-STING Pathway at the Intersection of Neurodegeneration and Neuroinflammation.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111963},
doi = {10.1016/j.brainresbull.2026.111963},
pmid = {42190894},
issn = {1873-2747},
abstract = {The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of the innate immune system designed to combat pathogens, is now implicated as a critical driver of sterile inflammation in the brain. This review synthesizes compelling evidence that in the aging and diseased central nervous system, endogenous cytosolic DNA, sourced from genomic instability, mitochondrial dysfunction, and activated retrotransposons, hijacks this pathway. Chronic cGAS-STING activation transforms microglia into inflammatory amplifiers, instigates neurotoxic astrocyte programs, and directly compromises neuronal health, creating a self-perpetuating cycle of neuroinflammation. We dissect the cell-type specific consequences within the neurovascular unit and establish the pathway's role in the pathogenesis of ALS/FTD, Alzheimer's, Parkinson's, and Huntington's diseases. Crucially, we evaluate the therapeutic potential of targeting this axis, discussing small-molecule inhibitors, oligonucleotide therapies, and upstream interventions to quell the source of immunogenic DNA. We also explicitly examine contradictory preclinical data, including the retracted PINK1-Parkin-STING report and context-dependent neurovascular findings, to provide a balanced appraisal of STING biology in the CNS. By reconciling its dual protective and pathogenic roles, this review posits cGAS-STING as a pivotal mechanism-based therapeutic node for halting the progression of neurodegenerative disorders.},
}

@article {pmid42190920,
year = {2026},
author = {Svobodova, B and Soukup, O and Korabecny, J},
title = {Revisiting butyrylcholinesterase in Alzheimer's disease: a hub linking cholinergic, metabolic and affective pathways.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103187},
doi = {10.1016/j.arr.2026.103187},
pmid = {42190920},
issn = {1872-9649},
abstract = {Selective butyrylcholinesterase (BChE) inhibition is gaining renewed attention as a potential therapeutic strategy for Alzheimer's disease (AD), particularly in advanced stages marked by a shift from acetylcholinesterase (AChE) to BChE dominance. Beyond cholinergic regulation, BChE participates in metabolic, inflammatory, and affective pathways, including the enzymatic control of acyl ghrelin that influences appetite, energy balance, and mood. Preclinical and experimental evidence suggests that selective BChE inhibition may modulate cholinergic tone, enhance cognition, and exert antidepressant- and anti-anhedonic-like effects, although clinical evidence remains limited and inconclusive. Genetic polymorphisms in BChE further shape disease progression and responses to cholinesterase therapy. This review integrates advances in BChE inhibitor development with evolving insights into BChE-dependent metabolic and neuropsychiatric mechanisms, highlighting selective BChE inhibition as a multifaceted therapeutic approach in AD.},
}

@article {pmid42190921,
year = {2026},
author = {Bhasha, S and Chintada, V and Munikumar, M and Maddineni, J and Nagulavancha, R and Malempati, T and Gadda, SS and Sankepally, KKR and Adi, PJ},
title = {Targeting Tau-Mitochondrial Crosstalk in Alzheimer's Disease: Integrative Multi-Omics and Artificial Intelligence-Driven Tools for the Development of Disease-Modifying Therapeutics.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103186},
doi = {10.1016/j.arr.2026.103186},
pmid = {42190921},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative illness marked by cognitive impairment, synaptic dysfunction and neuronal death. Tau protein abnormalities and mitochondrial dysfunction are key features of its pathogenesis, and both are involved in driving disease development. Emerging evidence suggests that pathogenic tau not only destabilizes microtubules but also directly compromises mitochondrial dynamics, bioenergetics and quality control, ultimately aggravating neurodegeneration. However, the molecular processes by which tau disease causes mitochondrial failure are poorly known. In this review, we discuss the tau-mitochondria interplay in AD and highlight how integrated multi-omics and computational approaches are boosting the development of disease-modifying treatments. We conducted an extensive evaluation of recent literature in key scientific databases related to tau biology, mitochondrial dysfunction, mitophagy, transcriptomics, proteomics, metabolomics, and computational drug development in AD. The results demonstrate that hyperphosphorylated tau leads to inhibition of mitochondrial transport, changes in membrane potential, impairment of oxidative phosphorylation and increased generation of reactive oxygen species (ROS). Multi-omics analyses show coordinated changes in molecular pathways affecting energy metabolism, synaptic maintenance and neuronal survival. Furthermore, computational and AI-based methods have enabled the recognition of novel tau-interacting proteins, mitophagy modulators and treatment candidates. The tau-mitochondrial interaction is a key pathogenic axis in Alzheimer's disease and provides prospective avenues for harnessing multi-omics and computational techniques to create mechanism-based treatments to restore mitochondrial function and synaptic integrity. This integrative paradigm provides a basis for next-generation precision therapies for neurodegenerative network dysfunction.},
}

@article {pmid42190922,
year = {2026},
author = {Schuller, AJ and Bibb, AM and Hager, MR and Yanouri, OA and Smith, EJ and Briggs, AM and Montrose, LB and Tjalkens, RB},
title = {Simulated wildfire smoke particulate matter elicits STING-dependent astrocyte-mediated inflammatory signaling and neurotoxicity.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103473},
doi = {10.1016/j.neuro.2026.103473},
pmid = {42190922},
issn = {1872-9711},
abstract = {Changing global wildfire landscapes necessitate exploration of the effects of exposure to wildfire smoke on health and disease. Exposure to this toxicant is not only associated with acute cardiopulmonary dysfunction, but is increasingly recognized as a serious risk factor for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, the cellular and molecular mechanisms which underlie this association are not well understood. One potential mechanism linking neurotoxic environmental exposures with neurodegeneration is glial-mediated neuroinflammation, which may be influenced by innate immune signaling through the cGAS-STING pathway in response to damaged or mislocalized DNA. To address this hypothesis, we here exposed primary astrocyte-enriched mixed glial cultures to laboratory generated wildfire smoke particulate matter extract and subsequently examined their reactivity and inflammatory signaling by applying cutting-edge techniques in high content microscopy, deep learning-based image analysis, and transcriptomics. We found that wildfire smoke exposure elicits DNA damage and results in STING signal transduction in astrocytes, including the production and release of inflammatory cytokines, as well as STING-dependent neurotoxicity. To better understand the mechanisms underlying this phenomenon, we integrated transcriptomic data from in vitro and in vivo wildfire smoke exposures studies, which revealed central hubs for functional enrichment surrounding interferon signaling. Together, these data strongly identify STING signaling as a central modulator of astrocyte-mediated inflammation resulting from wildfire smoke exposure.},
}

@article {pmid42190932,
year = {2026},
author = {Kim, JH and Lee, SR and Han, S and Kim, B and Han, KD and Lee, KY and Ahn, HJ and Oh, S and Lip, GYH and Choi, EK},
title = {Lower Risk of Dementia with Early Rhythm Control Therapy and a Healthy Lifestyle in Patients with New-Onset Atrial Fibrillation.},
journal = {Heart rhythm},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.hrthm.2026.05.039},
pmid = {42190932},
issn = {1556-3871},
abstract = {BACKGROUND: Atrial fibrillation (AF) is an independent risk factor for dementia.

OBJECTIVE: To investigate the association of combining early rhythm control (ERC) and healthy lifestyle (HLS) with the risk of incident dementia in patients with new-onset AF.

METHODS: The Korean National Health Insurance Service database included patients newly diagnosed with AF between 2009 and 2016. Patients were classified into four groups: those without ERC or HLS (group 1), those with HLS only (group 2), those with ERC only (group 3), and those with both ERC and HLS (group 4). The propensity score weighting method was used to balance baseline characteristics among the four groups. Incidental dementia was evaluated during follow-up.

RESULTS: A total of 199,947 patients were included (96,907, 53,293, 29,234, and 20,513 in groups 1, 2, 3, and 4, respectively). Compared to group 1, group 4 showed the lowest risk for all dementia (weighted hazard ratio, 95% confidence interval: 0.691, 0.649-0.735), followed by group 2 (0.754, 0.725-0.785), and group 3 (0.919, 0.876-0.964). For vascular dementia, group 4 had the lowest risk compared to group 1 (0.598, 0.507-0.705), whereas group 2 (0.802, 0.728-0.882) and group 3 (0.803, 0.708-0.911) showed similar risks. For Alzheimer's dementia, group 4 showed the lowest risk (0.728, 0.680-0.780), followed by group 2 (0.747, 0.715-0.782). In contrast, group 3 showed a comparable risk (0.958, 0.908-1.010) to group 1.

CONCLUSION: A combination of ERC and HLS might mitigate the risk of dementia in patients with new-onset AF. These findings support a holistic approach to preventing dementia in this population.},
}

@article {pmid42190976,
year = {2026},
author = {Adebiyi, O and Unaran, E and Machado, MMF and Saksida, LM and Menon, R and Káradóttir, RT and Bussey, TJ},
title = {From adaptive to maladaptive myelination: white matter dynamics in cognition and neurologic disorders.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106779},
doi = {10.1016/j.neubiorev.2026.106779},
pmid = {42190976},
issn = {1873-7528},
abstract = {Myelin is a fatty substance formed by processes of mature oligodendrocytes, which wrap around neuronal axons. Previously, myelin was believed to be important solely for the rapid conduction of electrical signals. However, over the past decade, research has revealed that its role goes far beyond this, including providing metabolic support to neurons and exhibiting significant plasticity. Myelin has also been thought to play a role in the pathogenesis of several neurodegenerative diseases. Furthermore, myelin has been implicated in various psychiatric disorders, including anxiety, depression, and schizophrenia, stimulating investigations into its involvement in normal cognitive function, learning, and memory. Understanding the intricate processes involved in myelin formation, damage, and repair is important in elucidating its contribution to neural circuit functions in health and disease. In this review, we discussed the unique structure of myelin and its contributions to the pathogenesis of neurological disorders such as Alzheimer's disease, epilepsy, multiple sclerosis, traumatic brain injury, schizophrenia, and stroke. Furthermore, we discuss the precise mechanisms by which myelin alterations in these disorders affect the synchronization and integration of neural activity, and how these changes impair executive functions such as learning, memory, attention, and decision-making. Additionally, we highlight recent findings of de novo myelination and myelin plasticity while identifying key knowledge gaps that need to be addressed to advance therapies to promote myelin repair in disease states.},
}

@article {pmid42190978,
year = {2026},
author = {Moura, AR and Magalhães, M and Dos Santos, C and Marinho, F and Henriques, R and Wimmer, GE and Dolan, RJ and Fragata, I},
title = {Digital episodic memory tools for the identification of amnestic mild cognitive impairment: a systematic review and an exploratory meta-analysis.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106756},
doi = {10.1016/j.neubiorev.2026.106756},
pmid = {42190978},
issn = {1873-7528},
abstract = {Within our ageing population, the prevalence of Amnestic Mild Cognitive Impairment (aMCI) is rising, underscoring a need for early detection strategies to mitigate potential progression to dementia. Traditional pen-and-paper cognitive tests remain standard but often fail to capture subtle early impairments. Digital episodic memory tasks have emerged as a promising alternative, offering automated scoring, increased accessibility, and potentially better sensitivity to cognitive decline. We systematically evaluated the diagnostic accuracy of digital episodic memory assessments for aMCI. Thirteen studies met inclusion criteria, with six (n = 510 participants) providing sufficient data for meta-analysis. Pooled estimates showed sensitivity of 0.78 (95% CI: 0.65-0.87), specificity of 0.79 (95% CI: 0.66-0.89), and AUC of 0.86, with low to moderate heterogeneity (I[2] = 36.1%), largely reflecting differences in task design and administration. Both quantitative and qualitative findings suggest digital episodic memory tasks can provide accessible, scalable, and effective tools for early aMCI detection. However, design variability and construct differences highlight the need for further validation across diverse populations and improved methodological standardisation before clinical implementation.},
}

@article {pmid42191023,
year = {2026},
author = {Ušacka, A and Šneidere, K and Freibergs, Z and Stepens, A},
title = {Cognitive tasks for evoking the P300 event-related potential in Alzheimer's disease and mild cognitive impairment: A scoping review.},
journal = {International journal of psychophysiology : official journal of the International Organization of Psychophysiology},
volume = {},
number = {},
pages = {113423},
doi = {10.1016/j.ijpsycho.2026.113423},
pmid = {42191023},
issn = {1872-7697},
abstract = {Event-related potentials (ERPs), particularly the P300 component, provide a noninvasive, cost-effective approach to probing neural dysfunction in Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, methodological and task-related variability across studies has hindered clinical translation. This scoping review systematically mapped cognitive tasks, stimulus parameters, and EEG acquisition pipelines used to elicit the P300 in AD and MCI and assessed their consistency in revealing group differences in P300 latency and amplitude relative to healthy controls. The review followed Joanna Briggs Institute methodology and PRISMA-ScR guidelines. Searches across PubMed, ProQuest, and ScienceDirect (2015-2025) identified empirical studies that employed EEG-based P300 paradigms to compare AD, MCI, and healthy older adults. Data on participant characteristics, task type, stimulus parameters, ERP outcomes, and EEG processing were extracted. Twenty-eight studies met the inclusion criteria. Three dominant paradigm groups were identified: auditory and visual oddball, working memory, and selective attention-executive tasks. Across studies, AD most consistently demonstrated prolonged P300 latency - most robustly in auditory oddball paradigms - whereas amplitude reductions were less reliable. In MCI, reduced amplitude was most consistently observed relative to controls under higher cognitive load, while prolonged latency emerged in selected visual oddball and selective attention-executive tasks. Stimulus duration (50-150 ms), moderate target probability (~20-30%), behavioral response, and sufficient trial counts enhanced sensitivity. Methodological heterogeneity in referencing, filtering, artifact rejection, and component quantification (e.g., peak vs mean amplitude) limited reproducibility. The P300 remains a promising electrophysiological biomarker for early cognitive decline. Latency prolongation might reflect AD-related slowing of processing, while amplitude reduction under cognitive load may capture MCI-related inefficiency of resources. Standardization for task design and EEG processing will be critical for establishing P300 as a clinically useful marker of pre-dementia progression.},
}

@article {pmid42191141,
year = {2026},
author = {Kim, M and Min, S and Jung, J and Lee, CH and Moon, YS and Kim, DH},
title = {Differential Associations Between Religiosity and Cognition in the Korean Elderly With Alzheimer's Disease.},
journal = {Psychiatry investigation},
volume = {23},
number = {5},
pages = {677-684},
doi = {10.30773/pi.2025.0394},
pmid = {42191141},
issn = {1738-3684},
support = {2021R1I1A3058026//National Research Foundation of Korea/ ; //Ministry of Education/ ; //Eisai Korea Inc./ ; },
abstract = {OBJECTIVE: Recent studies have shown the beneficial effects of religiosity on the cognitive function of people with Alzheimer's disease (AD). We compared cognitive function among groups with different religious affiliations and investigated the relationship between religiosity and subdomains of cognitive function in patients with AD.

METHODS: We recruited 247 patients with AD from psychiatric outpatient clinic. The Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-K) was used to investigate different domains of cognitive function in patients with AD. Religiosity was measured using the Duke University Religion Index (DUREL), which assesses organizational religious activity (ORA), non-organizational religious activity (NORA), and intrinsic religiosity (IR). The cognitive functions of Christian, Buddhist, and religiously non-affiliated groups were compared. Additionally, hierarchical stepwise multiple regression was used to determine the relationship between ORA, NORA, and IR and the subdomains of cognitive function.

RESULTS: The Christian group showed better functioning in memory and constructional praxis than the religiously non-affiliated group after controlling for age, sex, and education, whereas the Buddhist group did not differ from the religiously non-affiliated group. ORA, NORA, and IR were significantly related to the Mini Mental Status Examination in the Korean version of CERAD (MMSE-KC), constructional praxis, and wordlist memory. In the multiple regression analysis, ORA showed positive relationships with constructional praxis and word-list memory, whereas NORA and IR were positively associated with MMSE-KC and word-list recall, respectively.

CONCLUSION: Our results suggest that the superiority in the cognitive functions of the Christian group may be associated with a high level of religious activities and IR that significantly influences memory and visuospatial ability in the elderly with AD.},
}

@article {pmid42191142,
year = {2026},
author = {Liu, H and Niu, W and Wei, P and Zhang, M and Ye, Z and He, C},
title = {Exploring Body Roundness Index's Mediating Role in the Depression-Cognitive Performance Relationship Among US Adults (≥60 Years): Evidence From National Health and Nutrition Examination Survey.},
journal = {Psychiatry investigation},
volume = {23},
number = {5},
pages = {685-695},
doi = {10.30773/pi.2025.0375},
pmid = {42191142},
issn = {1738-3684},
support = {//Taiyuan Bureau of Science and Technology, Science, Technology/ ; 202270/WT_/Wellcome Trust/United Kingdom ; 2022KY439//Zhejiang Provincial Health Science and Technology Program/ ; },
abstract = {OBJECTIVE: Late-life depression is a known risk factor for cognitive decline, yet the role of central adiposity, measured by the body roundness index (BRI), remains unclear. This study examined whether BRI mediates the relationship between depressive symptoms and cognitive performance in older adults.

METHODS: Our analysis included 2,580 adults aged 60 and over, using data from NHANES. Depressive symptoms were assessed via the Patient Health Questionnaire-9 (PHQ-9), cognitive function was evaluated using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning and Delayed Recall (CERAD-WL/DR), Animal Fluency test (AFT), and Digit Symbol Substitution Test (DSST), and BRI was calculated from waist circumference and height. Analyses included weighted multivariable logistic regression, restricted cubic spline analyses, subgroup and sensitivity analyses, and mediation analyses.

RESULTS: Across all assessment modalities, there was a significant link between high PHQ-9 scores and cognitive performance. For continuous PHQ-9 scores, each 1-point increase corresponded to: CERAD (odds ratio [OR]=1.034, 95% confidence interval [CI]: 1.000-1.070, p=0.049), AFT (OR=1.046, 95% CI: 1.014-1.079, p=0.007), and DSST (OR=1.080, 95% CI: 1.040-1.123, p<0.001). Categorical analysis revealed particularly strong effects for moderate-to-severe depression (PHQ-9 ≥10) versus minimal symptoms (PHQ-9, 0-4): DSST (OR=2.562, 95% CI: 1.432-4.584, p=0.004), AFT (OR=1.834, 95% CI: 1.239-2.714, p=0.005), with CERAD showing marginal significance (OR=1.454, 95% CI: 0.936-2.259, p=0.090). Sensitivity analyses confirmed the stability of these associations in multiply imputed datasets. BRI exhibited a statistical mediation effect, accounting for 7.23% (β=-0.021, p=0.006) of the depression-DSST association, though mediation effects were nonsignificant for CERAD (6.21%, p=0.184) or AFT (4.41%, p=0.448).

CONCLUSION: Depression severity was independently linked to lower cognitive performance, with BRI partially mediating this relationship.},
}

@article {pmid42177534,
year = {2026},
author = {Jiang, Q and Hu, JN and Dong, HM and Xin, JY and Shi, AY and Zeng, GH and Liu, J and Wang, YJ},
title = {In vivo profiling of astrocyte secretome reveals brain-region specific regulatory networks in a mouse model of amyloid pathology.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00956-y},
pmid = {42177534},
issn = {1750-1326},
support = {82120108010//the Natural Science Foundation of China/ ; 2023YFC3605400//the National Key Research and Development Program/ ; },
abstract = {Coordinated cell-to-cell communications is crucial for the proper functioning and maintenance of brain activities, and its disruption contributes to neurological disorders, including Alzheimer's disease (AD). Altered astrocyte-neuron communications have been implicated in AD progression, yet the underlying regulatory networks remain poorly understood. Given that secretory proteins mediate both local and long-range intercellular signaling, we constructed a spatiotemporal profile of the astrocyte-derived secretome using in vivo TurboID proximity labeling in mice of amyloid pathology. Early alterations in the entorhinal cortex secretome were identified and enriched in metabolic pathways, whereas changes in the hippocampus were observed later, correlating with neuronal and synaptic maintenance. These findings suggest that early remodeling of the astrocyte secretome in the entorhinal cortex may be involved in AD pathogenesis, while later changes in the hippocampus contribute to neurodegeneration and cognitive decline. This work provides a systematic map of the dynamic, region-specific remodeling of the astrocyte secretome in AD, identifying novel spatiotemporal vulnerabilities and potential therapeutic targets.},
}

@article {pmid42177952,
year = {2026},
author = {Nieto, ÁVA and Diaz, AH and Millán, MH and Sagredo, D and Gacitua, JA},
title = {Molecular Pathways and Clinical Applications of Probiotics as Effective Supporters of Intestinal, Neurologic, and Cardiovascular Health: a Narrative Review.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110424},
doi = {10.1016/j.jnutbio.2026.110424},
pmid = {42177952},
issn = {1873-4847},
abstract = {PURPOSE OF REVIEW: This narrative review aims to synthesize current knowledge on the molecular mechanisms and clinical applications of probiotics across three major health domains: intestinal, neurologic, and cardiovascular.

RECENT FINDINGS: •Intestinal health: Probiotics such as Lactobacillus rhamnosus GG and Bifidobacterium lactis BB-12 reinforce epithelial integrity via upregulation of tight-junction proteins (occludin, claudin-1), attenuate inflammation through cytokine modulation (↑IL-10, ↓TNF-α, IL-6), and restore eubiosis in conditions including IBS, constipation, and antibiotic-associated diarrhea. • Neurologic health: "Psychobiotic" strains (e.g., L. rhamnosus JB-1, B. longum 1714, L. helveticus R0052 + B. longum R0175) modulate neurotransmitter synthesis (GABA, serotonin), dampen HPA-axis hyperactivity, and reduce neuroinflammation, yielding improvements in anxiety, stress resilience, cognitive function, and slowing brain-atrophy progression in MCI and Alzheimer's disease. • Cardiovascular health: Meta-analyses of 30+ RCTs demonstrate that probiotic supplementation (notably L. acidophilus, L. plantarum, B. longum) lowers total and LDL cholesterol (-7 to -10 mg/dL) via bile-salt hydrolase activity, SCFA-mediated GPR signaling, direct cholesterol assimilation, and modestly reduces systolic (-2 to -4 mmHg) and diastolic blood pressure through anti-inflammatory pathways and improved endothelial function. • Safety: While generally safe in healthy populations, rare adverse events (bacteremia, D-lactic acidosis, horizontal gene transfer) have been reported in immunocompromised or critically ill individuals, underscoring the need for individualized risk-benefit assessments and rigorous adverse-event surveillance.

SUMMARY: Probiotics exert strain-specific, multi-mechanistic benefits on gut barrier integrity, neuroendocrine signaling, and cardiometabolic regulation. To fully realize their therapeutic promise, future research must pursue large-scale, head-to-head clinical trials, integrate multi-omics and precision-design approaches, and establish standardized frameworks for safety monitoring and personalized formulation.},
}

@article {pmid42178007,
year = {2026},
author = {Mu, Y and Yu, S and Yang, Z and Chen, S and Sun, J},
title = {Identification and Validation of Glycosylation-Related Biomarkers in the Hippocampus for Alzheimer's Disease Diagnosis and Drug Repurposing.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179014},
doi = {10.1016/j.ejphar.2026.179014},
pmid = {42178007},
issn = {1879-0712},
abstract = {As a crucial type of post-translational modification, glycosylation plays a fundamental role in maintaining cellular homeostasis and is closely associated with the progression of Alzheimer's Disease (AD). Given the central involvement of the hippocampus in AD pathogenesis, elucidating the mechanisms of glycosylation in this brain region may provide critical insights and facilitate the development of precision medicine strategies for AD. We employed an integrated bioinformatics framework to identify glycosylation-related diagnostic biomarkers for AD. Limma and WGCNA were conducted on a hippocampal gene expression microarray dataset to detect glycosylation-associated DEGs, which were intersected with a glycosylation gene set obtained from GeneCards. Key diagnostic genes were selected using three machine learning algorithms in an independent cohort. The diagnostic model was subsequently validated in two additional independent microarrays datasets. Functional exploration and hippocampal heterogeneity were assessed at both bulk-tissue and single-cell levels. PPI analysis and NMF clustering further stratified AD patients into two subtypes. Finally, qRT-PCR validated the expression of biomarkers, and molecular docking based on the CTD suggested potential therapeutic candidates. Our analysis identified CKMT1B and AP1S1 as key downregulated glycosylation-related genes in AD. These genes were predominantly and highly enriched in hippocampal microglia at both bulk and single-cell levels and demonstrated strong diagnostic potential. PPI network analysis and NMF revealed that these hub genes could stratify AD patients into two distinct molecular subgroups. Furthermore, quercetin was identified as a potential multi-target therapeutic agent through database screening and CTD molecular docking studies. Collectively, this study bridges fundamental discovery with clinical translation by providing a diagnostic model, patient stratification subtypes, and a repositioned therapeutic candidate, outlining a promising path toward personalized AD management.},
}

@article {pmid42178013,
year = {2026},
author = {Pattanaik, S and Sahu, PK and Paidesetty, SK and Prusty, SK and Pakeeraiah, K and Panda, PK and Lopamudra, },
title = {Design, synthesis, and inhibition of oxidative, amyloidogenic, and cholinergic dysfunction of Saxagliptin-derived Schiff bases against STZ-induced sporadic AD-like pathology.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178987},
doi = {10.1016/j.ejphar.2026.178987},
pmid = {42178013},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) shares significant pathological convergence with diabetes, primarily through insulin resistance. This leads to oxidative stress, neuronal inflammation, plaque formation, cholinergic dysfunction, and impaired neuronal survival. Herein, we report 10 Saxagliptin (SXG, a potent DPP-IV inhibitor)-derived Schiff base derivatives that were virtually designed and screened. Five leads were prioritized using ADMET profiling and molecular docking, then synthesized via Schiff base condensation with selected aryl aldehydes to target AD progression associated with diabetes. Structural integrity, redox activity, and stability were confirmed by comprehensive characterization, including chromatographic and spectroscopic analyses, DFT calculations, and in vitro antioxidant assays. Neuroprotective potential was thus assessed in vivo by inducing AD-like pathology in rats with a single i.p. dose of STZ at 45 mg/kg, thereby reproducing brain insulin resistance, oxidative-nitrosative stress, and cholinergic dysfunction. Significant neurodegeneration in STZ-treated rats was evidenced by behavioral analyses, biochemical markers (AChE, Aβ42), oxidative stress indices (SOD, CAT, GSH, GPx, MDA, NO, MPO), and hippocampal histology. Treatment with SXG and derivatives at 0.5 mg/kg, orally, resulted in significant restoration of antioxidant defenses, inhibition of lipid peroxidation and NO overproduction, reduction of inflammatory oxidative bursts, and improved cognition in treated groups. Remarkably, derivatives 3c and 3e showed superior free-radical scavenging and greater regulation of redox biomarkers, which were associated with healthy, defined hippocampal cytoarchitecture and reduced neuronal pyknosis and necrosis compared with SXG. Additionally, 3e showed strong therapeutic efficacy by targeting oxidative stress, cholinergic, and amyloidogenic pathways synchronously.},
}

@article {pmid42178051,
year = {2026},
author = {Wang, C and Liu, J and Zhou, Y and Shan, X and Li, S and Ding, S and Zhuo, X and Li, Q and Yang, W and Zhang, X and Gu, L},
title = {Acacetin targets SNX5 to promote autophagy degradation of NLRP3 inflammasome against cognitive impairment in Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118103},
doi = {10.1016/j.bcp.2026.118103},
pmid = {42178051},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) is a chronic, low-grade inflammatory neurodegenerative disorder. Inhibiting the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a potential therapeutic strategy for AD, but no approved NLRP3-specific inhibitors are available for clinical use, and current agents often cause significant side effects despite their anti-inflammatory benefits. Acacetin, is a flavonoid compound that can penetrate the blood-brain barrier, with potential for treating AD.The purpose of this study is to clarify the relationship between the anti-AD effect of acacetin and its mechanism of inhibiting NLRP3.acacetin improved cognitive function and reduced neuronal damage in 3xTg mice. Further Acacetin directly binds to sorting nexin-5 (SNX5) and upregulates its expression. This, in turn, activates autophagy to degrade the NLRP3 inflammasome, alleviates inflammationin HT22 cells and BV2 cells. These findings suggest that Acacetin can exert an anti-AD effect by targeting SNX5 to activate autophagy and promote the degradation of the NLRP3 inflammasome, which underscore the importance of targeting SNX5 to suppress NLRP3 inflammasome activation in AD treatment.},
}

@article {pmid42178053,
year = {2026},
author = {Elkabes, S},
title = {Sexually dimorphic roles of toll-like receptors in the central nervous system.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106830},
doi = {10.1016/j.bbi.2026.106830},
pmid = {42178053},
issn = {1090-2139},
abstract = {Many neurological and psychiatric diseases and disorders show sex differences in prevalence, incidence, disease manifestation and response to treatment. Yet, historically, most clinical and pre-clinical studies have been conducted disproportionately or exclusively in male subjects. In recent years, this research bias has been increasingly addressed through human and animal studies where both sexes are appropriately represented. These investigations have identified sex-specific disease mechanisms driven by a combination of distinct genetic, anatomical, physiological, hormonal and neural factors in males and females. Sexual dimorphism in immune function has long been recognized. Toll-like receptors (TLRs), important mediators of the innate immune response to pathogens and endogenous danger signals, play sex-biased roles in peripheral immunity. Toll-like receptors are also expressed in cells intrinsic to the central nervous system (CNS). They initiate, not only neuroinflammation in CNS infections and disease and injuries, but also influence neurodevelopment and normal aging. Emerging evidence indicates that TLRs expressed in CNS cells contribute to neural pathology in a sex-specific manner, a research area that warrants further investigations. The aim of the present review is to highlight the sex-specific contribution of TLRs expressed in the CNS to chronic pain, neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's Disease and psychiatric disorders including major depressive disorder (MDD). Major findings are highlighted, essential concepts, controversies and knowledge gaps are discussed, and potential future directions are proposed. Attention is drawn to the importance of advancing this research area given that neuroinflammation is a key player in many CNS pathologies and TLRs are the essential drivers of neuroinflammation.},
}

@article {pmid42178096,
year = {2026},
author = {Roblin, L and Sampson, H and Murillo, I and Lake, R and Yasui, L and Hastings, ML and Wallace, DG},
title = {Evaluation of open field movement organization and spatial orientation in 5xFAD mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {150393},
doi = {10.1016/j.brainres.2026.150393},
pmid = {42178096},
issn = {1872-6240},
abstract = {Wandering behavior or becoming lost in familiar environments is frequently observed during progression of Alzheimer's Disease (AD) and may be a possible prodromal symptom of the disease but also is extremely dangerous for those suffering from this neurodegenerative disease. The accumulation of amyloid-beta peptide (Aβ) has been implicated in the neuropathology and cognitive deficits associated with AD. This study investigated changes in open field movement organization in a 5xFAD mouse model of AD that and the deposition of amyloid pathology. Mouse open field behavior was collected under dark and light conditions at three, six, nine, and twelve months of age. The resulting pattern of genotype differences consisted of a motor deficit rather than impaired use of self-movement or environmental cues. This work establishes a foundation for future studies to investigate the efficacy of therapeutic interventions.},
}

@article {pmid42178203,
year = {2026},
author = {Suomi, T and Kettunen, J and Pusa, T and Elo, LL},
title = {Clarifying the scope and capabilities of ROTS in differential expression analysis.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag335},
pmid = {42178203},
issn = {1367-4811},
abstract = {SUMMARY: Recently, Anwar et al. introduced a method combining the ROTS reproducibility optimisation procedure with empirical Bayes variance estimation from limma. Here, we clarify several methodological aspects to support accurate interpretation of the results. We emphasise that ROTS is a general reproducibility optimisation framework rather than a single statistical test and demonstrate that benchmarking outcomes in the reported spike-in case studies are highly sensitive to analysis and evaluation choices. Furthermore, our reanalyses of the spike-in datasets do not support the reported conclusions, and we were unable to reproduce the results of the clinical Alzheimer's disease case study. These findings highlight the importance of transparent benchmarking practices and careful interpretation of comparative results.

The ROTS package is available through Bioconductor. The reanalyses were performed using the original code, with the minimal additions described in the manuscript.},
}

@article {pmid42178337,
year = {2026},
author = {Abaspour, N and Roghani, M and Bagheri, M and Khalili, M},
title = {Pioglitazone protects against trimethyltin hippocampal injury by reducing pyroptosis, mitochondrial dysregulation and ER stress.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54103-0},
pmid = {42178337},
issn = {2045-2322},
support = {522458//shahed University/ ; },
abstract = {Hippocampus-specific neurotoxic trimethyltin (TMT) is routinely used to mimic a reliable murine phenotype of neurodegeneration as well as cognitive loss and is accordingly appropriate to analyze pathogenesis of the prevalent neurodegenerative disorders, i.e. Alzheimer's disease (AD), and to examine the effectiveness of novel therapeutics. Antidiabetic medication pioglitazone has exhibited neuroprotective effects with promising clinical indications for neurodegeneration-based illnesses. This study was accomplished for studying the neuroprotective effect of pioglitazone against TMT-initiated cognitive decline and allied hippocampal neurodegeneration. For this purpose, rats received intraperitoneal TMT (8 mg/kg) to generate a model of AD-like neurodegeneration and subsequently had oral daily administration of pioglitazone for 3 weeks (20 mg/kg). The acetylcholinesterase inhibitor and certified anti-AD drug donepezil (4 mg/kg) was similarly used as a positive control medicine. Pioglitazone treatment was accompanied by lower cognitive deficits in novel object recognition test and Barnes maze paradigm in addition to mitigation of astrogliosis severity with glial fibrillary acidic protein (GFAP) as its specific indicator and lower CA1 neuronal loss. Furthermore, pioglitazone partially normalized hippocampal factors of oxidative stress and neuroinflammation together with downregulation of pyroptotic parameters comprising caspase 1 and NLR family pyrin domain containing 3 (NLRP3). Moreover, less activity of acetylcholinesterase (AChE) and greater quantity of mitochondrial health-allied factors comprising peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), mitochondrial membrane potential (MMP), mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor γ (PPARγ) were likewise detected after pioglitazone treatment. These advantageous properties of pioglitazone were accompanied by inferior quantity of specific AD-allied markers comprising presenilin1 (PSEN1) and hyperphosphorylated tau (p-tau) as well as downregulation of endoplasmic reticulum (ER) stress, as observed by lower levels of PKR-like ER kinase (PERK), C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), and inositol-requiring enzyme 1α (IRE1α). While anti-AD donepezil treatment was associated with improvement of cognitive function, however, it was not capable to significantly yield most advantageous effects of anti-diabetic PPARg agonist pioglitazone. This study disclosed the underlying pathways for neuroprotective effect of pioglitazone in TMT neurodegeneration and AD-like phenotype.},
}

@article {pmid42178415,
year = {2026},
author = {Deng, C and Zhu, M and Yuan, J and Yin, T and Chen, H and Meng, S},
title = {Catalpol and tetramethylpyrazine relieve Alzheimer's disease by facilitating AQP4 protein expression and polarized distribution in hippocampal astrocytes via inducing the STAT3-mediated UCHL1 expression.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42178415},
issn = {1432-1912},
support = {20220213//Shanghai Sixth People's Hospital Medical Service Level Improvement Project Clinical Medical Technical Backbone Team Cultivation Project/ ; ZY(2021-2023)-0205-04//Three-year Action Plan (2021-2023) of Shanghai Municipality for Further Accelerating the Inheritance, Innovation, and Development of Traditional Chinese Medicine/ ; ZY(2021-2023)-0302//Construction of East China Area and Municipal TCM Specialist Disease Alliance/ ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder leading to dementia. This study investigated the effects of catalpol and tetramethylpyrazine (CT) on AD. AD mice were treated with CT, TGN020, 6RK73, and Stattic. The Morris water maze task was employed to assess spatial learning and memory. Histological staining was used to evaluate hippocampal neuronal damage, Aβ1-40 clearance, and AQP4 protein distribution in the hippocampus. An AD cell model was established by inducing Aβ1-42 in mouse astrocytes, followed by CT, 6RK73, and Stattic treatments. UCHL1 siRNA was transfected into astrocytes, and ubiquitination analysis was conducted. Gene expression was assessed via qRT-PCR and Western blot. CT improved spatial learning and memory in AD mice, mitigated hippocampal neuronal damage, enhanced Aβ1-40 clearance, increased UCHL1 and p-STAT3/STAT3 expression, and promoted AQP4 protein expression and its polarized distribution in the hippocampus. The improvement in spatial learning, memory, and hippocampal neuronal damage was diminished by TGN020. 6RK73 inhibited CT-induced AQP4 expression and its polarized distribution in hippocampal astrocytes. Stattic counteracted CT-induced upregulation of UCHL1 in the hippocampus. UCHL1 facilitated AQP4 deubiquitination. Silencing UCHL1 or treating with 6RK73 blocked CT-induced AQP4 expression and its polarized distribution in Aβ1-42-treated astrocytes. Stattic abolished CT-induced UCHL1 expression in Aβ1-42-treated astrocytes. CT likely promotes STAT3 phosphorylation, enhancing UCHL1 expression, which in turn facilitates AQP4 expression and its polarized distribution in hippocampal astrocytes, providing therapeutic benefits in AD. These findings suggest CT as a potential therapeutic agent for AD.},
}

@article {pmid42178432,
year = {2026},
author = {Khobrani, M and Al-Kuraishy, HM and Hussein, NR and Mustafa, AM and Batiha, GE},
title = {Neurosteroid-Mediated Neuroprotection via mTORC1/AMPK/BDNF Signaling Pathway in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42178432},
issn = {1559-1182},
mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; Humans ; *Brain-Derived Neurotrophic Factor/metabolism ; *Signal Transduction/drug effects ; Animals ; *Neuroprotection/drug effects ; *AMP-Activated Protein Kinases/metabolism ; *Mechanistic Target of Rapamycin Complex 1/metabolism ; *Neurosteroids/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide. AD is a neurodegenerative disease associated with progressive synaptic dysfunction, neuronal loss, and cognitive impairment. Current pharmacological therapies for AD offer only symptomatic relief and fail to halt or reverse the progression of the disease. It has been shown that neurosteroids (NSs), the endogenous modulators synthesized within the central nervous system (CNS), have emerged as promising therapeutic candidates in the management of AD by regulating of neuronal function, synaptic plasticity, and neurogenesis. Growing evidence suggests that NSs, particularly allopregnanolone (AP) and related analogues, exert neuroprotective effects by attenuating amyloid-β (Aβ) accumulation, reducing tau hyperphosphorylation, restoring of mitochondrial function, and suppressing of neuroinflammation. Importantly, NSs modulate key intracellular pathways which implicated in AD pathogenesis, such as mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and brain-derived neurotrophic factor (BDNF). Interestingly, NSs attenuate Aβ- and tau-induced neurotoxicity and neurodegeneration by enhancing neuroprotective autophagy, activating AMPK/BDNF signaling, and suppressing the mTOR signaling pathway. However, the exact role of NSs in relation to the mTOR/AMPK/BDNF signaling axis in AD is not fully explained. Thus, this review synthesizes current knowledge on the molecular mechanisms through which NSs influence the mTORC1/AMPK/BDNF signaling axis, highlighting their therapeutic potential in mitigating AD neuropathology. Understanding the multifaceted actions of NSs may pave the way for novel neuroprotective strategies and future clinical interventions in AD management.},
}

*Alzheimer Disease/metabolism/drug therapy/pathology
Humans
*Brain-Derived Neurotrophic Factor/metabolism
*Signal Transduction/drug effects
Animals
*Neuroprotection/drug effects
*AMP-Activated Protein Kinases/metabolism
*Mechanistic Target of Rapamycin Complex 1/metabolism
*Neurosteroids/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use

@article {pmid42178577,
year = {2026},
author = {Ruthirakuhan, M and Mills, M and Rosenberg, P and Haughey, N and Mintzer, J and Craft, S and Herrmann, N and Lerner, AJ and Levey, AI and Padala, PR and Porsteinsson, A and van Dyck, CH and Shade, D and Lanctôt, KL},
title = {Uncovering lipid biomarkers linked to methylphenidate efficacy in treating apathy in Alzheimer's disease: insights from the ADMET 2 trial.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02055-y},
pmid = {42178577},
issn = {1758-9193},
support = {R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Apathy is a prevalent neuropsychiatric symptom (NPS) in Alzheimer's disease (AD), linked to functional impairment and reduced quality of life. The Apathy in Dementia Methylphenidate Trial 2 (ADMET-2) found methylphenidate (MPH) had modest efficacy for treating apathy, but treatment responses varied. MPH blocks dopamine and noradrenaline transporters, inhibiting dopamine and noradrenaline reuptake. Lipids are closely tied to monamine transporter function through their structural and signaling roles in neurotransmission, neuroinflammation, and synaptic plasticity. This study aimed to identify lipid species associated with MPH response and explore lipid pathway disruptions in responders versus non-responders.

METHODS: Participants from ADMET-2 with baseline lipidomic data were included. Responders were defined by a ≥4-point improvement on the Neuropsychiatric Inventory Apathy subscale (NPI-A), or moderate-to-marked improvement on the ADCS-Clinicians Global Impression-Change (ADCS-CGIC). Baseline plasma samples underwent lipidomic profiling. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) in the MPH group was used to identify lipid species distinguishing responders from non-responders. Model performance was evaluated by area under the curve (AUC). Identified lipid species were analyzed in MetaboAnalyst for pathway enrichment. A secondary analysis in the placebo group assessed specificity of findings to MPH.

RESULTS: Of the 43 MPH-treated participants, 28 were NPI-apathy responders, and 10 were ADCS-CGIC responders. The PLS-DA model achieved robust discrimination between responders and non-responders (NPI-apathy: AUC = 0.82 +/- 0.05; ADCS-CGIC: AUC=0.84 +/- 0.07). Pathway analysis revealed disruptions in ceramide, phosphosphingolipid, and glycosphingolipid metabolism for NPI-apathy responders, and ceramide and glycosphingolipid metabolism for ADCS-CGIC responders. In 55 placebo-treated participants (30 NPI-apathy responders), an AUC of 0.79 +/- 0.05 was achieved, with pathway analysis indicating disruption in glycosphingolipid metabolism only.

CONCLUSIONS: This study demonstrates the utility of lipidomic profiling in identifying biomarkers of response to MPH in AD patients with apathy. The identified lipidomic species are broadly related to monoamine transporter function, reflecting their role in neurotransmission and synaptic plasticity. While glycosphingolipid metabolism appears broadly linked to changes in apathy, disruptions in ceramide and phospholipid metabolism may be specific to MPH treatment. Further study of these pathways may offer insights into the molecular mechanisms underlying apathy and treatment response, and could inform future biomarker-guided interventions.},
}

@article {pmid42178678,
year = {2026},
author = {Hattori, Y},
title = {Neurovascular unit failure as the opening chapter of dementia pathogenesis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452178},
doi = {10.1177/13872877261452178},
pmid = {42178678},
issn = {1875-8908},
abstract = {Neurovascular dysfunction is increasingly recognized as a central feature of dementia pathogenesis in the early or even preclinical stage, rather than merely a downstream effect of amyloid-tau neurodegeneration. Based on multimodal clinical evidence showing that cerebrovascular dysregulation can precede amyloid-β accumulation, this commentary emphasizes three converging lines: (1) hippocampal blood-brain barrier breakdown as an early, potentially amyloid-/tau-independent event, (2) vascular-first/parallel two-hit frameworks linking vascular risk factors to subsequent proteinopathy, and (3) early neurovascular coupling failure and chronic hypoperfusion as upstream drivers. Integrating blood-brain barrier and hemodynamic biomarkers may facilitate earlier biological subtyping and prevention.},
}

@article {pmid42178714,
year = {2026},
author = {Zeamer, AL and Lai, Y and Loew, E and Sanborn, V and Tracy, M and Jo, C and Ferdinand, D and Ward, DV and Bhattarai, SK and Drake, J and McCormick, BA and Bucci, V and Haran, JP},
title = {Microbiome functional gene pathways are indicative of cognitive performance in older adults at risk for Alzheimer's disease.},
journal = {Gut microbes},
volume = {18},
number = {1},
pages = {2676162},
doi = {10.1080/19490976.2026.2676162},
pmid = {42178714},
issn = {1949-0984},
mesh = {Humans ; *Alzheimer Disease/microbiology ; *Gastrointestinal Microbiome/genetics ; Aged ; Female ; Male ; *Cognition ; Middle Aged ; *Cognitive Dysfunction/microbiology ; Aged, 80 and over ; *Bacteria/classification/genetics/isolation & purification/metabolism ; Cohort Studies ; Metagenomics ; Metabolic Networks and Pathways/genetics ; },
abstract = {Disturbances in the gut microbiome are increasingly correlated with neurodegenerative disorders, including Alzheimer's disease. Multiple lines of emerging evidence are consistent with the microbiome's involvement in disease pathology in AD by triggering or potentiating systemic and neuroinflammation, thereby influencing disease pathology through the "microbiota-gut-brain axis." Currently, the copathologies contributing to cognitive decline and symptomatic progression in AD remain unknown and understudied. Changes in the gut microbiome composition may offer clues to potential systemic physiologic and neuropathologic changes that contribute to cognitive decline. Here, we recruited a cohort of 260 older adults (aged 60 y or older) living in the community and followed them over time, tracking objective measures of cognition, clinical information, and gut microbiome samples. Subjects were classified as healthy controls, exhibiting mild cognitive impairment, or having dementia based on clinical assessments. Using metagenomic sequencing and gene pathway analyses, we found that certain microbial-encoded metabolic pathways correlated with worse cognitive performance. Specifically, genes involved in the urea cycle, polyamine synthesis, or the metabolism of methionine and cysteine predicted worse cognitive performance. Our study suggests that the gut microbiome composition may be linked to cognitive impairment along the AD continuum and points to microbial metabolic pathways that may potentiate disease.},
}

Humans
*Alzheimer Disease/microbiology
*Gastrointestinal Microbiome/genetics
Aged
Female
Male
*Cognition
Middle Aged
*Cognitive Dysfunction/microbiology
Aged, 80 and over
*Bacteria/classification/genetics/isolation & purification/metabolism
Cohort Studies
Metagenomics
Metabolic Networks and Pathways/genetics

@article {pmid42178732,
year = {2026},
author = {Liu, C and Qin, X and Talisa, VB and Wang, J},
title = {Heterogeneous causal mediation analysis using Bayesian additive regression trees.},
journal = {Biometrics},
volume = {82},
number = {2},
pages = {},
doi = {10.1093/biomtc/ujag079},
pmid = {42178732},
issn = {1541-0420},
support = {R21AG087057/NH/NIH HHS/United States ; R01AG080590/NH/NIH HHS/United States ; S10OD028483/NH/NIH HHS/United States ; 2337612//National Science Foundation Faculty Early Career Development Program (CAREER) Award/ ; R305D200031//U.S. Department of Education Institute of Education Sciences Grant/ ; },
mesh = {Bayes Theorem ; Humans ; Computer Simulation ; Alzheimer Disease/genetics/pathology ; Regression Analysis ; *Causality ; *Mediation Analysis ; Apolipoproteins E/genetics ; Models, Statistical ; Genotype ; Biometry/methods ; Cognition ; },
abstract = {Causal mediation analysis provides insights into the mechanisms through which treatments affect outcomes. While mediation effects often vary across individuals, most existing methods focus solely on population-average effects, overlooking individual-level heterogeneity. To address this limitation, we propose a Bayesian regression tree ensemble method that flexibly models nonlinear relationships and captures treatment-by-mediator interactions in the mediation process. Using hierarchical posterior sampling, our approach provides credible intervals with nominal coverage rates for inferring heterogeneous mediation effects. Additionally, we leverage regression tree summaries to identify subgroups with distinct mediation effects and employ SHapley Additive exPlanation values to highlight key moderators and their influence on the mediation process. Comprehensive simulations demonstrate the method's accuracy in estimating and inferring heterogeneous mediation effects. Finally, we apply our method to investigate the heterogeneous mediation role of Alzheimer's disease pathology burden in the effect of apolipoprotein E genotype on late-life cognition.},
}

Bayes Theorem
Humans
Computer Simulation
Alzheimer Disease/genetics/pathology
Regression Analysis
*Causality
*Mediation Analysis
Apolipoproteins E/genetics
Models, Statistical
Genotype
Biometry/methods
Cognition

@article {pmid42178834,
year = {2026},
author = {Vidoni, ED and Mahnken, JD and Morris, JK and Wilkins, HM and Almaghraby, A and Honea, RA and Billinger, SA and Brunette, A and Parks, A and Perales-Puchalt, J and Hunt, SL and Baker, J and Arthur, AK and Fikru, SA and Cox, K and Burns, JM and Townley, RA},
title = {Operationalizing AD Biomarker Return of Research Results: Methods from the KU ADRC.},
journal = {Biopreservation and biobanking},
volume = {},
number = {},
pages = {19475535261447837},
doi = {10.1177/19475535261447837},
pmid = {42178834},
issn = {1947-5543},
abstract = {INTRODUCTION: Widespread implementation of Alzheimer's disease (AD) biomarkers in research settings introduces new opportunities and challenges for managing and returning complex, multi-modal testing results to research participants.

OBJECTIVES: To describe a structured, participant-centered biomarker data management and return of results workflow developed at a U.S. Alzheimer's Disease Research Center (ADRC), and to provide preliminary data on participant and clinician experience with return of results.

METHODS: We developed an automated, interdisciplinary workflow to integrate multimodal biomarker data (neuroimaging, fluid, and genetics) into research consensus diagnostic conferences and individualized participant Return of Results reports. To evaluate feasibility and participant experience, we conducted a non-randomized study in which participants receiving biomarker results rated anxiety, depression, and decision regret within one week and at 3-month follow-up.

RESULTS: The workflow was implemented using non-proprietary tools, with semi-automated data aggregation and nightly updates. Survey data indicated statistically significant changes in anxiety and depression following biomarker return of results, though the clinical relevance of these changes remains unclear, highlighting opportunities to improve utility.

CONCLUSIONS: Using and returning biomarker results is feasible, scalable, and well-tolerated within a research setting. This model may guide broader adoption of AD biomarker management and return of results to participants in future study designs.},
}

@article {pmid42178898,
year = {2026},
author = {Sousa, BP and Santos, KMD and Antunes, VR},
title = {Chemogenetic Stimulation of the Dorsal Motor Nucleus of the Vagus Mitigates Autonomic Dysfunction and Memory Decline in Rat Model of Alzheimer-Like Disease.},
journal = {Acta physiologica (Oxford, England)},
volume = {242},
number = {7},
pages = {e70261},
doi = {10.1111/apha.70261},
pmid = {42178898},
issn = {1748-1716},
support = {2023/08762-9//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 140359/2020-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 305570/2023-4//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
mesh = {Animals ; Male ; *Alzheimer Disease/physiopathology ; Female ; Rats ; *Memory Disorders/physiopathology/therapy ; Disease Models, Animal ; Rats, Long-Evans ; Rats, Transgenic ; *Vagus Nerve ; *Autonomic Nervous System Diseases/physiopathology ; Cholinergic Neurons ; Hippocampus/metabolism ; Chemogenetics ; },
abstract = {AIM: To test the hypothesis that Alzheimer-like metabolic neurodegeneration rat model leads to an autonomic dysfunction, memory impairment, and hippocampal amyloid pathology and that long-term chemogenetic stimulation of the dorsal motor nucleus of the vagus reverses these alterations.

METHODS: Male and female transgenic Long Evans rats received intracerebroventricular streptozotocin to induce sporadic Alzheimer-like pathology. Cardiovascular parameters and sympathetic and parasympathetic tone were evaluated in conscious animals. Episodic-like memory was assessed using the novel object recognition test. Hippocampal amyloid density was quantified by immunofluorescence. In male rats, cholinergic neurons of the dorsal motor nucleus of the vagus were selectively activated for 15 days using a chemogenetic approach, and autonomic, cognitive, and neuropathological outcomes were reassessed.

RESULTS: In male rats, the intracerebroventricular streptozotocin induced a significant increase in cardiac sympathetic tone, reduced object discrimination index performance, and increased hippocampal amyloid density compared with vehicle-treated controls, without altering mean arterial pressure or heart rate. Female rats showed no significant autonomic, memory, or hippocampal alterations at the same time point. Long-term chemogenetic stimulation of cholinergic neurons in the dorsal motor nucleus of the vagus in male rats reduced sympathetic tone to control levels, improved recognition memory, and attenuated hippocampal amyloid density compared with the non-stimulated control group.

CONCLUSION: These findings demonstrate a link between autonomic imbalance, memory dysfunction, and hippocampal amyloid pathology, and selective stimulation of the dorsal motor nucleus of the vagus restores autonomic balance and improves episodic-like memory and neuropathological outcomes, identifying this brainstem nucleus as a physiologically relevant therapeutic target in Alzheimer-related neuropathology.},
}

Animals
Male
*Alzheimer Disease/physiopathology
Female
Rats
*Memory Disorders/physiopathology/therapy
Disease Models, Animal
Rats, Long-Evans
Rats, Transgenic
*Vagus Nerve
*Autonomic Nervous System Diseases/physiopathology
Cholinergic Neurons
Hippocampus/metabolism
Chemogenetics

@article {pmid42178983,
year = {2026},
author = {Liu, JQ and Liu, H and Sun, YX and Li, Y and Liu, X and Wang, LQ and Yang, Z and Fu, Q and Xu, X and Chen, J and Zhang, Y and Zhou, J and Le, W and Cui, M and Liang, Y},
title = {Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e16846},
doi = {10.1002/advs.202516846},
pmid = {42178983},
issn = {2198-3844},
support = {U1967221//National Natural Science Foundation of China/ ; 32071212//National Natural Science Foundation of China/ ; U1967221//National Natural Science Foundation of China/ ; 22022601//National Natural Science Foundation of China/ ; 2024YFA1307300//National Key Research and Development Program of China/ ; 2023ZD0507202//National Major Science and Technology Projects of China/ ; },
abstract = {Cytoplasmic mislocalization and aggregation of transactive response DNA-binding protein-43 (TDP-43) is a common pathological feature of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease with TDP-43 pathology (AD-TDP); the exact role of protein disulfide isomerase (PDI), an enzyme with chaperone activity, in modulating the pathological behavior of TDP-43 is unknown. In this study, we report that wild-type PDI, through its specific interaction with TDP-43, markedly attenuates phase separation of TDP-43, competitively displaces G3BP1 to disassemble TDP-43/G3BP1 condensates, and further counteracts the pathological mislocalization, abnormal phosphorylation, and pathological aggregation of TDP-43 through the b' domain of the enzyme. Ultimately, this alleviates mitochondrial damage and neuronal toxicity caused by TDP-43 aggregation and suppresses UNC13A cryptic splicing in stressed cells. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS and AD-TDP patients. These findings not only provide new insights into the pathogenic mechanisms of TDP-43 in neurodegenerative diseases such as ALS and AD-TDP, but also propose PDI as a potential therapeutic target.},
}

@article {pmid42179001,
year = {2026},
author = {Rocha, IO and Delgado, CP and Nogara, PA and Rocha, JBT and Martins, MAP and Zanatta, N and Bonacorso, HG},
title = {Promising Flavonoid-Fused Aminoquinolines as Synthetic Alzheimer's Disease Models: Design, Synthesis, Anticholinesterase Activity, ADMET and Molecular Docking.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {27},
number = {10},
pages = {e70391},
doi = {10.1002/cbic.70391},
pmid = {42179001},
issn = {1439-7633},
support = {Code 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 23038.004173/2019-93//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 043/2019//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 88887511828/2020-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; Propesp 08-2023:PE08230723/026//Instituto Federal Sul-riograndense/ ; 305.379/2020-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Molecular Docking Simulation ; Humans ; Acetylcholinesterase/metabolism/chemistry ; *Drug Design ; *Aminoquinolines/chemistry/chemical synthesis/pharmacology ; *Flavonoids/chemistry/pharmacology ; Butyrylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; Molecular Structure ; },
abstract = {An efficient one-pot, two-step [4 + 2] cyclocondensation reaction of (±)-2-phenylchroman-4-ones (1) with various scaffolds of 2-aminobenzonitriles (2) was employed using AlCl3 as the catalyst in the presence of toluene as a solvent under conventional thermal heating. This method was used to synthesize a series of six novel examples of (±)-7-amino-6-aryl-6H-chromeno[4,3-b]quinolines (3), which were designed as potential cholinesterase inhibitors. Subsequently, the new chromeno[4,3-b]quinolines were evaluated for their AChE and BChE inhibitory activity and subjected to molecular docking studies. In vitro cholinesterase assays and in silico docking demonstrated that all newly modified tacrine analogs 3 exhibited higher HsBChE inhibitory activity compared to HsAChE. Specifically, the most effective human cholinesterase inhibitor was the compound (±)-7-amino-6-phenyl-6H-chromeno[4,3-b]quinoline (3aa), with an IC50 of 2.73 μM for HsAChE and 0.096 μM for HsBChE. These findings suggest that compound 3aa is a promising candidate for further assessment in synthetic Alzheimer's disease models.},
}

*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology/metabolism
*Alzheimer Disease/drug therapy/metabolism
Molecular Docking Simulation
Humans
Acetylcholinesterase/metabolism/chemistry
*Drug Design
*Aminoquinolines/chemistry/chemical synthesis/pharmacology
*Flavonoids/chemistry/pharmacology
Butyrylcholinesterase/metabolism/chemistry
Structure-Activity Relationship
Molecular Structure

@article {pmid42179062,
year = {2026},
author = {Li, D and Dai, W and Li, X and Li, H and Li, L and Zhao, Y and Wang, X and Zhang, L},
title = {Amyloid-β suppresses oligodendrocyte differentiation in adult oligodendrocyte precursor cells (OPCs), with inflammatory gene changes distinguishing it from developmental OPCs.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451403},
doi = {10.1177/13872877261451403},
pmid = {42179062},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) involves white matter deterioration, but how amyloid-β (Aβ) affects oligodendrocyte lineage cells at different maturation stages remains unclear.ObjectiveTo determine whether Aβ impairs oligodendrocyte differentiation and myelination in adult oligodendrocyte precursor cells (OPCs) and to identify molecular correlates via RNA-seq.MethodsOligodendrocyte lineage cells were examined in plaque-associated regions of 8-month-old 5x familial Alzheimer's disease (FAD) mice by immunohistochemistry. Primary OPCs from neonatal and adult rats were cultured with or without amyloid-β1-42 oligomers (oAβ42) to assess differentiation. Myelination was evaluated in organotypic slice cultures. RNA-seq and qPCR were performed to identify oAβ42-induced gene expression changes.ResultsIn 5xFAD mice, Olig2[+] cells were reduced near plaques, with CC1[+] mature oligodendrocytes showing a pronounced decrease, while PDGFRα[+] OPCs remained unchanged. In vitro, oAβ42 inhibited differentiation of both neonatal and adult OPCs, with adult OPCs exhibiting intrinsically slower maturation. Slice cultures revealed selective hypomyelination (reduced myelin basic protein) after oAβ42 treatment. RNA-seq showed that oAβ42 induced a distinct transcriptomic profile in adult OPCs, with upregulated genes enriched in immune/inflammatory pathways. Core inflammatory genes Nr4a1 and Tnf were significantly upregulated, validated by qPCR.ConclusionsoAβ42 plaque pathology is associated with oligodendrocyte maturation blockade. Aβ impairs OPC differentiation in purified cultures accompanied by inflammatory transcriptional changes. These findings highlight oligodendrocyte dysfunction in AD white matter pathology and reveal a specific oAβ42 response in adult OPCs.},
}

@article {pmid42179067,
year = {2026},
author = {Wang, X and Liu, T and Guo, Y and Huang, M and Lv, C and Huang, W and Zhang, K and Chen, H and Chen, F},
title = {Cerebral blood flow-iron susceptibility decoupling links cognition, amyloid pathology, and neuroinflammation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452664},
doi = {10.1177/13872877261452664},
pmid = {42179067},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by decreased cerebral blood flow (CBF) and abnormal iron deposition, whereas their relationship remains unclear.ObjectiveTo investigate the spatial pattern of CBF-iron deposition coupling across the AD spectrum and its associations with cognition, plasma biomarkers, and inflammation.Methods34 AD dementia, 86 mild cognitive impairment (MCI), and 26 cognitively normal (CN) were enrolled. Voxel-wise CBF-susceptibility coupling was calculated using three-dimensional pseudocontinuous arterial spin labeling and quantitative susceptibility mapping (QSM). Whole-brain region-based analyses of CBF, QSM, and CBF-susceptibility coupling were subsequently performed. Correlation and mediation analyses were conducted to evaluate the relationships of CBF-susceptibility coupling with plasma biomarkers, inflammatory factors, and cognitive function.ResultsCBF was significantly reduced in the AD dementia group and MCI group. No significant group differences were observed in QSM susceptibility. The AD dementia group showed significantly lower CBF-susceptibility coupling in multiple brain regions than CN and MCI groups, which was positively correlated with Mini-Mental State Examination (MMSE), Animal Fluency Test scores, and the plasma amyloid-β 42/40 (Aβ42/Aβ40) ratio. In the MCI group, coupling values were negatively correlated with IL-2 levels. CBF-susceptibility coupling in the bilateral supplementary motor areas of AD patients partially mediated the association between Aβ42/Aβ40 ratio and MMSE.ConclusionsCBF-susceptibility coupling is significantly decreased in AD dementia and appears more sensitive than single-modality measures, and is associated with cognitive decline, amyloid pathology, and inflammation. These findings suggest that disrupted CBF-iron metabolism coupling may be a pathogenic mechanism underlying cognitive impairment in AD, possibly driven by early neuroinflammation.},
}

@article {pmid42179068,
year = {2026},
author = {Kanani, K and Ramakrishnan, P and Neupane, S and Misra, M and Balmer-Brown, K and Halteman, S and Warrick, T and , },
title = {Environmental risk and genetic susceptibility in Alzheimer's disease: Impacts on cognitive function and biomarkers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451855},
doi = {10.1177/13872877261451855},
pmid = {42179068},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) involves interactions among genetic, environmental, and lifestyle factors, yet the contribution of environmental exposures to cognitive decline and biomarker changes remains unclear. Detoxification genes such as EPHX1 may influence susceptibility to environmental neurotoxicants.ObjectiveTo evaluate associations between environmental risk, cognitive outcomes, and AD biomarkers, and to examine potential contributions of detoxification genes.MethodsWe analyzed 5101 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) across four study phases. Environmental exposure was summarized using a composite Environmental Risk Score (ERS) derived from Rural-Urban Continuum Codes, Rural-Urban Commuting Area codes, Risk-Screening Environmental Indicators, and occupational exposure. Cognitive outcomes included Mini-Mental State Examination, Clinical Dementia Rating, Montreal Cognitive Assessment, Neuropsychological Test Battery, Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Executive Dysfunction Cognitive Assessment. Biomarkers included PET amyloid/tau, MRI hippocampal volume, and cerebrospinal fluid amyloid-β, tau, and neurofilament light chain. Multivariable regression models adjusted for sociodemographic factors and APOE ε4 carrier status.ResultsERS was significantly associated with CDR (β = -1.13E-07; 95% CI -1.98E-07, -2.75E-08; p = 0.00956) but not with other cognitive measures. EPHX1 showed a significant main effect on ADAS-Cog (β = 0.479; 95% CI 0.0305, 0.927; p = 0.0356). ERS × gene interaction terms were not significant. ERS was not associated with amyloid PET SUVR.ConclusionsEnvironmental risk showed limited associations with AD-related outcomes, while EPHX1 demonstrated a significant main effect on cognitive performance. Longitudinal studies are needed to clarify mechanisms linking environmental exposure and AD.},
}

@article {pmid42179069,
year = {2026},
author = {Zhang, T and He, M and Wang, Y and Gao, P and Xia, X and Li, J and Yin, Y and Zhao, G and Chen, O and Qu, M and Tang, Y and Qin, Q},
title = {Lipidomics reveals TREM2-associated dysregulation of plasma lipid metabolism in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450934},
doi = {10.1177/13872877261450934},
pmid = {42179069},
issn = {1875-8908},
abstract = {BackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is a genetic risk factor for Alzheimer's disease (AD). While TREM2 facilitates central nervous system lipid clearance, its influence on peripheral lipid metabolism remains unclear.ObjectiveTo investigate the association between plasma sTREM2 and peripheral lipid profiles in AD and to explore the mechanistic role of TREM2 in peripheral lipid regulation.MethodsWe conducted a cross-sectional study of 59 AD patients and 54 healthy controls and measured plasma biomarkers including sTREM2 as well as performed targeted lipidomics profiling. Mechanistic exploration was performed via plasma and hippocampal lipidomics in Trem2 knockout and APP/PS1 mice.ResultsPlasma sTREM2 levels were elevated in AD and were negatively correlated with the plasma p-tau217/Aβ42 ratio and p-tau217. Multivariate analysis revealed a distinct lipidomics signature in AD, in which 30 lipid species were significantly altered. We prioritized significantly altered biomarkers to inform a composite biomarker panel combining sTREM2 with a set of sphingomyelins, phosphatidylinositols, diacylglycerols, fatty acids, and cholesteryl esters, which showed strong discrimination between AD and controls (AUC = 0.93). In a mouse model of APP/PS1, we found that Trem2 knockout partially normalized plasma sphingomyelins and hexosylceramide levels. Finally, cross-tissue comparisons further suggested that TREM2 exerted distinct effects on peripheral sphingolipid metabolism that were less evident in hippocampal tissue.ConclusionsOur findings associate TREM2 with lipid dysregulation in AD and support development of a plasma sTREM2-lipid panel for patient classification.},
}

@article {pmid42179082,
year = {2026},
author = {Dong, L and Liu, C and Lv, X and Song, X and He, Y and Shi, F and Qian, Y and Liu, Y},
title = {Visualization of perivascular spaces in Alzheimer's disease using 5.0 T MRI: A preliminary study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451167},
doi = {10.1177/13872877261451167},
pmid = {42179082},
issn = {1875-8908},
abstract = {BackgroundPerivascular spaces (PVS) have been associated with neurodegenerative diseases such as Alzheimer's disease (AD); however, the added value of 5.0 T magnetic resonance imaging (MRI) for PVS visualization in AD remains unclear.ObjectiveThis study aimed to investigate the utility of 5.0 T MRI for PVS in AD patients and healthy controls (HCs).MethodsA total of 186 participants were enrolled, including 62 AD patients and 124 age- and sex-matched HCs. All AD patients underwent paired 3.0 T and 5.0 T MRI scans on the same day, while 62 HCs underwent only 3.0 T MRI and 62 HCs underwent only 5.0 T MRI. Axial T2-weighted imaging was used for PVS assessment. Evaluations included qualitative and quantitative analysis in the basal ganglia (BG) and centrum semiovale (CSO).ResultsIn AD patients, 5.0 T MRI demonstrated significantly higher PVS image quality scores and severity scores in the BG and CSO than 3.0 T MRI (p < 0.05). Quantitatively, 5.0 T MRI detected a greater PVS burden, evidenced by increased number, larger volume, longer length, and higher curvature of PVS in the bilateral BG (p < 0.001), and increased number and volume of PVS in the bilateral CSO (p < 0.05) compared to 3.0 T MRI. Furthermore, when compared to HCs using 5.0 T MRI, AD patients exhibited higher PVS severity scores and greater PVS burden in most regions than HCs (p < 0.05).Conclusions5.0 T high-resolution images provide superior image quality for PVS visualization and reveal more detailed morphological information of PVS in AD patients compared to 3.0 T MRI.},
}

@article {pmid42179083,
year = {2026},
author = {Aiello, EN and Cazzini, F and Moreschi, A and Curti, B and De Luca, G and Frisco, F and Saba, S and Patisso, V and Maranzano, A and Silani, V and Ticozzi, N and Verde, F and Poletti, B},
title = {The head turning sign "outside the clinic walls" in patients with mild cognitive impairment and dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452271},
doi = {10.1177/13872877261452271},
pmid = {42179083},
issn = {1875-8908},
abstract = {BackgroundIn clinical settings, the head turning sign (HTS) occurs when patients with cognitive complaints turn their head toward the accompanying person seeking assistance. Due to its nature, and unlike other non-canonical neurological signs of cognitive impairment, the HTS is likely to occur in ecological, daily-life scenarios too. However, this hypothesis has not been tested yet.ObjectiveTo assess the prevalence and clinical correlates of the "ecological HTS" (eHTS) in MCI and dementia due to chronic-degenerative etiologies.MethodsThis retrospective cohort included 112 patients with MCI/dementia due to Alzheimer's disease (AD; N = 71), frontotemporal lobar degeneration (N = 6), Lewy body disease (N = 6), chronic cerebrovascular diseases (CVD; N = 11), mixed (i.e., AD + CVD; N = 15) unspecified non-AD neurodegenerative etiologies (N = 3). We recorded the number of HTSs displayed by patients during the MMSE and inquired accompanying persons whether the HTS occurred in daily life too.ResultsThe overall prevalence of the eHTS in the cohort was 50%; its distribution was independent of demographics, disease severity (i.e., MCI versus dementia), and etiology. Within multiple logistic models, the presence of the eHTS + proved to be predicted both by lower scores on the Spatial Orientation subtest of the MMSE and by a higher number of HTSs during the execution of the MMSE. Moreover, a trend towards longer disease duration and the occurrence of the eHTS was found.ConclusionsIn MCI and dementia, the HTS is an ecologically valid non-canonical sign, frequently occurs in daily life too, associated with longer disease duration and spatial disorientation.},
}

@article {pmid42179084,
year = {2026},
author = {Kim, D and Jeong, H and Lim, HK and Ahn, SM and Song, M},
title = {Pharmacological targeting of the integrated stress response by 2BAct improves object recognition memory and reduces neuroinflammation in the 5xFAD model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450638},
doi = {10.1177/13872877261450638},
pmid = {42179084},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. The integrated stress response (ISR) contributes to impaired synaptic plasticity, neuronal dysfunction, and cognitive deficits in AD. However, research targeting the ISR as a therapeutic strategy for AD remains limited due to insufficient mechanistic insight.ObjectiveThis study aimed to evaluate the effects of 2BAct, an ISR inhibitor, on behavioral symptoms, amyloid-β (Aβ) and tau accumulation, and neuroinflammation in 5xFAD mice.MethodsTen-month-old 5xFAD mice received daily intraperitoneal (IP) injections of either 2BAct (10 mg/kg/day), donepezil (2 mg/kg/day; positive control), or vehicle for 23 consecutive days. Anxiety-like behavior and cognitive function were assessed using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Amyloid-β (Aβ), tau, and neuroinflammation markers were analyzed by immunofluorescence staining. ISR inhibition was evaluated by examining the phosphorylation level of eukaryotic initiation factor 2 alpha (eIF2α) using immunofluorescence staining and by analyzing ISR-related markers via RNA sequencing.Results2BAct treatment significantly improved object recognition performance and attenuated microglial activation and tau accumulation, without reducing Aβ burden. Reduced levels of phosphorylated eIF2α were also confirmed by immunofluorescence staining.ConclusionsThese findings suggest that 2BAct treatment improves cognitive performance and mitigates neuroinflammation while reducing tau accumulation. Although the therapeutic effects are limited, targeting the ISR with inhibitors such as 2BAct represents a potential therapeutic approach for AD. Further studies are required to elucidate the underlying molecular mechanisms and to address the limitations of ISR-based interventions.},
}

@article {pmid42179085,
year = {2026},
author = {Macoir, J and Lavoie, M and Laforce, R},
title = {Beyond language: A structured profile of number processing impairment in logopenic primary progressive aphasia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450931},
doi = {10.1177/13872877261450931},
pmid = {42179085},
issn = {1875-8908},
abstract = {BackgroundThe logopenic variant of primary progressive aphasia (lvPPA) is a language-led neurodegenerative syndrome commonly associated with Alzheimer's disease pathology and temporo-parietal degeneration. Although acalculia has been reported in lvPPA, numerical cognition has not been systematically investigated, and the specific profile of impairment remains poorly defined.ObjectiveTo characterize numerical cognition impairment in lvPPA using a comprehensive, theory-driven assessment battery and to examine its clinical relevance for diagnosis and cognitive characterization.MethodsFourteen individuals with lvPPA and twenty-eight demographically matched healthy controls completed the dCALQ, a standardized battery assessing number recognition and comprehension, number production (transcoding), and calculation. Participants also underwent global cognitive screening (Montreal Cognitive Assessment), language assessment (Detection Test for Language Impairments in Adults and the Aged), and measures of working memory and executive functioning. Group comparisons, intra-group domain analyses, correlation analyses, and receiver operating characteristic (ROC) analyses were performed.ResultsIndividuals with lvPPA showed significant impairments across all numerical domains compared with controls, with the most severe deficits in calculation, followed by transcoding, and milder impairment in number recognition and comprehension. Within the lvPPA group, performance differed significantly across domains, revealing a graded pattern of impairment. ROC analyses demonstrated excellent diagnostic accuracy for the dCALQ total score and strong discrimination for the calculation and transcoding domains.ConclusionsNumerical impairment is a robust and systematic feature of lvPPA rather than an incidental finding. The distinct numerical profile identified highlights the contribution of parietal-based cognitive dysfunction and supports the clinical utility of structured numerical assessment for cognitive characterization and diagnosis in dementia syndromes.},
}

@article {pmid42179089,
year = {2026},
author = {Tristão-Pereira, C and Casquero-Veiga, M and Malotaux, V and Quiroz, YT},
title = {Uncovering the causal link between cerebral glucose metabolism and cognitive function in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452181},
doi = {10.1177/13872877261452181},
pmid = {42179089},
issn = {1875-8908},
abstract = {Cerebral glucose metabolism is distinctly disrupted in Alzheimer's disease (AD), though its role in downstream cognitive decline remains unclear. Ueda et al. leverage Mendelian Randomization by integrating genetics, imaging and cognitive data to demonstrate that cerebral glucose metabolism is causally linked to cognitive performance. This approach lays the groundwork for novel therapeutic strategies by suggesting that metabolism-focused interventions may mitigate cognitive impairment in AD. Future studies should further integrate single-cell and multi-omics strategies to elucidate cellular and molecular pathways related to causal effects and explore the influence of co-pathologies and epigenetics on metabolic and cognitive performance.},
}

@article {pmid42179092,
year = {2026},
author = {Guilliams, C and Abner, E},
title = {Potential biases associated with reported parental history of dementia in the Alzheimer's Disease Research Center cohorts: Implications for secondary data analyses.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450630},
doi = {10.1177/13872877261450630},
pmid = {42179092},
issn = {1875-8908},
abstract = {AbstractBackgroundDeterminants of reported parental history of dementia among older adult research volunteers, and its relation to participation in brain aging studies, are incompletely understood.ObjectiveWe aimed to characterize older adults enrolled in Alzheimer's Disease Research Center (ADRC) cohorts by reported history of parental dementia according to age, APOE ε4 dose, sex, race, Hispanic ethnicity, education, and baseline cognitive status.MethodsData were drawn from the National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS). We included all participants who were age ≥ 65 at their most recent visit (N = 34,154). Participants were classified according to reported parental history of dementia (neither parent, mother only, father only, both parents, and unknown). Multinomial regression was used to estimate the adjusted odds ratios for reported parental history of dementia.ResultsDementia in at least one parent was reported by 40% of participants (n = 13,596), 52% (n = 17,881) reported that neither parent had dementia, and 8% (n = 2677) did not know. Participants reporting neither parent had dementia, or reported unknown history, were older, less educated, more likely to be minoritized, and were also most likely to be missing APOE genotype (28% and 37%, respectively) and to be diagnosed with cognitive impairment at baseline (62% and 75%, respectively).ConclusionsADRC participants who report no parental dementia history may represent a meaningfully different group of volunteers, and within this group there is also substantial heterogeneity among all of the characteristics of interest investigated, especially by race. These differences need to be carefully considered during secondary analyses of NACC UDS data.},
}

@article {pmid42179099,
year = {2026},
author = {Zhao, QF and Huang, LY and Zhu, YK and Hu, HY and Wang, HF and Zhang, W and Hu, H and Tan, L and , },
title = {YWHAG as a novel biomarker in Alzheimer's disease biological research framework.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450474},
doi = {10.1177/13872877261450474},
pmid = {42179099},
issn = {1875-8908},
abstract = {BackgroundYWHAG has been recognized as a promising biomarker for Alzheimer's disease (AD). However, the precise role of YWHAG within the revised 2024 diagnostic framework for AD remains unclear.ObjectiveOur study aimed to evaluate YWHAG with established biomarkers to delinea te the role of YWHAG and determine whether it could serve as a complementary biomarker within the 2024 diagnostic criteria.MethodsWe compared YWHAG with established biomarkers among 708 participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) across three domains: 1) diagnostic utility, 2) cross-sectional associations with clinical variables and brain structure, and 3) predictive value for clinical progression risk.ResultsOur results demonstrated the accuracy of YWHAG (AUC = 0.856) was comparable to that of FDG-PET (AUC = 0.912) and HVA (AUC = 0.879), but superior to that of T-tau (AUC = 0.796), NFL (AUC = 0.712), and GFAP (AUC = 0.617) in distinguishing AD versus controls. Moreover, YWHAG was consistently among the top three biomarkers most strongly associated with cognitive decline and brain atrophy, alongside HVA and FDG-PET. Furthermore, the YWHAG positive (Y+) group had a significantly higher risk of AD progression (HR = 2.45, 95% CI: 1.75-3.43) compared to the YWHAG negative (Y-) group (p < 0.001).ConclusionsWe identify YWHAG as a novel biomarker predictive of cognitive decline, brain atrophy, and AD progression. The performances of YWHAG are comparable to established biomarkers such as FDG-PET, HVA and T-tau, thereby providing a complement to the current AD diagnostic framework.},
}

@article {pmid42179352,
year = {2026},
author = {Yuan, C and Zhao, S and Li, S and Song, X and Chen, Z and , },
title = {Interpretable Deep Regression Models With Interval-Censored Failure Time Data.},
journal = {Statistics in medicine},
volume = {45},
number = {13-14},
pages = {e70609},
doi = {10.1002/sim.70609},
pmid = {42179352},
issn = {1097-0258},
support = {12471251//National Nature Science Foundation of China/ ; 2025A1515012851//Nature Science Foundation of Guangdong Province of China/ ; 2025A03J3083//Science and Technology Program of Guangzhou of China/ ; 14301918//Research Grant Council of the Hong Kong Special Administrative Region/ ; 14302519//Research Grant Council of the Hong Kong Special Administrative Region/ ; 14300425//Research Grant Council of the Hong Kong Special Administrative Region/ ; },
mesh = {Humans ; Likelihood Functions ; Computer Simulation ; Alzheimer Disease/diagnostic imaging ; Survival Analysis ; Regression Analysis ; Algorithms ; *Neural Networks, Computer ; *Models, Statistical ; *Deep Learning ; },
abstract = {Deep neural networks (DNNs) have become powerful tools for modeling complex data structures through sequentially integrating simple functions in each hidden layer. In survival analysis, recent advances of DNNs primarily focus on enhancing model capabilities, especially in exploring nonlinear covariate effects under right censoring. However, deep learning methods for interval-censored data, where the unobservable failure time is only known to lie in an interval, remain underexplored and limited to specific data types or models. This work proposes a general regression framework for interval-censored data with a broad class of partially linear transformation models, where key covariate effects are modeled parametrically while nonlinear effects of nuisance covariates are approximated via DNNs, balancing interpretability and flexibility. We employ sieve maximum likelihood estimation by leveraging monotone splines to approximate the cumulative baseline hazard function. To ensure reliable and tractable estimation, we develop an EM algorithm incorporating stochastic gradient descent. We establish the asymptotic properties of parameter estimators and show that the DNN estimator achieves minimax-optimal convergence. Extensive simulations demonstrate superior estimation and prediction accuracy over state-of-the-art methods. Applying our method to the Alzheimer's Disease Neuroimaging Initiative dataset yields novel insights and improved predictive performance compared to traditional approaches.},
}

Humans
Likelihood Functions
Computer Simulation
Alzheimer Disease/diagnostic imaging
Survival Analysis
Regression Analysis
Algorithms
*Neural Networks, Computer
*Models, Statistical
*Deep Learning

@article {pmid42179353,
year = {2026},
author = {Li, X and Diao, L and Cook, RJ},
title = {Variable Selection for Illness-Death Processes Under Dual Observation Schemes.},
journal = {Statistics in medicine},
volume = {45},
number = {13-14},
pages = {e70608},
doi = {10.1002/sim.70608},
pmid = {42179353},
issn = {1097-0258},
support = {FRN 13887/CAPMC/CIHR/Canada ; 1280961//Natural Sciences and Engineering Research Council of Canada/ ; },
mesh = {Humans ; Likelihood Functions ; *Disease Progression ; Computer Simulation ; Algorithms ; Alzheimer Disease/mortality ; *Models, Statistical ; Dementia/mortality ; },
abstract = {The classical illness-death process offers a useful framework for studying the progression of chronic disease while jointly modeling death. In many settings the time of disease progression is not observed directly, but progression status is recorded at intermittent assessment times. This creates a dual observation scheme where progression times are interval-censored and death is subject to right censoring. We present a penalized observed data likelihood for variable selection in multiplicative intensity-based models for the joint process, involving different penalty functions for different sets of regression coefficients. Optimization is carried out based on an innovative expectation-maximization algorithm that can be implemented using existing software. Simulation studies demonstrate the finite sample performance of the method, and an application to a dementia study from the National Alzheimer's Coordinating Center (NACC) illustrates the insights that can be gained.},
}

Humans
Likelihood Functions
*Disease Progression
Computer Simulation
Algorithms
Alzheimer Disease/mortality
*Models, Statistical
Dementia/mortality

@article {pmid42179444,
year = {2026},
author = {El Bitar, F and Al Dawsari, G and Qadi, N and Al Rajeh, S and Abouelhoda, M and Al Subaie, S and Majrashi, N and Magrashi, A and Al Amari, H and Alghamdi, F and Abdulaziz, S and Al-Mubarak, B and Al Tassan, N},
title = {Rare and novel genetic variants in sporadic and familial Alzheimer's disease: insights from the first Saudi cohort.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1765569},
pmid = {42179444},
issn = {2673-6217},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a complex brain disorder that is greatly affected by genetics. Next-generation sequencing (NGS) has facilitated the discovery of rare variants in new genes that may be linked to AD in different populations. However, we still know very little about the genetic makeup of AD in Saudi Arabia and other Arab populations.

OBJECTIVES: This study aims to explore rare variants that are predicted to be deleterious in a group of 64 Saudi patients diagnosed with sporadic and familial Alzheimer's disease (AD). These patients previously tested negative for mutations in genes known to cause AD and were genotyped for APOE alleles.

METHODS: We performed whole-exome sequencing (WES) on the Ion Proton platform. Then, we used our internal process for filtering, validating, and prioritizing variants.

RESULTS: Using stringent selection criteria, we identified 107 rare candidate variants with potential functional relevance. Of these, 26 (24.3%) were novel, while the remaining variants had been previously reported in public databases. Among these candidates, 33 were connected to AD, 28 to both AD and other neurodegenerative disorders (OND), 34 to OND-related functions, and 11 to broader processes like aging, inflammation, and neuronal regulation. We found rare missense variants in genes involved in important processes related to Alzheimer's disease. These processes include mainly Aβ and Tau pathology, kinase signaling, stress response, and neuroinflammation.

CONCLUSION: Our analysis reveals diverse genetic contributors to Alzheimer's disease in a population that remains largely underrepresented in genomic studies. We identified candidate variants in 53% of the patients, highlighting the value of expanding AD genetics research to non-European populations.},
}

@article {pmid42179525,
year = {2026},
author = {Ryu, DH and Cho, JY and Jung, JW and Cha, HH and Kim, HM and Park, NY and Ahn, NH and Lee, JH and Park, JS and Lee, DS and Yang, SH and Kim, HY},
title = {Lactic Acid Bacteria-Mediated Fermentation Drives Metabolic Remodeling of Centella Asiatica (L.) Urb. toward Acidic Triterpenoids with Neuroinflammation-Related Bioactivity.},
journal = {ACS omega},
volume = {11},
number = {19},
pages = {28607-28618},
pmid = {42179525},
issn = {2470-1343},
abstract = {Centella asiatica Urb. is a medicinal plant rich in triterpenoid constituents with a reported neurobiological relevance. Its major metabolites are glycosylated triterpenoids, such as asiaticoside and madecassoside, whereas the corresponding acidic triterpenoids, including asiatic acid and madecassic acid, are typically present at low abundance. Given the increasing interest in how metabolic forms of natural products influence biological activity, this study investigated whether lactic acid bacteria (LAB)-mediated fermentation could induce metabolic remodeling of C. asiatica through microbial biotransformation. LAB fermentation markedly altered the secondary metabolite profile, which was characterized by a reduction in phenolic compounds and glycosylated triterpenoids and a pronounced enrichment of acidic triterpenoids. This compositional shift was accompanied by changes in bioactivity, including a decreased antioxidant capacity but enhanced anti-inflammatory effects in macrophage cells. Fermented C. asiatica significantly suppressed the expression of proinflammatory cytokines (TNF-α and IL-1β) and modulated amyloid-β and tau protein aggregation behavior in vitro. Furthermore, in an Alzheimer's disease transgenic mouse model, fermented extracts were associated with reduced amyloid plaque deposition, as assessed by Thioflavin S staining. Collectively, these results demonstrate that LAB-mediated fermentation drives functional metabolic remodeling of C. asiatica by altering the triterpenoid composition and bioactivity profiles. This work highlights microbial biotransformation as a versatile strategy for modulating the biological attributes of plant-derived natural products and for exploring relationships between chemical form and bioactivity in complex biological systems.},
}

@article {pmid42179538,
year = {2026},
author = {Acharya, K and Ainavarapu, SRK and Das, R},
title = {Cosolutes Modulate Polyubiquitin Fibrillation.},
journal = {ACS omega},
volume = {11},
number = {19},
pages = {28004-28014},
pmid = {42179538},
issn = {2470-1343},
abstract = {Ubiquitin, a 76-residue polypeptide, functions as a post-translational modifier and forms polyubiquitin (polyUb) chains on substrate proteins to activate diverse cellular functions. Ubiquitin is often found in the lesions associated with neurodegenerative disorders like Alzheimer's and Huntington's disease. It was recently observed that polyubiquitin chains, under in vitro conditions, often form β-sheet-rich fibrillar amyloid aggregates. However, the exact mechanism of conversion from monomer polyUb to amyloid-like fibrils is poorly understood. We report that polyubiquitin forms higher-order oligomeric fibrils and temperature, pH, and ionic strength modulate polyubiquitin (polyUb) fibrillation. Cosolutes such as ionic liquids and macromolecular crowding agents also enhance the aggregation rate. These findings uncover that temperature/cosolutes lower the energy barrier to populate a partially unfolded form (M*), which drives amyloid-like fibril formation. Other factors increase the effective protein concentration of these partially unfolded forms, accelerating aggregation. These insights provide the fundamental basis for ubiquitin chain aggregation, which is necessary to guide the development of therapies and diagnostics.},
}

@article {pmid42179740,
year = {2026},
author = {Chen, R and Chiu, SY and DeSimone, JC and Wang, WE and Barmpoutis, A and Mcmillan, CT and Radhakrishnan, H and Irwin, DJ and Clark, L and Kantarci, K and Boeve, BF and Vaillancourt, DE},
title = {Automated Imaging Differentiation for Dementia: Including Alzheimer Disease Dementia and Dementia with Lewy Bodies.},
journal = {Neurology open access},
volume = {2},
number = {2},
pages = {},
pmid = {42179740},
issn = {2998-7601},
abstract = {BACKGROUND AND OBJECTIVES: Differentiation of Alzheimer's disease dementia (ADD) and dementia with Lewy bodies (DLB) remains a challenge. Free-water imaging has been investigated in neurodegenerative diseases and was found to be associated with neurodegeneration and neuroinflammation. This retrospective cohort study tested whether Automated Imaging Differentiation for Dementia (AIDD), combining diffusion free-water imaging (FWI) and support vector machine, predicts ADD vs DLB with high accuracy.

METHODS: Diffusion MRI data was rendered from ADNI, NACC, and PDBP. Free-water and free-water corrected fractional anisotropy were calculated for each participant using a bi-tensor model. Diffusion metrics were randomly assigned to training and testing sets. The primary outcome was the area under the curve (AUC) in the test set. AIDD was paired with antemortem MRI to predict postmortem pathology.

RESULTS: A total of 519 diffusion scans were processed with 258 ADD (mean age 73.7 (8.8), 50% male), 129 DLB (mean age 69.3, 88% male), and 132 controls (mean age 73.6 (6.8), 40% male). The machine learning sample included 387 scans,129 ADD with a mean age of 72.8 (8.7), 52.7% male; 129 DLB with a mean age of 69.3 (8.1), 87.6% male; and 129 controls with a mean age of 73.7 (6.8), 39.5% male). AIDD showed high training AUC for ADD vs DLB = 0.995 (95% CI, 0.985-1.000), ADD vs controls = 0.992 (95% CI, 0.982-1.000), DLB vs controls = 0.991 (95% CI, 0.983-0.999), and controls vs ADD/DLB = 0.990 (95% CI, 0.979-1.000). The testing AUCs were similar: ADD vs DLB = 0.995, ADD vs controls = 0.958, DLB vs controls = 0.939, controls vs ADD/DLB = 0.903. AIDD predictions were confirmed pathologically in a cohort of 13 patients.

DISCUSSION: This study demonstrates that machine learning in combination with free-water imaging can differentiate ADD, DLB, and normal aging with high clinical and pathological accuracy. Advancement in early detection of dementia can lead to more appropriate treatment plans, especially for DLB, and improved disease stratification that have hindered drug development trials.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that Automated Imaging Differentiation for Dementia, combining diffusion free-water imaging and machine learning accurately distinguishes Alzheimer's Disease from Dementia with Lewy bodies.},
}

@article {pmid42179743,
year = {2026},
author = {Yu, Z and Li, H and Wang, Y and Shen, F and Wang, Y},
title = {Aerobic exercise versus acupuncture as adjuncts to acetylcholinesterase inhibitors in Alzheimer's disease: a systematic review and Bayesian network meta-analysis.},
journal = {American journal of clinical and experimental immunology},
volume = {15},
number = {2},
pages = {37-49},
pmid = {42179743},
issn = {2164-7712},
abstract = {Acetylcholinesterase inhibitors (AChEIs) remain the standard therapy for Alzheimer's disease (AD), yet their cognitive and functional benefits are limited, creating a strong need for effective adjunctive treatments. Aerobic exercise and acupuncture have been proposed as promising complements to AChEIs because of their potentially synergistic neurotrophic and cholinergic effects. To compare these treatment combinations, we carried out a Bayesian network meta-analysis (BNMA) of randomized controlled trials (RCTs). These studies were sourced from major English and Chinese databases and examined cognitive and functional outcomes. In total, 37 RCTs were included, covering 2,188 participants. Among all, combined acupuncture (SUCRA = 78.92%) and fire needle therapy (SUCRA = 78%) demonstrated the highest probability of improving Mini Mental State Examination scores, while moderate intensity aerobic exercise ranked best for the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog, SUCRA = 23.3%) and the Barthel Index (SUCRA = 71.1%). Combined acupuncture was ranked highest for the Alzheimer's Disease Assessment Scale-Activities of Daily Living (ADAS-ADL, SUCRA = 94.3%), although its effects did not reach statistical significance. Across analyses, heterogeneity was minimal (I[2] ≤ 4%), model convergence was stable, and no publication bias was detected. Overall, this BNMA suggests that combined or thermal acupuncture offers the strongest cognitive gains alongside AChEIs, whereas moderate-intensity aerobic exercise provides the most reliable functional support. Because overall functional improvements were modest and evidence for some interventions remains limited, the benefits appear selective rather than broad. Larger, standardized trials are needed to clarify these patterns and guide their use in practice.},
}

@article {pmid42179817,
year = {2026},
author = {Hosseini, I and Northey, JM and D'Cunha, NM and Fernandez Rojas, R and Shrestha, A and Ghahramani, M},
title = {A systematic review and meta-analysis on dual-task sensor-based motion analysis for dementia detection.},
journal = {Frontiers in digital health},
volume = {8},
number = {},
pages = {1728588},
pmid = {42179817},
issn = {2673-253X},
abstract = {INTRODUCTION: Early diagnosis of dementia may be improved by objective, scalable tests that capture how cognitive tasks interfere with movement. This study examined the use of instrumented dual-task paradigms for dementia detection and characterisation.

METHODS: We performed a PRISMA-guided systematic review and meta-analysis of peer-reviewed studies that used dual-task paradigms in adults with clinically defined dementia and an appropriate comparator. We extracted primary motor tasks, secondary cognitive or motor loads, sensor modalities, and analytic approaches. Walking outcomes were meta-analysed using inverse-variance weighted random-effects models, including subgroup analyses for single-task versus dual-task conditions and for arithmetic versus memory and verbal fluency assessments.

RESULTS: The literature was dominated by cognitive-motor dual-task paradigms in Alzheimer's disease cohorts. Inertial measurement units and force plates were the most common instruments, and most studies used classical statistics, with fewer applying machine learning. Pooled effects showed consistent group differences; compared with controls, people with dementia walked more slowly, took shorter steps, and showed less steady timing. Although heterogeneity was substantial across studies, the direction of effects was stable, and dual-task conditions generally amplified group differences relative to single-task performance. Arithmetic loads tended to accentuate changes linked to speed and cadence, whereas memory and verbal fluency assessments tended to prolong timing measures. Balance, turning, and some upper-limb outcomes also differentiated groups.

DISCUSSION: Instrumented dual-task assessments appear to enhance detection of cognitive-motor impairment in dementia and may complement existing evaluations. To support clinical translation, future work should extend beyond Alzheimer's disease, standardise task instructions and reporting, and evaluate multi-modal, validated analytic approaches across different dementia subtypes.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251114199, CRD420251114199.},
}

@article {pmid42179845,
year = {2026},
author = {Nakazaki, M and Lankford, KL and Ukai, R and Hirota, R and Oka, S and Sasaki, M and Kocsis, JD and Honmou, O},
title = {Mesenchymal stromal/stem cell-derived extracellular vesicles in brain disorders: mechanisms of repair and recovery.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1819046},
pmid = {42179845},
issn = {1662-5102},
abstract = {Mesenchymal stem/stromal cell-derived small extracellular vesicles (MSC-sEVs) have emerged as promising cell-free therapeutics for central nervous system (CNS) disorders including stroke, traumatic brain injury (TBI), dementia, and multiple sclerosis (MS). MSC-sEVs offer advantages of low immunogenicity, ease of storage, and ability to cross the blood-brain barrier. This review provides a comprehensive analysis of the mechanisms by which MSC-sEVs have been reported to promote neural repair and recovery in preclinical models, through two convergent categories of action. First, MSC-sEVs exert direct neurorestorative effects, including activation of endogenous neural stem cells via Wnt/beta-catenin and PI3K/Akt/mTOR signaling, neuroprotection through PTEN/Akt-mediated anti-apoptotic and antioxidant pathways, preservation of mitochondrial function through mitophagy regulation, and promotion of neurite outgrowth and synaptogenesis through cytoskeletal remodeling and growth signaling. Second, MSC-sEVs modulate the injury microenvironment by shifting microglia and infiltrating macrophages toward anti-inflammatory phenotypes through NF-kB pathway modulation, converting reactive astrocytes to neuroprotective states, promoting angiogenesis and blood-brain barrier restoration, and enhancing oligodendrogenesis and remyelination. These effects are mediated largely through the transfer of microRNAs and other bioactive cargo to target cells at the injury site, although the relative contribution of individual cargo components remains to be fully established. We discuss how these actions address the pathophysiology of stroke, Alzheimer's disease, vascular dementia, TBI, and MS, highlighting disease-specific mechanisms and the current gap between preclinical evidence and clinical validation. Finally, we address challenges for clinical translation, including standardization of critical quality attributes and potency assays, route-dependent biodistribution, safety considerations, and dosing optimization. We also discuss engineering strategies for enhanced efficacy, including surface modification for CNS-targeted delivery, source cell preconditioning, cargo engineering, and scaffold-based sustained release systems. Although no clinical trials have yet evaluated MSC-sEV therapy specifically for neurological disorders, the growing body of safety data from non-neurological MSC-sEV trials and the extensive clinical experience with parent MSC therapies provide a foundation for future CNS-focused studies. MSC-sEVs hold substantial potential as a cell-free approach for neurological disorders that currently lack effective regenerative therapies, although realization of this potential will require rigorous clinical validation.},
}

@article {pmid42179865,
year = {2026},
author = {Arp, AM and Bloom, GS and D'Abreu, A and Fansler, A and Meegan, K and Ratcliffe, S and Kapur, J and Manning, C},
title = {The use of memantine for prevention of Alzheimer's disease: Pilot feasibility study rationale and protocol.},
journal = {Contemporary clinical trials communications},
volume = {51},
number = {},
pages = {101644},
pmid = {42179865},
issn = {2451-8654},
abstract = {BACKGROUND: Alzheimer's disease (AD) affects over 6 million older adults in the Untiled States. Evidence suggests the neuropathology leading to the disorder begins decades earlier, calling for a preventative treatment that can be administered to at risk individuals. Memantine hydrochloride, an NMDA receptor antagonist, is a possible candidate for prophylactic treatment by diminishing excessive NMDA receptor activity.

METHODS: This is a 2-year, double-blind, randomized, placebo-controlled trial of memantine hydrochloride (1:1 randomization allocation using randomly permutated blocks of unequal size). Participants are APOε4 carriers slightly under the average age of AD symptom onset (50-65 years of age) with a positive family history of a first degree relative with AD. Amyloid PET scans are performed pre and post treatment. Cognitive assessments and physical and neurological examinations are completed at regular intervals throughout the feasibility trial.

DISCUSSION: This study will assess the feasibility of the use of memantine hydrochloride for prevention of AD. The primary aim is to determine feasibility of participants who a) enrolled among those found eligible, and b) completed the study among those randomized to a study arm. Exploratory aims include examination of cognitive and safety assessments. Although not powered to determine efficacy, the study will provide direction on design elements needed for a Phase III clinical trial. No formal hypotheses are included in this feasibility trial.

TRIAL REGISTRATION: Clinical Trials NCT05063851.},
}