@article {pmid41820211,
year = {2026},
author = {Panda, SP and Kumar, S and Singh, M and Singh, V},
title = {Molecular Complexities of Dementia: PAISA Mutations and Targeting TAF2N as Therapeutic Avenues.},
journal = {Current gene therapy},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115665232389636251115111503},
pmid = {41820211},
issn = {1875-5631},
abstract = {Millions of individuals worldwide are affected by Alzheimer's disease dementia (ADD) and frontotemporal dementia (FTD), with FTD characterized by degeneration of the frontal and temporal lobes leading to cognitive and behavioral impairments. A subset of Alzheimer's cases exhibits familial inheritance, with the PAISA mutation, a glutamic acid to alanine substitution at codon 280 (E280A) in the PSEN1 gene, being a primary cause of early-onset dementia. PSEN1 encodes a key component of the γ-secretase complex, which cleaves amyloid precursor protein (APP) to generate beta-amyloid (Aβ) peptides. The PAISA mutation disrupts normal Aβ processing, leading to overproduction or accumulation of Aβ, formation of amyloid plaques, and accelerated progression of dementia. Its prevalence is particularly high in Colombian families, giving rise to the term "PAISA mutation." The APOE genotype further modulates the clinical manifestation in PAISA carriers, with APOE2 potentially delaying disease onset, whereas APOE4 is associated with earlier onset. Recent research highlights TAF2N (also known as RBP56, encoded by TAF15) as a promising therapeutic target, as its modulation may regulate AD-associated genes, reduce toxic Aβ isoforms, modulate tau and APP pathways, protect neurons, and enhance synaptic function. Overall, understanding the molecular effects of PAISA mutations and exploring TAF2N-targeted therapies offers novel avenues for addressing early-onset familial AD, providing insights into broader mechanisms of disease pathogenesis.},
}

@article {pmid41820136,
year = {2026},
author = {Zambelas, J and Huang, Y and Zhao, H and Wong, STC},
title = {Tumor-derived cystatin C enables amyloid clearance.},
journal = {Trends in immunology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.it.2026.02.007},
pmid = {41820136},
issn = {1471-4981},
abstract = {Li et al. described a tumor-derived neuroimmune mechanism that promotes clearance of established amyloid pathology in Alzheimer's disease. secreted cystatin C activates TREM2-dependent microglial phagocytosis, reducing plaques and improving cognition. This work introduces a context-dependent neuroimmune-modulatory strategy that shifts Alzheimer's therapy from broad immune activation toward substrate-coupled amyloid clearance.},
}

@article {pmid41819777,
year = {2026},
author = {Alhasan, AS and Alhasan, MS and Milburn, J and Ghunaim, HA and Khalil, M and Almaghraby, A and Alharthi, O and Hamoud, S and Essibayi, MA and Elhassan, YH and Feltrin, F and Singh, S and A Lakhani, D and Azzam, AY},
title = {Baseline FDG-PET Brain hypometabolism as a predictive biomarker of cognitive decline and Alzheimer's disease risk.},
journal = {The journal of nutrition, health & aging},
volume = {30},
number = {5},
pages = {100823},
doi = {10.1016/j.jnha.2026.100823},
pmid = {41819777},
issn = {1760-4788},
abstract = {INTRODUCTION: Brain glucose hypometabolism precedes cognitive decline in Alzheimer's disease, however its role in determining long-term cognitive trajectories remains under studied in current literature in a clear manner. We investigated whether baseline brain glucose metabolism predicts cognitive decline rates and disease conversion risk in a large longitudinal cohort.

METHODS: We analyzed 4,732 participants (1,685 with longitudinal cognitive data) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with fluorodeoxyglucose positron emission tomography (FDG-PET), Mini-Mental State Examination (MMSE), and Alzheimer's Disease Assessment Scale (ADAS) measurements over ten years. Mixed-effects models investigated time × brain glucose metabolism interactions on cognitive decline. Cross-validation assessed predictive accuracy for mild cognitive impairment and Alzheimer's disease conversion.

RESULTS: Brain glucose metabolism was found to modulate the cognitive decline rates (time × FDG interaction: MMSE β = 0.746, P-value <0.001; ADAS β = -1.595, P-value <0.001). High versus low glucose metabolism demonstrated 1.49 MMSE points/year and 3.19 ADAS points/year protection. Among cognitively normal participants, low glucose metabolism increased Alzheimer's disease conversion risk four-fold (incidence rate ratio = 3.79, 95%CI: 2.94-4.88). Predictive models achieved high accuracy for Alzheimer's disease conversion (AUC = 0.826) with good calibration (Brier score = 0.092). High-metabolism individuals showed essentially stable cognition over ten years follow-up duration as evident in the ADNI dataset.

CONCLUSIONS: We found that brain glucose metabolism is a notable determinant of cognitive decline progression, especially for Alzheimer's disease risk, providing quantifiable metabolic protection against decline. Our results demonstrate brain glucose hypometabolic findings from baseline FDG-PET as a precision biomarker for therapeutic stratification and support further interventions for cognitive preservation for further research, validation and development purposes that should be further evaluated and investigated in further clinical trials that may lead to better preventive and therapeutic benefits for cognitive functions preservation and prevention of cognitive decline process in high-risk individuals.},
}

@article {pmid41819741,
year = {2026},
author = {Vautier, MF and Chrem Mendez, P and Jerez Ferreyra, G and Massazza, V and Apecetche, M and Rodríguez Varela, MS and Clas, G and Nievas, M and Allegri, R and Sevlever, GE and Scassa, ME and Surace, EI and Marazita, MC and Romorini, L},
title = {Generation of a human induced pluripotent stem cell line (FLENIi004-A) from an Autosomal-Dominant Alzheimer's disease PSEN1 p.M146L patient.},
journal = {Stem cell research},
volume = {93},
number = {},
pages = {103958},
doi = {10.1016/j.scr.2026.103958},
pmid = {41819741},
issn = {1876-7753},
abstract = {Human induced pluripotent stem cell (hiPSC) line FLENIi004-A was generated from peripheral blood mononuclear cells (PBMCs) using the lentiviral-hSTEMCCA-loxP vector. FLENIi004-A was derived from a 41-year-old Argentinean Caucasian male patient with Autosomal-Dominant Alzheimer's Disease, who carried the heterozygous PSEN1 p.M146L mutation. The hiPSC line retained the PSEN1 mutation, and its pluripotency and trilineage differentiation potential were confirmed.},
}

@article {pmid41819555,
year = {2026},
author = {Martins, WC and Mendes, LRC and Junqueira, MC and Pereira, CMS and Gilbbert, PC and Schommer, SO and Campos, SS and Rodrigues, RPC and Santos, VRP and Brito, TM and Dobrachinski, F and Lima, E and Rios-Santos, F and Vandresen-Filho, S},
title = {Baru (Dipteryx alata) nut oil attenuates amyloid-β-induced cognitive deficits by modulating neuroinflammation and BDNF signaling pathway.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/1028415X.2026.2641534},
pmid = {41819555},
issn = {1476-8305},
abstract = {Introduction: Current treatments for Alzheimer's disease (AD) are primarily supportive and have limited efficacy in slowing disease progression. Therefore, the search for new therapeutic agents is essential to improve cognitive deficits or potentially prevent the advancement of this neurodegenerative disorder. Baru oil (BO) contains several bioactive compounds that may possess neuroprotective effects. However, no studies have investigated the potential beneficial effects of BO in the context of AD.Aim and Methods: This study aimed to investigate the neuroprotective effects of BO in a rodent model of AD. Mice were pretreated orally with vehicle or BO 1 or 3 g/kg/day for 45 days. On the 30th day, mice were infused i.c.v with amyloid-beta (Aβ) or PBS. A positive control group was orally treated with memantine (20mg/kg/day) for 15 days after Aβ or PBS infusion. Following behavioral assessments, mice were euthanized and the brains were removed for biochemical assays.Results: Similar to memantine treatment, pretreatment with both doses of BO prevented Aβ-induced memory impairments in the Morris water maze and the object recognition task. Pretreatment with BO 3g/kg/day prevented Aβ-induced increase in lipid peroxidation in the hippocampus. BO pretreatment mitigated the Aβ-induced reductions in hippocampal expression levels of BDNF, TrkB, and p-CREB. BO prevented the Aβ-induced increase in COX-2 and NOS-2 expression in the hippocampus.Conclusion: BO reversed Aβ-induced cognitive deficits. These neuroprotective effects were associated with the mitigation of hippocampal oxidative stress and neuroinflammation, alongside the restoration of the BDNF/TrkB/p-CREB signaling pathway. Our findings highlight Baru oil as a promising multifactorial therapeutic agent for AD.},
}

@article {pmid41819509,
year = {2026},
author = {Cui, WB and Meng, XY and Zhang, XS and Lou, HX and Fan, PH},
title = {Broussonetia papyrifera Fruit Extract Attenuates Alzheimer's Pathogenesis via Disrupting the Vicious Cycle of Aβ and Oxidative Stress in C. elegans and Cellular Models.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121513},
doi = {10.1016/j.jep.2026.121513},
pmid = {41819509},
issn = {1872-7573},
abstract = {The dried fruit of Broussonetia papyrifera (L.) Vent., known as Fructus Broussonetiae (FB) in Traditional Chinese Medicine, is a kidney-nourishing herb historically prescribed to combat fatigue and age-related cognitive decline. This traditional application suggests potential efficacy against multifactorial neurodegenerative disorders like Alzheimer's disease (AD) AIM OF THE STUDY: This study aimed to investigate whether the ethyl acetate fraction of FB (FBA) could attenuate AD pathogenesis by disrupting the reciprocal exacerbation between Aβ proteotoxicity and oxidative stress.

MATERIALS AND METHODS: The neuroprotective effects and mechanisms of FBA were evaluated in Caenorhabditis elegans models expressing human Aβ and in mammalian cellular models. Assessments included behavioral assays, histological staining, measurements of mitochondrial function, oxidative stress markers, and transcriptomic analyses. Key bioactive constituents were traced through bioactivity-guided fractionation.

RESULTS: FBA significantly alleviated Aβ-induced paralysis, improved locomotor performance, and reduced Aβ oligomerization and deposition in C. elegans. Concurrently, FBA restored mitochondrial function by enhancing membrane potential and abundance, and mitigated oxidative damage. In cellular models, FBA inhibited Aβ secretion, attenuated glutamate-induced excitotoxicity, and improved ATP production. At the molecular level, these benefits were linked to enhanced cellular defense mechanisms, including activation of the NRF2-mediated antioxidant pathway (elevated HO-1 and NQO1) and regulation of apoptotic signaling via reduced TP53 activity and an increased BCL-2/BAX ratio.

CONCLUSIONS: This study elucidates the modern pharmacological basis by which the active fraction of Broussonetia papyrifera fruit (FBA) disrupts the vicious cycle of Aβ-oxidative stress through multiple mechanisms, thereby improving Alzheimer's disease pathology. It provides a scientific explanation for its traditional anti-aging effects.},
}

@article {pmid41819485,
year = {2026},
author = {Qiao, Y and Huang, M and Sun, C and Du, X and Wang, Y and Liu, Y and Zhang, L and Guo, Y and Peng, L and Peng, D},
title = {Ajugol ameliorates mitochondrial dysfunction and cognitive decline in Alzheimer's Disease via BNIP3-dependent mitophagy.},
journal = {Neuropharmacology},
volume = {291},
number = {},
pages = {110923},
doi = {10.1016/j.neuropharm.2026.110923},
pmid = {41819485},
issn = {1873-7064},
abstract = {Defective mitophagy plays key roles in mitochondrial dysfunction, inflammation, and energy deprivation, and this defect can lead to synaptic loss and cognitive decline in Alzheimer's disease (AD). Although pharmacological enhancement of mitophagy has been found to ameliorate cognitive impairment in AD models, therapeutic strategies directly targeting this pathway remain limited. Ajugol, a bioactive iridoid glycoside isolated from Rehmannia glutinosa, has recently been identified as a potential metabolic regulator. In this study, we demonstrated that ajugol markedly alleviates mitochondrial damage and mitophagy impairment in 5 × FAD mice and HT22 cells. Mechanistically, ajugol upregulates BCL2-interacting protein 3 (BNIP3), which recruits LC3 to damaged mitochondria, thereby promoting mitophagosome formation and ultimately contributing to improved cognitive function. Notably, Bnip3 knockdown in hippocampal neurons abolished the beneficial effects of ajugol in 5 × FAD mice, exacerbating mitophagy defects and mitochondrial dysfunction, ultimately impairing cognitive performance. These findings highlight a previously unrecognized mechanism by which ajugol mitigates amyloid pathology, synaptic dysfunction, and cognitive decline in 5 × FAD mice and HT22 cells by enhancing BNIP3-mediated mitophagy, providing a potential therapeutic strategy for AD intervention.},
}

@article {pmid41819428,
year = {2026},
author = {Kiyak-Kirmaci, H and Hazar-Yavuz, AN and Polat, EB and Dogan, MO and Tok, F and Cilingir-Kaya, OT and Elcioglu, HK},
title = {Empagliflozin and dapagliflozin, Sodium Glucose Cotransporter 2 Inhibitors, may improve cognitive dysfunctions: in silico and in vivo findings.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116158},
doi = {10.1016/j.bbr.2026.116158},
pmid = {41819428},
issn = {1872-7549},
abstract = {Type 2 Diabetes Mellitus (T2D) accelerates cognitive decline through a complex interaction of metabolic, oxidative, inflammatory, and vascular pathways and is widely recognized as a significant risk factor for Alzheimer's disease (AD). Sodium-glucose cotransporter (SGLT)2 inhibitors are widely used in the treatment of T2D, and accumulating evidence suggests that they may influence neurodegenerative processes beyond their glycemic effects. In this context, the present study investigated the potential contributions of empagliflozin (EMPA) and dapagliflozin (DAPA) to cognitive function by evaluating their in silico interactions with targets associated with oxidative stress, inflammation, and neuroprotection, including SGLT1, SGLT2, acetylcholinesterase (AChE), superoxide dismutase (SOD), receptor for advance glycation end-products (RAGE), and interleukin (IL)-1β. Furthermore, cognitive impairments in streptozotocin/nicotinamide-induced T2D were investigated in vivo by behavioral tests in rats. Biochemical alterations in brain tissues were evaluated using ELISA measurements, which encompassed the levels of SOD, RAGE, and IL-1β. Hematoxylin and eosin (H&E) staining was used to evaluate the structure of hippocampal and cortical tissue for histological assessment. Molecular docking analyses indicated that EMPA showed notably stronger interactions with AD-relevant targets such as SGLT1/2 and AChE than DAPA. Both EMPA and DAPA elevated SOD levels in brain tissue. Consistent with these biochemical improvements, behavioral assessments demonstrated enhanced learning and memory performance in treated rats relative to the T2D group. Nonetheless, histological analyses revealed that both drugs produced improvements in the cortex and hippocampus. In conclusion, EMPA and DAPA may modulate T2D-associated AD through multiple metabolic pathways, and further investigation is warranted to elucidate their contributions.},
}

@article {pmid41819365,
year = {2026},
author = {Krier, D and Abouelfath, A and Jové, J and Amieva, H and Carcaillon-Bentata, L and Wittwer, J},
title = {Healthcare utilisation among older adults with dementia in France: A comparative analysis of a Dementia Village and traditional nursing homes.},
journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jval.2026.02.011},
pmid = {41819365},
issn = {1524-4733},
abstract = {OBJECTIVE: The Dementia Village (DV) model is emerging as an alternative to traditional nursing homes (NHs) for individuals with Alzheimer's disease and related dementias. This study evaluates the impact of the French Dementia Village, Village Landais Alzheimer Henri Emmanuelli (VLAHE), on healthcare utilisation among older adults with dementia.

METHODS: This study employs an indirect comparative cohort design using data from two sources: a longitudinal observational study of VLAHE residents and an ad hoc cohort from the French Nationwide claims database of NH residents. To improve comparability, the Matching-Adjusted Indirect Comparison (MAIC) method was applied. Weighted statistical tests and logistic regression models were used, yielding odds ratios with 95% confidence intervals. The outcomes analysed include hospital admission rates, hospital stay duration, mortality, and place of death over a two-year follow-up period between January 2021-December 2022.

RESULTS: VLAHE residents had fewer hospitalisations and shorter stays (10.5 vs. 15.2 days, p = 0.0004) than comparable NH residents, particularly for acute care. Quarterly hospitalisation rates were consistently lower (6.4% vs. 11.1%), while no significant differences were found for psychiatric or rehabilitation stays. Fewer VLAHE residents died in hospital (9% vs. 31%), suggesting improved end-of-life care (OR: 5.75, 95% CI [1.75-18.90]).

CONCLUSIONS: The VLAHE model may reduce hospitalisations and enhance end-of-life care through a structured, patient-centred approach. However, due to a potential residual clinical differences between groups and limitations of the matching method, further longitudinal research is needed to confirm its effectiveness.},
}

@article {pmid41819312,
year = {2026},
author = {Cai, G and Zhang, J and Jiao, J and Yan, M},
title = {Eukaryotic elongation factor 2 kinase (eEF2K): Mechanisms and pharmacological significance in metabolic diseases.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {151385},
doi = {10.1016/j.ijbiomac.2026.151385},
pmid = {41819312},
issn = {1879-0003},
abstract = {Eukaryotic elongation factor 2 kinase (eEF2K) is an atypical Ca[2+]/calmodulin-dependent serine/threonine kinase that inhibits the elongation phase of protein synthesis by phosphorylating its sole known substrate, eukaryotic elongation factor 2 (eEF2). As protein synthesis is one of the most energy-intensive cellular processes, eEF2K functions as an energy-conservation mechanism under nutrient or energy stress, thereby maintaining cellular homeostasis. It has emerged as a central hub linking energy metabolism, cellular stress responses, and disease progression. In metabolic diseases, aberrant eEF2K activity contributes to pathological processes. In type 2 diabetes (T2D) and its complications, eEF2K modulates insulin signaling, mitochondrial function, and stress responses, whereas in atherosclerosis, it affects endothelial function, inflammation, and autophagy, promoting disease progression. Consequently, eEF2K is considered a promising therapeutic target. Despite increasing interest, systematic studies on eEF2K in metabolic regulation remain limited, and its precise roles in metabolic reprogramming, immune-inflammatory modulation, and stress adaptation are not fully elucidated. Pharmacological strategies-including direct inhibitors, indirect modulators, targeted protein degraders (TPD), and paradoxical activators-are under exploration, offering novel avenues for treatment. This review summarizes the structure and regulatory network of eEF2K, highlights its roles in energy metabolism, oxidative stress, autophagy, and inflammation, and discusses its pathophysiological significance and therapeutic potential in T2D, atherosclerosis (AS), and Alzheimer's disease (AD), providing insights for future research and drug development. In addition, eEF2K is regarded as a "central hub linking metabolic inflammation, protein translation, and autophagy," highlighting its potential as a target for TPD therapies. This perspective provides broader disease coverage, deeper mechanistic insights, and new directions for drug development in metabolic and neurodegenerative disorders.},
}

@article {pmid41819277,
year = {2026},
author = {Bacchin, C and Luciani, M and Troncone, L and Balla, C and Berto, S and Wolf, BJ and Del Monte, F},
title = {Cardiomyopathy and aging integrally contribute to the unfolded protein response collective pathways.},
journal = {Journal of molecular and cellular cardiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.yjmcc.2026.03.001},
pmid = {41819277},
issn = {1095-8584},
abstract = {Proteins are essential elements controlling cellular processes. Their synthesis and assembly are vital to the cell as their defect would have deleterious consequences. A finely tuned conserved biological machinery known as the protein quality control (PQC) is in place to correct the defect. The PQC includes the unfolded protein response (UPR), devoted to recognizing, unfolding and refolding abnormally arranged proteins, and the clearance apparatuses composed of the Ubiquitin Proteasome System (UPS) and the Endoplasmic Reticulum Associated Protein Degradation (ERAD). Abnormally folded proteins accumulate in idiopathic dilated cardiomyopathy (iDCM). In this study we investigated the transcriptional and translational landscapes of the UPR and UPS systems using polymerase chain reaction (PCR) and western blotting (WB) of myocardial tissues from iDCM patients and age, ethnicity and biological sex matched control cases. Our results show an increase of the three main UPR axis at the transcription and translational levels, suggesting an activation/inactivation of all axes, with altered PTM/cleavage/splicing eliciting abnormal downstream function. Notably, aging independently affects this machinery in diseased and control individuals. In addition, mutation in presenilin gene associated with Alzheimer's disease led to post-translational changes of the UPR components suggesting that genetic risk may exacerbate the natural age and disease-driven protein dyshomeostasis. In conclusion, our findings highlight that abnormalities of UPR are a still largely unexplored feature in heart failure to be view in its entirely. The combined alteration of several target proteins of these pathways configures defective proteostasis as a condition of misfolded peptides accumulation ultimately exhausting the cell survival capabilities.},
}

@article {pmid41819259,
year = {2026},
author = {Stanslaski, S and Netoff, TI},
title = {State-Dependent Fornix-Hippocampal Communication and the Impact of Deep Brain Stimulation: Insights from Supervised Learning, Granger Causality and Causal Discovery Analyses.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {103070},
doi = {10.1016/j.brs.2026.103070},
pmid = {41819259},
issn = {1876-4754},
abstract = {BACKGROUND: Deep brain stimulation (DBS) of the fornix (FX) is being explored as a therapy for memory impairment in Alzheimer's disease, but clinical trials have yielded mixed results. The physiological mechanisms underlying these outcomes, particularly the state-dependent dynamics of fornix-hippocampal (HC) communication, remain poorly understood.

OBJECTIVE: To dissect the state-dependent dynamics of FX-HC communication and assess the impact of continuous DBS using chronic local field potential (LFP) recordings, spectral analysis, machine learning, and advanced causal inference techniques.

METHODS: Three ovine subjects were implanted with DBS leads targeting the FX and HC. Chronic LFP recordings were obtained during awake and overnight periods, with and without stimulation. Spectral analysis identified theta band (4-8 Hz) as the frequency of interest. Unsupervised k-means clustering and linear discriminant analysis classified high-theta and low-theta states. This state definition was used to differentiate state-dependent dynamics in communication between the fornix and hippocampus. Granger causality and causal discovery methods quantified the directionality and strength of FX-HC interactions.

RESULTS: Bidirectional, state-dependent communication was observed: during high-theta states HC→FX drive was dominant over FX->HC, while in low-theta states FX→HC drive was enhanced over high-theta states. Continuous FX stimulation disrupted this balance, overdriving FX→HC connectivity and attenuating HC→FX feedback, effectively creating an "electrical lesion." Causal discovery analyses corroborate these findings.

CONCLUSIONS: Continuous fornix DBS disrupts physiological bidirectional communication within the FX-HC network, which may underlie the limited efficacy seen in clinical trials. These results highlight the need for adaptive or cycled stimulation paradigms to preserve endogenous network function and optimize therapeutic outcomes.},
}

@article {pmid41819220,
year = {2026},
author = {Jian, L and Liu, Y and Peng, W},
title = {Oligodendrocyte Dysfunction in Alzheimer's Disease: Integrating Spatial Epigenomics and Metabolic Circuitry in Demyelination - A Critical Review.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103099},
doi = {10.1016/j.arr.2026.103099},
pmid = {41819220},
issn = {1872-9649},
abstract = {Traditional Alzheimer's disease (AD) research has predominantly focused on neuronal pathology within the amyloid-tau-neurodegeneration (ATN) framework, emphasizing β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTS), and neuroinflammation as primary drivers of disease progression. Recently, converging evidence suggests that oligodendrocytes (OLs) and myelin abnormalities are not merely downstream consequences of neuronal injury. Instead, OL dysfunction may emerge early and actively shape disease trajectories. In this critical review, we synthesize findings from spatial epigenomics, metabolic circuitry analysis, single-nucleus RNA sequencing (snRNA-seq), and multimodal neuroimaging to reassess the OLs contributions to AD pathophysiology. We further summarizetherapeutic strategies that target OL dysfunction, including metabolic rescue approaches, epigenetic modulation, remyelination-oriented interventions, and approaches that suppress OL-derived Aβ. Overall, we propose an "OL epigenetic-metabolic axis" as an underappreciated pathological hub in AD. This framework challengesthe conventional victim-perpetrator narrative by repositioning OLs from passive casualties to context-dependent drivers and amplifiers of neurodegeneration. By clarifying how spatially patterned epigenetic dysregulation intersects with metabolic collapse to impair myelin integrity and axonal support, this review provides a rationale for developing innovative neuroprotective strategies aimed at OL repair, remyelination, and metabolic restoration.},
}

@article {pmid41819119,
year = {2026},
author = {Oveisgharan, S and Yang, J and Wang, T and Bennett, DA and Buchman, AS},
title = {Repeated measures of physical activity before dementia diagnosis in community-dwelling older adults: a longitudinal study.},
journal = {The lancet. Healthy longevity},
volume = {},
number = {},
pages = {100824},
doi = {10.1016/j.lanhl.2026.100824},
pmid = {41819119},
issn = {2666-7568},
abstract = {BACKGROUND: Many studies have reported that a single measure of physical activity in older adults is associated with incident dementia. In this study, we examined repeated measures of physical activity to determine if this association with incident dementia varied.

METHODS: Participants were from a community-based longitudinal study of older adults (the Rush Memory and Aging Project [MAP]). MAP participants were recruited from retirement centres and subsidised long-term care facilities across northeastern Illinois (USA). Physical activity level was extracted from biennial multiday wrist-wearing sensor recordings. Dementia diagnosis was based on neuropsychological test scores, clinical history, and examination. Joint modelling integrating a linear mixed-effects model and a Cox model was used to prospectively test the association of repeated measures of physical activity and dementia, and a time-varying effects model was used to retrospectively examine the association of dementia with repeated measures of physical activity before dementia diagnosis.

FINDINGS: Our analyses included 972 older adults (mean age 80·5 years, SD 7·3) with frequent (mean 4·9, SD 2·6) biennial measurements of physical activity. 745 (77%) of 972 participants were female and 227 (23%) were male. 286 (29%) of the 972 participants developed dementia, which was clinically diagnosed as Alzheimer's disease. Although the joint model indicated an association between physical activity and incident dementia (hazard ratio [HR] 0·78, 95% CI 0·69-0·88; p<0·0001), the model accuracy was stronger for physical activity closer to dementia diagnosis. Baseline physical activity was not related to the risk of dementia more than 7 years after baseline (HR 1·00, 95% CI 0·69-1·45; p=0·99), whereas physical activity at year 6 was (0·55, 0·37-0·80; p=0·0021). In a time-varying effects model, repeated physical activity was not associated with incident dementia except during the last 2 years before dementia diagnosis.

INTERPRETATION: Physical activity might be a modifiable protective factor for dementia in old age. However, analyses of repeated measures of physical activity suggest that further work is needed to define the timing of the beneficial effects of physical activity relative to the onset of dementia.

FUNDING: National Institutes of Health.},
}

@article {pmid41818943,
year = {2026},
author = {Gu, L and Liu, J and Shan, X and Li, S and Zheng, M and Wang, C and Tan, Y and Zhuo, X and Li, Q and Yang, W and Zhang, X},
title = {Flavonoids of Ziziphora clinopodioides improve Alzheimer's cognitive impairment and inhibit NLRP3 inflammasome activation via autophagy-lysosome pathway.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {154},
number = {},
pages = {158028},
doi = {10.1016/j.phymed.2026.158028},
pmid = {41818943},
issn = {1618-095X},
abstract = {BACKGROUND: Ziziphora clinopodioides Lam. (Z. clinopodioides), a distinctive medicinal plant endemic to Xinjiang, is predominantly centers on cardiovascular diseases. However, its possible therapeutic value in neurologic conditions have not been thoroughly examined, especially in Alzheimer's disease (AD).

PURPOSE: This study elucidates the intervention effect and mechanism of Z. clinopodioides on cognitive dysfunction in vivo and in vitro.

METHODS: UPLC-Q-Exactive-HR MS/MS technology was employed to analysis the chemical components of Z. clinopodioides and that enter into the serum and brain. the extract of Z. clinopodioides and linarin were administered orally to 3 × Tg-AD mice. Behavioral assessments were carried out and AD-pathology indicator were detected. Additionally, network pharmacology and non-target metabolomics were combined to analyze the potential mechanism.

RESULTS: Flavonoids from Z. clinopodioides (ZCF) were identified as the main components, with linarin being the most abundant. ZCF and linarin improved spatial memory, reduced Aβ deposition and Tau phosphorylation, and suppressed glial cell activation. Mechanistically, ZCF and linarin decreased NLRP3 protein levels and NF-κB phosphorylation, while enhancing LC3B, p62, and Cathepsin D expression, resulting in reduced IL-1β and IL-18 secretion in 3 × Tg mice, HT22 cells or BV2 cells-effects reversed by autophagy inhibition. ZCF promoted NLRP3 and p62 co-localization, leading to NLRP3 degradation via autophagy without affecting its mRNA levels.

CONCLUSION: ZCF restores the autophagy-lysosome pathway and suppresses NLRP3 inflammasome activation, significantly improving cognitive dysfunction in 3 × Tg-AD mice, and highlighting ZCF or linarin as promising candidates for AD treatment.},
}

@article {pmid41818915,
year = {2026},
author = {Sabban, EL and Tanelian, A},
title = {Revisited case for intranasal neuropeptide Y based therapeutics: From preclinical to clinical.},
journal = {Neuropeptides},
volume = {117},
number = {},
pages = {102605},
doi = {10.1016/j.npep.2026.102605},
pmid = {41818915},
issn = {1532-2785},
abstract = {Compelling evidence from a variety of approaches attributes manifold benefits to NPY in the brain. NPY can reduce stress, depressive symptoms, pain, neuroinflammation, seizures, and is implicated in attenuating alcohol use disorder and neurodegenerative diseases, such as Alzheimer's, Machado-Joseph and Huntington Disease. NPY enhances immune regulation, neuro-proliferation, memory and cognition. However, its therapeutic potential has not yet been realized. Intranasal nose to brain (N2B) delivery is a non-invasive approach that can provide high bioavailability with limited side effects. Here we discuss therapeutic opportunities and challenges of N2B administration of NPY and related agonists. Preclinical N2B administration of NPY, either alone or with other compounds, to experimental animals has been very successful. For example, a single NPY intranasal infusion to male rats was able to prevent, as well as reverse, many behavioral impairments triggered by Single Prolonged Stress model for PTSD. Females were found to require higher doses of NPY, or pretreatment with a DPPIV inhibitor, to provide resilience. In humans, limited studies found that intranasal administration of NPY in saline was well tolerated and showed promise for PTSD or depression at highest dose administered. However, saline should be avoided in favor of water for aqueous delivery, and each sex should be analyzed separately. Overall, these findings call for further work to enhance N2B delivery of NPY or selective agonists to human brain to harness NPY's exciting therapeutic potential.},
}

@article {pmid41818828,
year = {2026},
author = {Gao, J},
title = {MTC-MSFFNet: a multi-task classification model based on multi-source feature fusion for Alzheimer's disease.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae510f},
pmid = {41818828},
issn = {2057-1976},
abstract = {Predicting the stages of Alzheimer's disease (AD) is crucial for delaying disease progression and enabling early intervention. A large amount of existing research focuses on the classification of cognitively normal (CN), mild cognitive impairment (MCI), and AD. However, the two subtypes of MCI-stable mild cognitive impairment (sMCI) and progressive mild cognitive impairment (pMCI)-should not be overlooked. Therefore, this study aims to accurately diagnose the disease stage of patients (CN, MCI, or AD) and further distinguish between sMCI and pMCI. In this work, a multi-task classification model based on multi-source feature fusion, termed MTC-MSFFNet, is proposed to accomplish two diagnostic tasks: (1) CN vs. MCI vs. AD, and (2) sMCI vs. pMCI.We select the hippocampus (HIP) and entorhinal cortex (ERC) as feature maps for the three-class task, and the hippocampus (HIP) and gray matter (GM) for the sMCI/pMCI task. The MTC-MSFFNet integrates a multi-source feature fusion module which combining brain structure maps with structural magnetic resonance imaging (sMRI) data, a task-specific weight learning module guided by brain structural information, and dedicated task heads for each classification objective. The proposed method is evaluated on a mixed dataset constructed from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Open Access Series of Imaging Studies (OASIS). Experimental results demonstrate that MTC-MSFFNet achieves an average accuracy of 98.09% for CN vs. MCI vs. AD classification and 95.16% for sMCI vs. pMCI classification. These results indicate that the proposed approach has significant potential to assist clinicians in developing targeted and personalized treatment plans.},
}

@article {pmid41818733,
year = {2026},
author = {O'Connor, MK and Shirk, SD and McLaren, JE and Nguyen, AH and Pugh, K and Sullivan, MA and Metcalf, EE and Harrington, S and Moo, LR},
title = {A Telehealth-Adapted Dementia Caregiver Skills Training Intervention (TeleCARE): Single-Arm Pre-Post Intervention Study.},
journal = {JMIR aging},
volume = {9},
number = {},
pages = {e81256},
doi = {10.2196/81256},
pmid = {41818733},
issn = {2561-7605},
mesh = {Humans ; *Caregivers/psychology/education ; Female ; Male ; *Telemedicine ; *Dementia/psychology/nursing/therapy ; Pilot Projects ; Aged ; Middle Aged ; Aged, 80 and over ; Surveys and Questionnaires ; Feasibility Studies ; },
abstract = {BACKGROUND: Dementia caregivers often want to support aging at home, but as neuropsychiatric symptoms (NPS) become more severe, caregiver challenges increase, often resulting in negative outcomes for both the caregiver and care recipient and institutionalization. Project CARE is a manualized in-person group intervention for dementia caregivers designed to reduce negative caregiver outcomes by teaching skills to manage NPS in care recipients in the home environment. Interventions that occur in person, however, can be difficult for caregivers to attend. Telehealth-based interventions are possible alternatives that reduce barriers to attendance.

OBJECTIVE: The primary objective of this pilot study was to evaluate the feasibility and acceptability of offering CARE via telehealth (TeleCARE). The secondary objective was to explore quantitative outcome trends and effect sizes postintervention outcomes of TeleCARE for both caregivers and care recipients.

METHODS: Rates of recruitment, attendance, and completion were used to assess the feasibility of TeleCARE. Data on technology use and telehealth-based adaptations were also collected. Acceptability was measured using participants' rated satisfaction with the intervention immediately postintervention. Questionnaires were administered at baseline and immediately and 3 months postintervention. Primary outcomes for exploratory analysis included NPS presence, severity, and caregiver NPS-related distress. Secondary outcomes included caregiver depression, anxiety, stress, self-efficacy, positive aspects of caregiving, and meaning and purpose in life.

RESULTS: Of the 109 caregivers contacted for recruitment, 24 (22%) caregivers enrolled in TeleCARE, and 20 (83%) caregivers, predominantly female spouses, completed the study. Feedback from participants in the TeleCARE test group 1 (n=3) was used to modify the intervention to improve the telehealth experience, including adding procedures to improve safety, encourage rapport building, address etiquette, and ensure privacy. The final version of TeleCARE included 7 weekly synchronous video sessions. Ten out of 17 participants (59%) attended all 7 sessions, and all participants attended at least 5 sessions. Satisfaction ratings suggested adequate intervention acceptability. Most participants (11/17, 65%) required technological support, which was needed throughout the intervention. Quantitative trends were observed toward postintervention decreases in care-recipient NPS severity (Cohen d=0.16), caregiver depression (d=0.15), anxiety (d=0.23), and caregiver self-efficacy (d=0.21), as well as increases in positive aspects of caregiving (d=0.18) and meaning and purpose in life (d=0.09). Most improvements were not sustained at the 3-month follow-up.

CONCLUSIONS: In this pilot feasibility study, dementia caregivers were successfully recruited and engaged in TeleCARE. Overall, TeleCARE was deemed feasible and acceptable. The current findings suggest that offering interventions via telehealth requires modifications and technological support for older caregiver engagement but is a feasible and acceptable means of offering services.},
}

Humans
*Caregivers/psychology/education
Female
Male
*Telemedicine
*Dementia/psychology/nursing/therapy
Pilot Projects
Aged
Middle Aged
Aged, 80 and over
Surveys and Questionnaires
Feasibility Studies

@article {pmid41818703,
year = {2026},
author = {Tang, J and Sun, Y and Lin, X and Zhao, X and Mao, C and Wan, M and Li, J and Guan, Y},
title = {Energy Compensation Strategy: The Frontier of Neurodegenerative Disease Treatment.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00964},
pmid = {41818703},
issn = {1948-7193},
abstract = {Neurodegenerative diseases are a major threat to global public health. Recent studies have revealed that mitochondrial DNA damage and the imbalance of protein homeostasis during aging constitute the core pathological basis of neurodegeneration. The resulting energy metabolism disorders are the common pathogenic hubs of multiple neurodegenerative diseases. In this review, we focus on representative neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and Huntington's disease, and systematically discuss their pathology related to metabolic disorders. We introduce various energy compensation strategies: (1) rebuilding the energy supply by enhancing mitochondrial function; (2) implementing systemic metabolic remodeling; (3) supplementing alternative energy substrates; (4) utilizing direct energy delivery technology. This review also highlights the technical bottlenecks of existing energy compensation strategies, guiding future research on neurodegenerative diseases.},
}

@article {pmid41818679,
year = {2026},
author = {Al Qannas, F and Zhou, A and Gasevic, D and Ryan, J and Owen, AJ},
title = {Interactions Between Omega-3 Fatty Acids and Genetic Variants in Contributing to Cognitive Decline and Cardiovascular Disease Risk in Older Adults: A Systematic Review.},
journal = {Nutrition reviews},
volume = {},
number = {},
pages = {},
doi = {10.1093/nutrit/nuag019},
pmid = {41818679},
issn = {1753-4887},
support = {//Monash Graduate Scholarship (Monash University, Australia)/ ; },
abstract = {CONTEXT: Omega-3 fatty acids are suggested to have protective effects against dementia and cardiovascular disease (CVD). Some evidence suggests that genetic elements, including the apolipoprotein E epsilon-4 (APOE-ε4) allele, may modify this association. However, the findings are inconsistent.

OBJECTIVE: In this study we sought to systematically review whether genetic variants modify the association between fish intake or omega-3 fatty acids and cognitive decline or CVD in community-dwelling adults aged 65 years and older.

DATA SOURCES: We searched the Embase, Medline, and Scopus electronic databases, along with the platform Web of Science, from inception to December 10, 2024.

DATA EXTRACTION: The search yielded 2349 papers. Title and abstract screening, along with full-text review, were independently performed by 2 reviewers. 15 studies met the inclusion criteria. Data extraction was completed by 1 reviewer and independently cross-checked by another. Risk of bias was assessed using standard tools.

DATA ANALYSIS: Due to substantial heterogeneity in the available evidence, instead of meta-analysis, a narrative review approach was adopted. A relatively small number of studies reported conflicting results for the dementia, Alzheimer disease (AD), and CVD outcomes; however, higher omega-3 biomarker levels/fish intake appeared to be associated with slower cognitive decline in APOE-ε4 carriers.

CONCLUSIONS: There is some limited evidence suggesting that APOE-ε4 may modify the association between omega-3 intake and cognitive decline in older adults, although the current body of research is inconsistent. This inconsistency highlights the need for additional research to better understand this association to support the development of personalized nutrigenetic-informed interventions to optimize health in later life.

PROSPERO registration No. CRD42024623183.},
}

@article {pmid41818290,
year = {2026},
author = {Liao, K and Du, D and Li, J and Huang, J and Fan, X and Chen, C and Wu, S and Yan, B and Li, H},
title = {Interpretable integration of unpaired multi-omics for Alzheimer's diagnosis via cross-modal transformer reconstruction.},
journal = {PLoS computational biology},
volume = {22},
number = {3},
pages = {e1014074},
doi = {10.1371/journal.pcbi.1014074},
pmid = {41818290},
issn = {1553-7358},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited diagnostic tools and poorly understood molecular underpinnings. Although multi-omics technologies hold promise for early detection, integrating unpaired transcriptomic and epigenetic data remains a major challenge due to modality heterogeneity and small sample sizes. We present AE-Trans, an interpretable dual-channel Transformer framework that aligns RNA and DNA methylation data through cross-modal reconstruction and multi-head attention. AE-Trans achieves superior performance on prefrontal cortex datasets (accuracy = 0.9736, AUC = 0.9910) and demonstrates strong generalizability to external regions temporal cortex cohorts across brain regions (accuracy = 0.7389, AUC = 0.8432). To validate the performance within the same brain region, we tested AE-Trans on an external unpaired multi-omics dataset from the prefrontal cortex. Additionally, we validated the model on a paired multi-omics dataset to assess whether it could achieve good results in real-world scenarios. In the unpaired dataset from the external same brain region, AE-Trans achieved an accuracy of (accuracy = 0.87) and AUC of (AUC = 0.94), while in the real-world paired multi-omics dataset, the accuracy was (accuracy = 0.88) and AUC was (AUC = 0.93). These results demonstrate that AE-Trans not only validates well on external unpaired datasets, but also generalizes effectively to real-world multi-omics paired datasets, highlighting its robustness in practical applications. Through counterfactual integrated gradients, we identified key features associated with immune regulation, hormonal signaling, and neuronal metabolism. These were validated via pathway enrichment and logistic regression (AUC = 0.9749), confirming the biological relevance of model-derived markers. Furthermore, AE-Trans generalized well to two independent RNA datasets, where latent representations not only improved classification (AUCs = 0.92 and 0.89) but also stratified patients into subgroups with significantly different prognoses. These results highlight AE-Trans as a robust and explainable tool for multi-omics integration, supporting early diagnosis, biomarker discovery, and individualized risk prediction in Alzheimer's disease.},
}

@article {pmid41818192,
year = {2026},
author = {Akan, O and Chandreswaran, V and Soldan, HD and Bierbrauer, A and Axmacher, N and Wolf, OT and Merz, CJ},
title = {Cortisol treatment impairs path integration and alters grid-like representations in the male human entorhinal cortex.},
journal = {PLoS biology},
volume = {24},
number = {3},
pages = {e3003661},
doi = {10.1371/journal.pbio.3003661},
pmid = {41818192},
issn = {1545-7885},
mesh = {Humans ; *Entorhinal Cortex/drug effects/physiology ; Male ; *Hydrocortisone/pharmacology/administration & dosage ; Magnetic Resonance Imaging ; Adult ; Young Adult ; *Spatial Navigation/drug effects/physiology ; Brain Mapping ; Caudate Nucleus/drug effects/physiology ; },
abstract = {Acute stress triggers the release of cortisol, which broadly affects cognitive processes. Path integration, a specific navigational process, relies heavily on grid cells in the entorhinal cortex. The entorhinal cortex contains glucocorticoid receptors and is therefore likely to be influenced by cortisol, though little is known about this relationship. Given the role of the entorhinal cortex in neurological diseases such as Alzheimer's Disease, investigating the effects of cortisol on this brain region may offer insights into how stress affects these diseases. In this study, we examined the effects of cortisol on human path integration in 39 healthy men across two sessions. On each day, they received either 20 mg cortisol or a placebo and performed a virtual homing task during functional magnetic resonance imaging (fMRI). Cortisol markedly impaired path integration performance, independent of incoming distance or the presence of spatial cues, but did not affect navigational pattern as measured by proximity to the landmark. fMRI results showed that cortisol increased the activation of right caudate nucleus in the presence of landmarks. Using a representational similarity analysis, we observed grid-like representations in the right entorhinal cortex specifically on day one under placebo, but these were diminished by cortisol. Grid-like representations were associated with PI performance dependent on the availability of spatial cues and cortisol administration, suggesting that cortisol may interfere with the typical relationship of grid cells and PI. Overall, the study indicates that cortisol-induced disruption in grid cell function in the entorhinal cortex may underly stress effects on path integration.},
}

Humans
*Entorhinal Cortex/drug effects/physiology
Male
*Hydrocortisone/pharmacology/administration & dosage
Magnetic Resonance Imaging
Adult
Young Adult
*Spatial Navigation/drug effects/physiology
Brain Mapping
Caudate Nucleus/drug effects/physiology

@article {pmid41818176,
year = {2026},
author = {Thapa, M and Kumari, A and Chin, CY and Choby, JE and Akbari, E and Bogati, B and Jin, F and Furr, E and Chopyk, DM and Koduri, N and Pahnke, A and Burns, TL and Elrod, EJ and Burd, EM and Weiss, DS and Grakoui, A},
title = {Translocation of bacteria from the gut to the brain in mice.},
journal = {PLoS biology},
volume = {24},
number = {3},
pages = {e3003652},
doi = {10.1371/journal.pbio.3003652},
pmid = {41818176},
issn = {1545-7885},
mesh = {Animals ; *Gastrointestinal Microbiome/physiology/drug effects ; *Brain/microbiology/metabolism ; Mice ; *Bacterial Translocation/physiology ; Diet, High-Fat/adverse effects ; Mice, Inbred C57BL ; Male ; Enterobacter cloacae/physiology ; Vagus Nerve/microbiology ; Dysbiosis/microbiology ; },
abstract = {Recent advances suggest a correlation between gut dysbiosis and neurological diseases, however, relatively little is known about how gut bacteria impact the brain. Here, we reveal that bacteria can translocate directly from the gut to the brain in small numbers when mice are fed an atherogenic, high-fat diet (Paigen diet) that causes alterations in gut microbiome composition and gut barrier permeability. The bacteria were not found in other systemic sites or the blood, but were detected in the vagus nerve. Right cervical vagotomy reduced bacterial burden in the brain, implicating the vagus nerve as a conduit for bacterial translocation from the gut to the brain. Antibiotic treatment perturbed the composition of the gut microbiome and correspondingly changed the bacteria that localized to the brain in the setting of Paigen diet feeding. To further establish the gut as the origin of bacterial translocation to the brain, we gavaged exogenous Enterobacter cloacae into Paigen diet-fed mice, subsequently detecting the E. cloacae in the gut and brain. In addition, we monocolonized germ-free mice with E. cloacae and only cultured the bacteria from the brains of mice fed Paigen diet, but not those fed standard diet. Localization of bacteria to the brain in Paigen diet-fed mice was reversible with return to normal diet. Bacteria were also detected in the brain of murine models of Alzheimer's, Parkinson's, and autism spectrum disorder fed standard diet. These data reveal a bacterial translocation axis from the gut to the brain, impacted by environmental (diet) and genetic factors, and warrant further investigation to determine if this phenomenon also occurs in humans and to elucidate whether it may play a role in diverse neurological conditions.},
}

Animals
*Gastrointestinal Microbiome/physiology/drug effects
*Brain/microbiology/metabolism
Mice
*Bacterial Translocation/physiology
Diet, High-Fat/adverse effects
Mice, Inbred C57BL
Male
Enterobacter cloacae/physiology
Vagus Nerve/microbiology
Dysbiosis/microbiology

@article {pmid41817951,
year = {2026},
author = {Nath, R and Ashique, S and Nehra, B and Debnath, I and Ghosh, S and Chawla, PA and Al-Salem, FM and Yasmin, S and Hussain, MS and Das, L and Chakraborty, A and Chakraborty, A and Sridhar, SB and Das, J and Debnath, B and Ansari, MY},
title = {Rational drug design and synthesis of novel bioactive molecules with oxygen heterocycles, including AChE and BChE inhibitory properties and SAR studies.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {41817951},
issn = {1573-501X},
abstract = {Oxygen-containing heterocycles were reviewed as privileged scaffolds that had driven recent advances in rational drug design and synthetic methodology. The manuscript synthesized literature (2015-2025) on oxadiazoles, coumarins, morpholines, pyrans, furans, benzofurans and chromones and summarized how these scaffolds were engineered to optimize potency, selectivity and CNS drug-like properties. Mechanistic analyses demonstrated that oxygen atoms and carbonyl or ether functionalities consistently mediated key hydrogen-bonding and π-interactions within the catalytic anionic site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), rationalizing observed AChE/BChE SAR and dual-site binding. Representative medicinal chemistry campaigns were highlighted: coumarin and coumarin-hybrid series provided potent dual-site inhibitors; 1,2-oxadiazoles or 1,3,4-oxadiazoles produced sub to low-nanomolar AChE/BChE leads; morpholine-bearing scaffolds afforded favourable BBB permeability and mixed-type inhibition; and pyranone-carbamate hybrids delivered highly BChE-selective inhibitors with promising in vivo cognitive effects. Synthetic strategies (multicomponent reactions, metal-catalysed cyclizations and green/one-pot protocols) were reviewed and correlated with scaffold diversification and improved ADME profiles. The review concluded by identifying gaps limited unified docking/SAR databases and sparse translational safety data and proposed a workflow combining fragment-based design, dual-site targeting and early ADME profiling to accelerate lead optimisation toward clinically relevant cholinesterase modulators. This focused synthesis of structure activity, mechanism and synthetic access was intended to inform future heterocycle-centric programs against neurodegenerative targets.},
}

@article {pmid41817439,
year = {2026},
author = {Babygirija, R and Green, CL and Sonsalla, MM and Le, IMF and Xiao, F and Yandell, S and Calubag, MF and Trautman, ME and Tobon, A and Matoska, R and Yeh, CY and Opara, CI and Grunow, I and Vertein, D and Schlorf, S and Knopf, BA and Rigby, MJ and Harris, DA and Keller, MP and Attie, AD and Puglielli, L and Jang, C and Lamming, DW},
title = {Restriction of Individual Branched-Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e15220},
doi = {10.1002/advs.202515220},
pmid = {41817439},
issn = {2198-3844},
support = {//UW Distinguished Research Fellow/ ; //Dalio Philanthropies/ ; NS094154/NS/NINDS NIH HHS/United States ; GM148487/GM/NIGMS NIH HHS/United States ; AG078794/AG/NIA NIH HHS/United States ; AG078794/AG/NIA NIH HHS/United States ; AG088813/AG/NIA NIH HHS/United States ; RC2DK125961/GF/NIH HHS/United States ; AG062715//Wisconsin Alzheimer's Disease Research Center/ ; CA014520//University of Wisconsin Carbone Cancer Center Experimental Animal Pathology Laboratory/ ; AG092586//Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging/ ; I01-BX004031//U.S. Department of Veterans Affairs/ ; IS1-BX005524//U.S. Department of Veterans Affairs/ ; AA029124/AA/NIAAA NIH HHS/United States ; DK125961/DK/NIDDK NIH HHS/United States ; 23AARG-1029665/ALZ/Alzheimer's Association/United States ; AG078794/AG/NIA NIH HHS/United States ; AG078794/AG/NIA NIH HHS/United States ; AG088813/AG/NIA NIH HHS/United States ; F32AG077916/AG/NIA NIH HHS/United States ; K99AG084921/AG/NIA NIH HHS/United States ; HF-AGEAGE-009//Hevolution Foundation/ ; PostdoctoralFellowship//Glenn Foundation for Medical Research/ ; },
abstract = {Dietary protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Each BCAA has distinct physiological and molecular effects, and while restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the role of each individual BCAA on AD is unknown. Here, we investigate the impact of restricting leucine, isoleucine, or valine on metabolism, AD pathology, molecular signaling, and cognition in male and female 3xTg AD mice. Mice were fed BCAA-restricted diets for nine months starting at six months of age. Restriction of either isoleucine or valine, but not leucine, improved metabolic health. We observed distinct, BCAA-specific effects on AD pathology, molecular signaling, and gene expression in both sexes as well as shared molecular responses in males. Restricting any BCAA improved short-term memory in males, with isoleucine having the strongest effect, while valine restriction led to the greatest cognitive benefits for females. These findings suggest that targeted BCAA restriction, particularly of isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay AD.},
}

@article {pmid41817369,
year = {2026},
author = {Wu, Z and Wang, Y and Wu, N and Lu, M and Shi, J},
title = {Procyanidins and Their Therapeutic Potential Against Bone/Cartilage Diseases.},
journal = {Molecular nutrition & food research},
volume = {70},
number = {6},
pages = {e70365},
doi = {10.1002/mnfr.70365},
pmid = {41817369},
issn = {1613-4133},
support = {LQ24H140004//Zhejiang Provincial Natural Science Foundation of China/ ; 82170984//National Natural Science Foundation of China/ ; 82501200//National Natural Science Foundation of China/ ; 2025ZR048//Zhejiang Provincial Administration of Traditional Chinese Medicine Youth Talent Plan Project/ ; GZY-KJS-ZJ-2025-094//National Traditional Chinese Medicine Comprehensive Reform Demonstration Zone Science and Technology Cooperation Project/ ; COHF-KY202511//China Oral Health Foundation Research Grant/ ; },
mesh = {*Proanthocyanidins/therapeutic use/pharmacology/chemistry/pharmacokinetics ; Humans ; Animals ; Osteoporosis/drug therapy ; Antioxidants/pharmacology/therapeutic use ; *Bone Diseases/drug therapy ; Fractures, Bone/drug therapy ; Biflavonoids/therapeutic use ; Arthritis/drug therapy ; Anti-Inflammatory Agents/pharmacology ; },
abstract = {Bone and cartilage diseases impair labor capacity and cause significant economic losses. As a dietary flavonoid, procyanidins have a wide range of sources and possess antioxidant, anti-inflammatory, and anti-tumor properties. They are used to treat various diseases such as tumors, cardiovascular diseases, and Alzheimer's disease. Recent studies have shown that procyanidins inhibit osteoclast activation, ameliorate the inflammatory environment, protect cartilage from damage by inflammatory factors, and reduce bone loss. Larger polymer procyanidins extracted from plants are oligomers that cannot be utilized by the human body. Polymeric procyanidins rely on chemical- or enzyme-assisted methods to depolymerize into oligomeric compounds. This article discusses the role of procyanidins in bone and cartilage diseases such as osteoporosis, arthritis, and fractures; summarizes the basic process of procyanidin extraction; analyzes the advantages and disadvantages of commonly used depolymerization methods; and emphasizes the potential of new biomaterials and targeted drug delivery methods to improve the bioavailability and biological activity of procyanidins.},
}

*Proanthocyanidins/therapeutic use/pharmacology/chemistry/pharmacokinetics
Humans
Animals
Osteoporosis/drug therapy
Antioxidants/pharmacology/therapeutic use
*Bone Diseases/drug therapy
Fractures, Bone/drug therapy
Biflavonoids/therapeutic use
Arthritis/drug therapy
Anti-Inflammatory Agents/pharmacology

@article {pmid41817348,
year = {2026},
author = {Beura, S and Bhadoriya, DRS and Dash, S and Das, AK and Ghosh, A},
title = {Context-Specific Genome-Scale Metabolic Modeling to Unravel the Metabolic Rewiring in Human Diseases.},
journal = {Biotechnology journal},
volume = {21},
number = {3},
pages = {e70213},
doi = {10.1002/biot.70213},
pmid = {41817348},
issn = {1860-7314},
support = {CRG/2020/002080//Department of Science and Technology-GoI/ ; BT/PR37958/GET/119/297/2020//Department of Biotechnology-GoI/ ; SPARC/2019-2020/P1991/SL//Scheme for Promotion of Academic and Research Collaboration (SPARC), MHRD-GoI/ ; },
mesh = {Humans ; *Models, Biological ; *Metabolic Networks and Pathways/genetics ; *Metabolic Diseases/metabolism/genetics ; Neoplasms/metabolism/genetics ; Computer Simulation ; Genome, Human ; },
abstract = {Disruptions in cellular metabolism contributes to the development and progression of various diseases. A comprehensive understanding of these metabolic alterations is essential for developing targeted therapeutic interventions that can address the underlying disease mechanisms. Although the advancements in multi-omics research offers an overview of metabolic reprogramming in diseased conditions, they often fall short of precisely characterizing the intricate metabolic alterations and their functional implications in human health. Genome-scale metabolic models (GEMs) has emerged as an advanced in silico framework for deciphering cellular metabolic activities. Integrating multi-omics data in human GEMs enables the reconstruction of context-specific models, offering a more precise representation of metabolic rewiring in diseased individuals compared to healthy counterparts. Here, we review recent advances in the reconstruction of context-specific genome-scale metabolic models, highlighting their role in studying metabolic alterations across various human diseases such as cancer, diabetes, Parkinson's, Alzheimer's, and nonalcoholic fatty liver. Those context-specific GEMs have facilitated identification of metabolic vulnerabilities, the prediction of novel drug targets, and the assessment of therapeutic interventions. Advancements in model reconstruction algorithms and the assurance of experimental validation will be crucial for unlocking the full potential of context-specific GEMs in understanding complex metabolic diseases and developing targeted therapeutic strategies.},
}

Humans
*Models, Biological
*Metabolic Networks and Pathways/genetics
*Metabolic Diseases/metabolism/genetics
Neoplasms/metabolism/genetics
Computer Simulation
Genome, Human

@article {pmid41817117,
year = {2026},
author = {McNeme, S and Kumar, A and Yim, YY and Hughes, BW and St Romain, C and Li, Y and Kumar, A and Bao, Q and Estill, M and Fan, S and Takatka, N and Chen, EP and Rivera, M and Chen, H and Robison, AJ and Machius, M and Haggarty, SJ and Chin, J and Nestler, EJ and Zhou, J and Rudenko, G},
title = {Efficient In Vivo Pharmacological Inhibition of ΔFOSB, an AP-1 Transcription Factor, in the Brain.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00890},
pmid = {41817117},
issn = {1948-7193},
abstract = {ΔFOSB, an unusually stable member of the AP-1 family of transcription factors, mediates long-term maladaptations that play a key role in the pathogenesis of drug addiction, cognitive decline, dyskinesia, and several other chronic neurological and psychiatric conditions. We have recently identified that 2-phenoxybenzenesulfonic acid-containing compounds disrupt the binding of ΔFOSB to DNA in vitro in cell-based assays, and one such compound, JPC0661, disrupts ΔFOSB binding to genomic DNA in vivo in the mouse brain with partial efficiency. JPC0661 binds to a groove outside of the DNA-binding cleft of the ΔFOSB/JUND bZIP heterodimer in a cocrystal structure. Here, we generated a panel of analogs of JPC0661 to establish structure-activity relationships and improve its in vivo efficacy by replacing its amino-pyrazolone cap moiety with various substituents. We show that one such analog, YL0441, disrupts the binding of ΔFOSB to DNA in vitro and in vivo and suppresses ΔFOSB function in cell-based assays. Importantly, infusion of YL0441 into the hippocampus of APP mice (a mouse model for Alzheimer's disease neuropathology) leads to virtually complete loss of ΔFOSB bound to genomic DNA as detected by CUT&RUN sequencing. Our findings corroborate that the binding/release of AP1 transcription factors to DNA can be controlled via small molecules in vivo, even by analogs of a compound that binds to a groove outside of the DNA-binding cleft, and that our lead can be optimized via medicinal chemistry to yield a much more efficacious inhibitor of ΔFOSB function in vivo. These findings define a strategy to design small-molecule inhibitors for other AP-1 and AP-1-related transcription factors, in particular, those involved in neuropsychiatric and neurological disorders.},
}

@article {pmid41817071,
year = {2026},
author = {Mallika, AP and Mathuranath, PS and Menon, RN and Banerjee, M},
title = {A Novel Rare Homozygous R47C Variant in TREM2 with Frontal Variant Alzheimer's Disease.},
journal = {Neurology India},
volume = {74},
number = {2},
pages = {277-281},
doi = {10.4103/neurol-india.Neurol-India-D-25-00391},
pmid = {41817071},
issn = {1998-4022},
mesh = {Humans ; *Receptors, Immunologic/genetics ; *Membrane Glycoproteins/genetics ; *Alzheimer Disease/genetics ; Male ; Homozygote ; Female ; Mutation/genetics ; Aged ; Cognitive Dysfunction/genetics ; Middle Aged ; Frontotemporal Dementia/genetics ; },
abstract = {Triggering Receptor expressed on Myeloid cells 2 (TREM2) mutations can cause Nasu-Hakola disease, a rare form of dementia, and are also linked to an increased risk of Alzheimer's disease (AD) and frontotemporal dementia (FTD). The TREM2 receptor plays a role in microglial cell function, including response to injury and amyloid beta pathology in the brain. Variants in TREM2, particularly in exon 2, can disrupt its function, contributing to AD pathology, such as accumulation of amyloid beta plaques and tau tangles. In this study, we conducted screening of exon 2 in TREM2 to identify mutations in a carefully characterized cohort comprising individuals with AD, FTD, and mild cognitive impairment (MCI) from South India. We report the identification of a homozygous p.R47C variant (rs753325601) in a case diagnosed with frontal variant AD. Our finding reinforces the correlation between TREM2 genetic variations and the manifestation of atypical AD phenotypes, highlighting the significance of TREM2 mediated pathogenic mechanisms in modulating disease presentation.},
}

Humans
*Receptors, Immunologic/genetics
*Membrane Glycoproteins/genetics
*Alzheimer Disease/genetics
Male
Homozygote
Female
Mutation/genetics
Aged
Cognitive Dysfunction/genetics
Middle Aged
Frontotemporal Dementia/genetics

@article {pmid41816994,
year = {2026},
author = {Evans, A and Bernatchez, P},
title = {A Retrospective Analysis of Human Angiotensin II Receptor Blockers (ARB) Pharmacokinetics, Dosages and Cmax Values for the Experimental Modelling of Pleiotropic and Supratherapeutic Activities.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {138},
number = {4},
pages = {e70203},
doi = {10.1111/bcpt.70203},
pmid = {41816994},
issn = {1742-7843},
support = {/CAPMC/CIHR/Canada ; //GADA Canada/ ; //Canadian Institutes for Health Research and GADA Canada/ ; },
mesh = {Humans ; *Angiotensin II Type 1 Receptor Blockers/pharmacokinetics/pharmacology/administration & dosage ; Retrospective Studies ; Blood Pressure/drug effects ; Dose-Response Relationship, Drug ; Receptor, Angiotensin, Type 1/metabolism/drug effects ; *Models, Biological ; *Angiotensin Receptor Antagonists/pharmacokinetics/pharmacology ; *Antihypertensive Agents/pharmacokinetics/pharmacology/administration & dosage ; Benzimidazoles/pharmacokinetics ; Biphenyl Compounds ; Valsartan/pharmacokinetics ; Tetrazoles/pharmacokinetics/pharmacology ; },
abstract = {Angiotensin II (AngII) receptor blockers (ARBs) are medications that lower systolic blood pressure (BP) by antagonizing the AngII type 1 receptor (AT1). However, ARBs have documented or suspected therapeutic properties in diseases not caused by high BP including diabetes, muscular dystrophy, chronic obstructive pulmonary diseases (COPD) and Alzheimer's disease. ARBs have multiple pleiotropic properties; 'on-target' AT1-dependent pleiotropy can arise from blocking AngII-AT1 binding in non-BP-regulating cells or via inverse or biased ARB-AT1 agonism. In addition, activation of cells lacking AT1 by ARBs suggests the presence of AT1-independent 'off-target' pleiotropy, whereas supratherapeutic properties in the absence of further BP lowering have also been reported. Herein, to determine how ARB pleiotropy and supratherapeutic properties can be modelled in vitro or ex vivo, we perform a retrospective analysis of the literature that characterizes their maximal human plasma concentration, Cmax, which is higher and more likely to trigger pleiotropy than their low nanomolar, AT1-blocking concentrations. Our findings suggest that Cmax is variable and heterogeneous between ARBs, with upper range values as high as 13.6 micromolar in the case of valsartan and lower range values as low as 0.4 micromolar for candesartan. We propose that modelling of ARB pleiotropy be conducted at these concentrations, whereas higher concentrations will mimic supratherapeutic applications.},
}

Humans
*Angiotensin II Type 1 Receptor Blockers/pharmacokinetics/pharmacology/administration & dosage
Retrospective Studies
Blood Pressure/drug effects
Dose-Response Relationship, Drug
Receptor, Angiotensin, Type 1/metabolism/drug effects
*Models, Biological
*Angiotensin Receptor Antagonists/pharmacokinetics/pharmacology
*Antihypertensive Agents/pharmacokinetics/pharmacology/administration & dosage
Benzimidazoles/pharmacokinetics
Biphenyl Compounds
Valsartan/pharmacokinetics
Tetrazoles/pharmacokinetics/pharmacology

@article {pmid41816971,
year = {2026},
author = {Rubin, M and Naik-Talapadatur, A and Majerova, P and Hrabe, J and Kovac, A and Hrabetova, S},
title = {Extracellular Diffusion of Tau Protein Is Slower Than Similar-Sized IgG Protein and Dextran Polysaccharide in Entorhinal Cortex but Not in Prefrontal Cortex.},
journal = {The European journal of neuroscience},
volume = {63},
number = {6},
pages = {e70460},
doi = {10.1111/ejn.70460},
pmid = {41816971},
issn = {1460-9568},
support = {RGP0036/2020//Human Frontier Science Program/ ; //Summer Undergraduate Research Program at the School of Graduate Studies at Downstate/ ; APVV-21-0321//Slovak Research and Development Agency/ ; },
mesh = {*tau Proteins/metabolism ; Animals ; *Entorhinal Cortex/metabolism ; *Prefrontal Cortex/metabolism ; *Dextrans/metabolism ; Humans ; Mice ; *Immunoglobulin G/metabolism ; Male ; *Extracellular Space/metabolism ; Diffusion ; Mice, Inbred C57BL ; },
abstract = {In brain's extracellular space (ECS), proteins form an important part of endogenous macromolecular traffic. Each protein has unique diffusion characteristics governed by its size and, potentially, by charge-based interactions with extracellular matrix. The goal of this study was to provide quantitative data for extracellular diffusion of a human full-length Tau protein (Tau), a large intrinsically disordered protein with positively charged domains including specific heparan sulfate binding sites, in entorhinal cortex (EC) and prefrontal cortex (PFC), two brain regions affected by tauopathies. To this end, diffusion measurements with integrative optical imaging method in agarose gel and acute mouse brain slices determined diffusion permeability in the ECS of these two brain regions for Tau and for several control macromolecules: weakly negatively charged immunoglobulin G, neutral apolipoprotein E with a heparan sulfate binding site, and neutral or positively charged dextran polysaccharides. We found that diffusion permeability for Tau was similar in PFC and EC. In contrast, all other macromolecules were less hindered in EC with the exception of the positively charged dextran, suggesting that charge-based interactions between Tau and negatively charged extracellular matrix retard its extracellular diffusion. In conclusion, the extracellular diffusion of Tau in the EC is exceptionally slow in comparison to the other proteins and neutral dextrans. EC is the brain region linked to an onset of Alzheimer's disease, and the elements of extracellular microenvironment that govern Tau diffusion inside it will affect both its distribution and its clearance and could therefore play an important role in tauopathies such as the Alzheimer's disease.},
}

*tau Proteins/metabolism
Animals
*Entorhinal Cortex/metabolism
*Prefrontal Cortex/metabolism
*Dextrans/metabolism
Humans
Mice
*Immunoglobulin G/metabolism
Male
*Extracellular Space/metabolism
Diffusion
Mice, Inbred C57BL

@article {pmid41816968,
year = {2026},
author = {Li, Y and Yu, S and Lu, K and Zhang, Y and Dong, M and Peng, Y and Xue, L and Alam, W and Shui, Y and Zhou, Y and Ma, W and Bao, M and Li, P and Luo, P and Lu, T and Li, J and Zhang, K and Wang, Y and Yang, S and Yin, N and Faiola, F and Gao, Z and Zhou, J and Zhao, F and He, Y and Koziol, MJ},
title = {ALKBH3 m1A Demethylase Deficiency Reduces Alzheimer's Amyloid-β Pathology.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e22572},
doi = {10.1002/advs.202522572},
pmid = {41816968},
issn = {2198-3844},
support = {2019-I2M-5-015//Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences/ ; IS23091//Beijing Natural Science Foundation/ ; 2022-ZZ-005//Beijing Postdoctoral Research Foundation Fellowship/ ; 2020-YJ-002//Beijing Postdoctoral Research Foundation Fellowship/ ; },
abstract = {Amyloid-beta (Aβ) aggregation, mitochondrial dysfunction, and cognitive decline are hallmarks of Alzheimer's disease (AD), but its initiating molecular events remain unknown. Given that RNA modifications regulate neurodevelopment and neurodegeneration, we explore their functional role in 5xFAD mice, an Aβ AD model. We discover that N1-methyladenosine (m1A) is the most altered RNA modification, and that its regulator demethylase, ALKBH3 is upregulated. Strikingly, Alkbh3 reduction decreases Aβ plaques and restores cognition. Conversely, elevated ALKBH3 levels, observed in AD patients, compromise neuronal morphology and mitochondrial function by impairing mitophagy (degradation of dysfunctional mitochondria), a known driver of neuronal dysfunction. Mechanistically, we reveal that ALKBH3 removes m1A from PINK1 mRNA, the mitophagy master regulator. Given that ALKBH3 is elevated in human AD, causally linked to mitophagy impairment, and confers neuroprotection when depleted, we present ALKBH3 as a mechanistically validated therapeutic target in AD.},
}

@article {pmid41816965,
year = {2026},
author = {Cheung, C and Anita, NZ and Filigrana, P and Fornage, M and Gonzalez, KA and Gallo, LC and Isasi, CR and Kaplan, RC and Li, X and Márquez, F and Parada, H and Perreira, KM and Ramos, AR and Rundek, T and Tarraf, W and Testai, FD and DeCarli, C and González, HM and Sofer, T},
title = {APOE and plasma AD biomarkers: The role of genetic ancestry in Hispanics/Latinos.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71213},
doi = {10.1002/alz.71213},
pmid = {41816965},
issn = {1552-5279},
support = {R01AG075758//National Institute on Aging (NIA)/ ; R01AG048642//National Institute on Aging (NIA)/ ; R56AG048642//National Institute on Aging (NIA)/ ; },
mesh = {Humans ; *Hispanic or Latino/genetics ; Female ; Male ; *Alzheimer Disease/genetics/blood/ethnology ; Biomarkers/blood ; tau Proteins/blood ; Aged ; Amyloid beta-Peptides/blood ; *Apolipoproteins E/genetics ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; Middle Aged ; Aged, 80 and over ; Apolipoprotein E4/genetics ; Peptide Fragments/blood ; White ; },
abstract = {BACKGROUND: Apolipoprotein E (APOE) alleles are well-established genetic risk factors for Alzheimer's disease (AD), but their effects on AD biomarkers (amyloid beta [Aβ]42/40, phosphorylated tau [p-tau]181, neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]) may vary across populations due to ancestry-, age-, and sex-related differences. We hypothesized that these effects vary across Hispanic/Latino background groups with distinct ancestral admixture.

METHODS: We analyzed ε2 and ε4 allele associations with AD biomarkers using survey-weighted linear regression models, adjusting for demographic covariates. Secondary analyses examined genetic analysis group- and ancestry-specific effects.

RESULTS: ε4 was associated with lower Aβ42/40 and higher p-tau181and GFAP levels, but not with NfL, suggesting its role in Aβ and tau deposition and neuroinflammation. ε4 associations were stronger in those with higher European and lower African ancestry.

DISCUSSION: These findings expand on prior studies suggesting that genetic ancestry modifies APOE-associated AD risk in Hispanic/Latino populations and highlight the importance of capturing ancestry-based heterogeneity in AD biomarker research.},
}

Humans
*Hispanic or Latino/genetics
Female
Male
*Alzheimer Disease/genetics/blood/ethnology
Biomarkers/blood
tau Proteins/blood
Aged
Amyloid beta-Peptides/blood
*Apolipoproteins E/genetics
Glial Fibrillary Acidic Protein/blood
Neurofilament Proteins/blood
Middle Aged
Aged, 80 and over
Apolipoprotein E4/genetics
Peptide Fragments/blood
White

@article {pmid41816928,
year = {2026},
author = {Marier, A and Fernández Arias, J and Aumont, É and Hall, BJ and Macedo, AC and Rahmouni, N and Bezgin, G and Vitali, P and Rosa-Neto, P and Montembeault, M},
title = {Language deficits across PET-based Braak stages of tau accumulation in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71286},
doi = {10.1002/alz.71286},
pmid = {41816928},
issn = {1552-5279},
support = {MOP-11-51-31/CAPMC/CIHR/Canada ; RFN 152985/CAPMC/CIHR/Canada ; 159815/CAPMC/CIHR/Canada ; 162303/CAPMC/CIHR/Canada ; MOP-11-51-31-team1//Canadian Consortium of Neurodegeneration and Aging/ ; NIRG-12-92090//Weston Brain Institute and the Alzheimer's Association/ ; NIRP-12-259245//Weston Brain Institute and the Alzheimer's Association/ ; CFI Project 34874//Brain Canada Foundation/ ; 33397//Brain Canada Foundation/ ; 2020-VICO-279314//Fonds de Recherche du Québec- Santé/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology/complications ; Positron-Emission Tomography ; *tau Proteins/metabolism ; Male ; Female ; Aged ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; *Language Disorders/diagnostic imaging/etiology ; Aged, 80 and over ; Neuropsychological Tests ; *Brain/diagnostic imaging/metabolism ; Cohort Studies ; },
abstract = {INTRODUCTION: Language complaints in cognitively unimpaired (CU) individuals may reflect Alzheimer's Disease (AD) pathology and future objective impairments.

METHODS: 211 participants (138 CU, 45 with mild cognitive impairment (MCI), and 28 with dementia) from the TRIAD cohort underwent [18]F-MK-6240 tau-PET and [18]F-AZD-4694 amyloid-PET. Word-finding complaints, confrontation naming, semantic fluency, phonemic fluency and word-knowledge were evaluated.

RESULTS: Complaints about forgetting the names of objects appeared in early tau stages (Braak 1-2), followed by naming difficulties (Braak 3-4), and widespread language impairments in later stages (Braak 5-6). Across the biologically-defined AD continuum, lower language performance was associated with tau accumulation predominantly in left-temporal language regions. In CU, only subjective word-finding complaints related to tau, indicating language concerns could reflect underlying pathology before measurable cognitive decline.

DISCUSSION: Language measures support early detection and staging of AD pathophysiology and contribute to better align cognitive assessment with biological definitions of the disease.},
}

Humans
*Alzheimer Disease/diagnostic imaging/metabolism/pathology/complications
Positron-Emission Tomography
*tau Proteins/metabolism
Male
Female
Aged
*Cognitive Dysfunction/diagnostic imaging/metabolism
*Language Disorders/diagnostic imaging/etiology
Aged, 80 and over
Neuropsychological Tests
*Brain/diagnostic imaging/metabolism
Cohort Studies

@article {pmid41816922,
year = {2026},
author = {Hussain, Z and Ng, D and Leighton, S and Deligianni, F and Ritchie, C and Cavanagh, J},
title = {Plasma inflammatory biomarker profiles across the Alzheimer's disease spectrum in the Bio-Hermes cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71257},
doi = {10.1002/alz.71257},
pmid = {41816922},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/blood ; Biomarkers/blood ; Male ; Female ; Aged ; *Cytokines/blood ; Glial Fibrillary Acidic Protein/blood ; *Cognitive Dysfunction/blood ; Cohort Studies ; Neurofilament Proteins/blood ; *Inflammation/blood ; Amyloid beta-Peptides ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Inflammation contributes to Alzheimer's disease (AD), but its stage-specific and amyloid-dependent patterns remain unclear.

METHODS: We analyzed 964 participants from the Bio-Hermes cohort (cognitively normal [CN] = 404, mild cognitive impairment [MCI] = 302, mild AD = 258). Plasma levels of 32 cytokines, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified alongside core AD biomarkers. Associations with cognition, amyloid, apolipoprotein E (APOE) ε4, and clinical outcomes were assessed using analysis of covariance, partial correlations, and regression models.

RESULTS: Twenty-four cytokines, NfL, and GFAP differed across cognitive groups. Amyloid stratification revealed a core amyloid-independent profile (14 cytokines + NfL) and a broader amyloid-specific profile including GFAP, interleukin (IL)-1β, and IL-18, implicating microglial inflammasome and astrocytic activation. Stage-dependent patterns suggested inflammation may act as early driver, concurrent process, or late amplifier. Paradoxical associations (e.g., eotaxin-2, IL-2R with better memory) and APOE ε4-linked immune differences indicated context-dependent roles.

DISCUSSION: This exploratory study reveals biologically plausible, inflammatory heterogeneity in AD and highlights plasma cytokine profiles as candidate biomarkers and therapeutic targets, warranting investigation.},
}

Humans
*Alzheimer Disease/blood
Biomarkers/blood
Male
Female
Aged
*Cytokines/blood
Glial Fibrillary Acidic Protein/blood
*Cognitive Dysfunction/blood
Cohort Studies
Neurofilament Proteins/blood
*Inflammation/blood
Amyloid beta-Peptides
Aged, 80 and over

@article {pmid41816863,
year = {2026},
author = {Sun, Z and Li, C and Bai, R and Ge, Y and Wang, C},
title = {Advanced MRI of the choroid plexus: Applications in aging and dementia.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261429043},
doi = {10.1177/0271678X261429043},
pmid = {41816863},
issn = {1559-7016},
abstract = {The choroid plexus (ChP), a highly vascularized epithelial organ within the brain ventricles, sustains cerebrospinal fluid (CSF) production, regulates the blood-CSF barrier (BCSFB), and coordinates neuroimmune responses. Beyond these classical roles, the ChP is increasingly recognized as an active interface within brain clearance pathways, facilitating CSF-interstitial fluid (ISF) exchange and contributing to metabolic waste removal. Structural and functional disruption of the ChP/BCSFB accompanies aging and has been linked to the pathogenesis of neurodegenerative disorders. Magnetic resonance imaging (MRI) provides a powerful, non-invasive platform for in vivo characterization of the ChP. This review summarizes recent advances in MRI techniques tailored to ChP imaging, including quantitative assessments of microstructure, perfusion, permeability, and dynamic water exchange, and highlights their applications in aging and dementia. Converging evidence suggests that MRI-derived indices of ChP integrity are associated with cognitive status and may facilitate early detection and longitudinal monitoring of disease trajectories, particularly in Alzheimer's disease and related dementias (AD/ADRD). Continued development and application of advanced MRI approaches will be essential for further elucidating the role of the ChP in neurodegeneration and for evaluating its potential clinical utility.},
}

@article {pmid41816611,
year = {2026},
author = {Liu, T and Wetzel, L and Roy, D and Zhang, K and Zhu, Z and Kumaraguru, P and Gorthi, V and Jeon, H and Woo, JA and Kang, DE},
title = {APP E590D mutation increases generation of Aβ and Aη peptides and exacerbates tauopathy.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {21},
pmid = {41816611},
issn = {3005-1940},
abstract = {Accumulation of Amyloid β (Aβ), a peptide derived from endocytic processing of the amyloid precursor protein (APP), is a critical initial step in the development of Alzheimer's disease (AD). While the APP695[E590D] mutation was previously discovered in 2 pathologically confirmed AD patients, the pathogenicity of this mutation has remained uncertain due to its exceptional rarity. Here, we characterize the APP695[E590D] mutation by evaluating multiple APP metabolites and determining its effects on tauopathy in cellular and animal models. We show that APP695[E590D] not only increases Aβ through endocytic β-secretase processing but also increases Aη, an alternative APP-derived synaptotoxic peptide. We further demonstrate that APP695[E590D] promotes tauopathy by increasing tau seeding and aggregation in cellular models and exacerbating phospho-tau pathology and neuroinflammation in tau[P301S] mice. These results reveal a unique modality by which APP695[E590D] impinges on AD pathology by enhancing both Aβ and Aη generation and accelerating tauopathy.},
}

@article {pmid41816610,
year = {2026},
author = {Kuzma, A and Valladares, O and Greenfest-Allen, E and Cantwell, L and Katanic, Z and Kirsch, M and Nicaretta, H and Ren, Y and White, H and Wilk, A and Kuksa, P and Lee, WP and Leung, YY and Schellenberg, GD and Wang, LS},
title = {Genomic stewardship in Alzheimer's disease: a decade of insights from the NIAGADS platform.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {19},
pmid = {41816610},
issn = {3005-1940},
abstract = {Fourteen years ago, Alzheimer's disease (AD) genetics entered an era of exponential data growth, but the infrastructure to support and steward that data had yet to catch up. Large-scale genomic discovery demands more than storage; it requires coordination, ethical rigor, and a platform architecture that transforms raw data into shared knowledge. In response, the National Institute on Aging launched the Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), not simply to house genetic data for AD and AD-related dementias (ADRD), but to enable its responsible reuse. What began in 2012 as a repository has evolved into an integrated system for policy-aligned access, harmonized data production, and broad community engagement. A detailed overview of NIAGADS was recently published as a Perspective in Alzheimer's & Dementia[1]. In this Commentary, we reflect on key lessons from building and operating NIAGADS at national scale, with the goal of informing the next generation of genomic platforms.},
}

@article {pmid41816609,
year = {2026},
author = {Olson, MN and Barton, NJ and Feng, L and Chigas, SM and Tran, K and Orszulak, AR and Johnson, JM and Dawes, P and Shrestha, C and Umaiyalan, VR and Huang, YH and Sundstrom, J and Murray, LF and Wang, Q and Oh, HS and Orzalli, MH and Knipe, DM and Readhead, B and Chan, Y and Lim, ET},
title = {A high-throughput, quantitative platform using 2D dissociated human cerebral organoids to model neuroinflammation in Alzheimer's disease.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {20},
pmid = {41816609},
issn = {3005-1940},
abstract = {Neuroinflammation is a key process associated with Alzheimer's disease (AD). There is interest in developing New Approach Methodologies (NAMs) by using human in-vitro complex systems such as brain organoids, combined with machine learning and computational approaches, to reproducibly and robustly evaluate monoclonal antibodies and other therapeutic modalities on these human-derived systems. Herpesviruses such as herpes simplex virus 1 (HSV-1) had been shown to be associated with AD risk and molecular pathology. Building on top of previously reported work, we used herpes simplex virus 1 (HSV-1) infection in 2D dissociated cells from human cerebral organoids (dcOrgs) to recapitulate AD-associated molecular readouts, such as high co-abundance of intracellular beta amyloid (Aβ) and phosphorylated tau (pTau) with HSV-1. Secreted Aβ42/40 ratios in conditioned media were lower from HSV-1-infected dcOrgs, compared to mock dcOrgs. Differentially expressed transcripts from bulk and single-cell RNA sequence data in HSV-1-infected dcOrgs were enriched for AD-associated GWAS genes. Our high-throughput, quantitative framework represents a comprehensive approach to harness on the strengths of 2D dcOrgs for high-throughput applications such as therapeutic screens and can complement the 3D brain organoids and animal models for neuroinflammation in AD.},
}

@article {pmid41816551,
year = {2026},
author = {Angelopoulou, E and Tsinia, N and Hatzopoulou, M and Despoti, A and Kamtsadeli, V and Papadogiani, M and Stanitsa, E and Kyriakidis, V and Papageorgiou, S and Papatriantafyllou, JD},
title = {From mild behavioral impairment-checklist (MBI-C) to MBI-distress (MBI-D): a paired assessment and clinical correlates of domain-specific caregiver distress in MCI due to AD.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1736570},
pmid = {41816551},
issn = {2813-3919},
abstract = {BACKGROUND: Mild behavioral impairment (MBI) captures later-life onset neuropsychiatric symptoms (NPS) that may herald neurodegeneration. The emotional impact of these early behavioral changes on caregivers is under-measured in pre-dementia care.

OBJECTIVE: To develop a brief, domain-aligned caregiver distress scale for MBI (MBI-D) and examine clinical correlates of MBI-related caregiver distress in mild cognitive impairment due to AD (MCI-AD).

METHODS: One hundred and four participant-informant dyads with MCI-AD at a Greek memory clinic were included. Caregivers completed the Greek MBI-C and the new five-item MBI-D (one item per ISTAART-AA MBI domain). Internal consistency (Cronbach's α), non-parametric tests, and Spearman correlations assessed bivariate associations. Multiple linear regression identified independent correlates of MBI-D total. Prespecified covariates were age, education, sex, global cognition (MMSE or ACE-R), disease duration, and MBI-C (total or domains).

RESULTS: Internal consistency of the MBI-D was moderate (α = 0.617; standardized α = 0.627; mean inter-item r = 0.25). MBI-D total correlated strongly with MBI-C total (ρ = 0.789, p < 0.001), and each MBI-D domain correlated with its corresponding MBI-C domain (ρ = 0.478-0.850, all p < 0.001). Disease duration was associated with MBI-D total and with apathy-related distress (ρ = 0.302, p = 0.002 and ρ = 0.392, p < 0.001, respectively). In multivariable regression, MBI-C total and education were independent predictors of MBI caregiver distress (β = 0.804, p < 0.001, and β = 0.135, p = 0.017, respectively). In the MBI-C domains model, impulse dyscontrol, apathy and emotional dysregulation independently related to higher distress (B = 0.513, β = 0.482, p < 0.001, B = 0.315, β = 0.278, p < 0.001, and B = 0.289, β = 0.227, p = 0.001 respectively), while cognitive performance (MMSE and ACE-R) did not have a significant impact.

CONCLUSION: The MBI-D, strongly coupled with MBI-C, is a concise, clinically practical and scalable measure of MBI-related caregiver distress in MCI-AD, capturing both symptom burden and domain-specific distress in a single administration. Impulsivity, apathy, and affective dysregulation are highlighted as priority targets for early, caregiver-focused interventions advancing innovative, prevention-oriented dementia care delivery.},
}

@article {pmid41816512,
year = {2026},
author = {Eliav, T and Alguayn, F and Zlotnik, Y and Horev, A},
title = {Cerebral Venous Insufficiency as a Contributing Factor in Dementia: An Emerging Hypothesis.},
journal = {Stroke (Hoboken, N.J.)},
volume = {6},
number = {1},
pages = {e002083},
pmid = {41816512},
issn = {2694-5746},
abstract = {Emerging evidence suggests that disturbances in cerebral venous outflow may play a meaningful role in the development and progression of cognitive impairment. The brain's glymphatic system, which facilitates the clearance of metabolic waste, including β-amyloid and tau, relies on stable venous pressure gradients to drive perivascular and interstitial fluid movement. Venous insufficiency, whether from structural narrowing or functional outflow obstruction, can disrupt these gradients, reducing clearance efficiency and promoting protein accumulation, neuroinflammation, and white matter injury. Age-related changes in venous compliance, increased pulsatility, and stenosis of the dural venous sinuses have been observed in patients with mild cognitive impairment and dementia, raising the possibility that such hemodynamic alterations may be a significant part of neurodegenerative pathology. As venous sinus stenosis is a potentially treatable condition, it may represent a future therapeutic target. This review synthesizes current knowledge on the interplay between venous circulation and glymphatic function in brain health, outlines the mechanistic basis for venous contributions to cognitive decline, and highlights the need for systematic investigation of further therapeutic treatments in the context of age-related cognitive impairment.},
}

@article {pmid41816361,
year = {2026},
author = {Das, V and Hajdúch, M},
title = {Oncology drug repurposing as a blueprint for Alzheimer's therapy.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70231},
pmid = {41816361},
issn = {2352-8737},
abstract = {Alzheimer's disease (AD) imposes substantial personal, social, and economic burdens, yet current therapies provide only modest slowing of clinical decline. Recent approvals of amyloid-targeting antibodies confirm target engagement but also expose the limitations of single-target strategies in a disease shaped by interacting processes, including amyloid pathology, tau aggregation, neuroinflammation, vascular dysfunction, and metabolic disturbances. These limitations suggest that therapeutic approaches should target multiple pathways rather than isolated lesions. Over the past two decades, cancer therapy has shifted toward rational combinations, multi-target interventions, drug repurposing, and adaptive trial designs. Several of these principles are directly relevant to AD. Recent studies, including work showing that combinations of approved anticancer agents can reverse AD-related network dysfunction across multiple brain cell types, suggest that repurposing oncology drugs for neurodegeneration is biologically plausible. An added advantage is that repurposing builds on existing safety, pharmacokinetic, and clinical experience, which may reduce development time and cost. In this Perspective, we discuss how oncology-informed repurposing strategies, combined with biomarker-based enrichment, system-level pharmacology, and adaptive platform trials, could support more integrated therapeutic development for AD. We also consider practical translational and regulatory issues, including expectations for demonstrating combination benefit, managing drug-drug interactions, and navigating intellectual property pathways. Together, these cross-disciplinary strategies offer a realistic path toward treatments that can produce durable, population-level benefits.},
}

@article {pmid41816335,
year = {2026},
author = {Yang, J and Tsourdinis, GE and Holas, C and Maienschein-Cline, M and Lalonde, R and Fukuchi, KI},
title = {MiR-34a deficiency enhances nucleic acid sensing and type I IFN signaling in a mouse model of Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1694824},
pmid = {41816335},
issn = {1664-3224},
mesh = {Animals ; *MicroRNAs/genetics ; *Alzheimer Disease/genetics/metabolism/immunology ; Mice ; Disease Models, Animal ; *Interferon Type I/metabolism ; Signal Transduction ; Mice, Knockout ; Microglia/metabolism/immunology ; Hippocampus/metabolism ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Male ; *Nucleic Acids/immunology ; },
abstract = {BACKGROUND: A number of microRNAs are implicated in aging, cell senescence, inflammation, and neurodegenerative diseases. Particularly, miR-34a levels in the brain are increased in Alzheimer's disease (AD) but its mechanistic role in AD pathogenesis is unknown.

METHODS: In order to investigate the role of miR-34a in AD, we produced an AD mouse model, Tg-SwDI mice, with whole body/constitutive miR-34a knockout (KO). Their cognitive function was evaluated by Morris water maze. Immunohistochemistry and immunofluorescence were used for neuropathological evaluation. Bulk RNA-seq followed by bioinformatics was used for hippocampal transcriptomics. The effect of miR-34a knockdown on expression of interferon-stimulated genes (ISG) was determined using cultured microglial cells and quantitative PCR.

RESULTS: MiR-34a KO improved long-term memory in Tg-SwDI mice, which was associated with decreases in the ratio of insoluble Aβ42 to Aβ40 and with increases in soluble and insoluble Aβ40 in the cerebral cortex. Anti-Iba1 immunofluorescence revealed increases in activated microglia. Bulk RNA-sequencing of the hippocampus followed by a gene set enrichment analysis (Enrichr) identified "cellular response to type I interferon" and "type I interferon signaling pathway" as the most prominent gene sets in miR-34a KO Tg-SwDI mice compared to miR-34a wild-type Tg-SwDI mice. Many interferon-stimulated genes (ISGs) that characterize interferon responsive microglia (IRM) were upregulated in miR-34a KO Tg-SwDI mice. MiR-34a knockdown strongly enhanced ISGs expression in TLR7 ligand-stimulated BV2 and primary microglia.

CONCLUSION: Our results suggest that miR-34a inhibits the transition of microglia to the IRM state that may modulate synaptic and cognitive functions in neurodegenerative diseases and aging.},
}

Animals
*MicroRNAs/genetics
*Alzheimer Disease/genetics/metabolism/immunology
Mice
Disease Models, Animal
*Interferon Type I/metabolism
Signal Transduction
Mice, Knockout
Microglia/metabolism/immunology
Hippocampus/metabolism
Mice, Transgenic
Amyloid beta-Peptides/metabolism
Male
*Nucleic Acids/immunology

@article {pmid41816247,
year = {2026},
author = {de la Monte, SM and Tong, M and Sutherland, G},
title = {Molecular and biochemical correlates of frontal lobe white matter degeneration in humans with alcohol use disorder.},
journal = {Advances in drug and alcohol research},
volume = {6},
number = {},
pages = {15431},
pmid = {41816247},
issn = {2674-0001},
abstract = {BACKGROUND: Alcohol-related brain damage caused by heavy alcohol misuse is associated with cognitive-motor impairment and white matter (WM) degeneration. Oligodendrocytes and myelin are major targets, but the underlying mechanisms remain incompletely characterized, particularly in humans.

PURPOSE: This study investigates the nature of oligodendrocyte dysfunction in anterior frontal lobe tissue from humans with alcohol use disorder (AUD), focusing on molecular and biochemical pathologies that may underlie WM ARBD.

METHODS: Cores of fresh frozen human postmortem frontal lobe WM from adults with AUD or no history of substance use disorder (N = 6/group) were analyzed with duplex enzyme-linked immunosorbent assays, multiplex immunoassays, and multiplex RNA hybridization panels.

RESULTS: AUD anterior frontal lobe WM tissue exhibited myelin loss with significant changes in oligodendrocyte/myelin glycoprotein immunoreactivity and mRNA expression, increased glial fibrillary acidic protein, and reduced expression of mRNA transcripts encoding upstream components of the insulin and insulin-like growth factor networks, aspartyl-asparaginyl-β-hydroxylase, and the Notch signaling pathway. In contrast, neuroinflammatory mediators and Alzheimer's disease (AD) biomarkers were largely unaffected.

CONCLUSION: Human AUD anterior frontal lobe WM pathology is accompanied by significant alterations in oligodendrocyte and astrocyte function, with alterations in Notch and insulin/IGF signaling. The findings provide new information on the mechanisms of AUD-mediated WM degeneration as well as potential strategies for diagnosing ARBD in humans.},
}

@article {pmid41816196,
year = {2026},
author = {Windon, CC and Tsoy, E and Livaudais-Toman, J and Neilands, TB and Palmer, NR and Heston, MB and Johnson, JK and Hanna, L and Gatsonis, C and Romanoff, J and Steingrimsson, J and Carrillo, MC and Dilworth-Anderson, P and Hillner, BE and Siegel, BA and Whitmer, RA and Wilkins, CH and Smith, K and Blazhenets, G and La Joie, R and Miller, BL and Possin, KL and Rabinovici, GD},
title = {Association of residential neighborhood disadvantage with amyloid PET positivity among cognitively impaired individuals.},
journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging},
volume = {2},
number = {1},
pages = {},
pmid = {41816196},
issn = {2997-3805},
abstract = {INTRODUCTION: Relationships between Alzheimer's disease neuropathology, residential neighborhood, and cognitive impairment remain incompletely understood.

METHODS: We examined whether residence within a disadvantaged neighborhood was associated with amyloid positron emission tomography (PET) positivity. We used data from the observational, multisite, Imaging Dementia-Evidence for Amyloid Scanning study that included cognitively impaired Medicare beneficiaries. Our secondary analysis examined multivariable-adjusted associations between neighborhood disadvantage (measured by Area Deprivation Index [ADI] deciles 1-90 vs. 91-100 representing greatest disadvantage) and amyloid PET positivity.

RESULTS: Among 15,346 White, 829 Latino, 637 Black/African American, and 321 Asian individuals, 51% were female, mean age was 75.7 years, 535 (3.8%) resided in ADI 91 to 100 decile, and 61.6% were amyloid PET positive. The ADI 91-100 decile was associated with lower odds of PET positivity by visual interpretation (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.67-0.96, p ≤ .001) but not PET Centiloid value ≥ 40 versus ≤ 10 (OR 0.81, 95% CI 0.66-1.01, p = 0.060).

CONCLUSION: Residence in the most disadvantaged neighborhoods may be associated with lower amyloid pathology in cognitively impaired individuals.},
}

@article {pmid41816052,
year = {2026},
author = {Bai, H and Zhou, Z and Dai, K and Shen, W and Chen, H and Zhang, Z},
title = {Distortion-free diffusion-weighted imaging using echo planar time-resolved imaging with prospective motion correction: a feasibility study in motion-sensitive patients.},
journal = {Quantitative imaging in medicine and surgery},
volume = {16},
number = {3},
pages = {214},
pmid = {41816052},
issn = {2223-4292},
abstract = {BACKGROUND: Diffusion-weighted imaging (DWI) has been widely used in clinical applications with single-shot or multi-shot echo planar imaging (EPI), but suffers from geometric distortions and motion artifacts. This study aimed to evaluate the clinical feasibility and image quality of combining echo planar time-resolved imaging (EPTI) with markerless prospective motion correction (PMC) in motion-sensitive patients.

METHODS: We evaluated 3-shot EPTI-DWI with PMC against single-shot EPI-DWI in one healthy volunteer who performed controlled head movements and in 38 patients (24 adolescent patients with anxiety disorder and 14 with Alzheimer's disease). Two radiologists independently rated image quality on a five-point scale. Interreader agreement was evaluated using the intraclass correlation coefficient (ICC), and image quality scores were compared with the Wilcoxon signed-rank test. Apparent diffusion coefficients (ADC) were derived and compared between EPI-DWI and EPTI-DWI in predefined regions of interest using linear regression and Bland-Altman analysis.

RESULTS: In the volunteer experiment, enabling PMC during EPTI-DWI effectively corrected motion-induced artifacts compared with EPTI without PMC. Across 38 patients, EPTI-DWI with PMC significantly reduced geometric distortion vs. EPI-DWI (4.74±0.43 vs. 3.46±0.54; P<0.001), improved diagnostic confidence (4.66±0.56 vs. 4.26±0.38; P<0.001), and increased overall image quality (4.76±0.41 vs. 4.39±0.44; P<0.01) with no difference in anatomical clarity (4.66±0.57 vs. 4.74±0.45; P=0.49). Interreader agreement was moderate-to-excellent (ICC =0.77-0.88). ADC values showed strong correlation between EPTI-DWI and EPI-DWI (r=0.89, P<0.001). Bland-Altman analysis revealed a small positive bias of EPTI-DWI relative to EPI-DWI (mean bias, 63.72×10[-6] mm[2]/s; 95% limits of agreement, 0.20×10[-6]-127.25×10[-6] mm[2]/s).

CONCLUSIONS: EPTI-DWI with PMC provided high-resolution, distortion-free diffusion imaging improved overall image quality compared to EPI-DWI. The technique proved feasible in motion-sensitive patients, highlighting its potential for broader clinical application.},
}

@article {pmid41816005,
year = {2026},
author = {Bettcher, B and McLachlan, M and Zammit, M and McVea, A and DiFilippo, AH and Murali, D and Pirasteh, A and Jonaitis, E and Landhough, R and Betthauser, T and Johnson, S and Christian, BT},
title = {Longitudinal amyloid burden with combined [[11]C]PiB and [[18]F]NAV4694 PET scans.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {41816005},
issn = {2837-6056},
abstract = {The β-amyloid radiotracer [[18]F]NAV4694 is a desirable alternative to [[11]C]PiB, possessing similar imaging characteristics and favorable radiopharmaceutical distribution. This work examined the consistency of amyloid measures between [[11]C]PiB and [[18]F]NAV4694 as participants transition between radiotracers in longitudinal studies. Thirty-five participants with ≥1 [[11]C]PiB scans, followed by a [[18]F]NAV4694 scan, were recruited from ongoing AD studies at the University of Wisconsin. Amyloid stability was evaluated in Aβ- individuals and amyloid accumulation was evaluated in Aβ+ individuals. In Aβ- participants, [[18]F]NAV4694 measures were consistent with the preceding [[11]C]PiB measures, showing no significant differences in CL values. Aβ+ participants exhibited an average annualized Aβ accumulation of 6.0 ± 1.8 CL/yr, consistent with modeled [[11]C]PiB Aβ projected outcomes. [[18]F]NAV4694 demonstrated both consistency in trending amyloid accumulation and constancy in sustained Aβ- participants compared with [[11]C]PiB. This study highlights how both radiotracers can be integrated within a single analytical framework under a uniform processing pipeline.},
}

@article {pmid41815723,
year = {2026},
author = {Li, C and Li, C},
title = {Editorial: Technology developments and clinical applications of artificial intelligence in neurodegenerative diseases.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1802039},
doi = {10.3389/fneur.2026.1802039},
pmid = {41815723},
issn = {1664-2295},
}

@article {pmid41815635,
year = {2026},
author = {Jung, Y and Counts, SE and Hampstead, BM and Peltier, SJ and Paulson, HL and Giordani, B and Bhaumik, AK and Beck, JS and Damoiseaux, JS},
title = {Plasma neurofilament light is associated with hippocampal volume and memory performance but not functional connectivity in older adults with and without mild cognitive decline.},
journal = {Aging brain},
volume = {9},
number = {},
pages = {100157},
pmid = {41815635},
issn = {2589-9589},
abstract = {Plasma neurofilament light chains (pNfL) have shown promise as a biomarker for tracking and predicting neurodegeneration, such as cortical atrophy and hypometabolism, in Alzheimer's Disease (AD). However, it is still not clear whether neurofilament light chains (NfL) also reflect alterations in the functional connectivity (FC) of the default mode network (DMN), a functional network showing alterations in earlier stages of AD. In this cross-sectional study including 62 cognitively unimpaired (CU) and 47 cognitively impaired (CI) older adults likely due to AD, we measured FC in the posterior midline DMN, and its FC with frontal DMN, temporoparietal DMN, and hippocampus. We also examined whether the previously observed relationships between pNfL and hippocampal volume, as well as memory function, are replicated in our dataset. pNfL showed no association with DMN FC in either the CI or the CU group. However, higher pNfL was associated with lower right hippocampal volume and memory score in the CI group. Our results support the utility of pNfL as a biomarker tracking hippocampal atrophy and memory function but not for predicting DMN FC in older adults with cognitive decline of Alzheimer's type.},
}

@article {pmid41815605,
year = {2026},
author = {Gupta, DK and Kumar, R},
title = {Gut-Derived Metabolites and Cognitive Health: Roles of Short-Chain Fatty Acids and Trimethylamine N-oxide.},
journal = {Cureus},
volume = {18},
number = {2},
pages = {e103206},
pmid = {41815605},
issn = {2168-8184},
abstract = {The gut microbiota has emerged as an important regulator of host physiology, extending well beyond digestion and metabolism. Increasing attention has focused on the gut-brain axis, a bidirectional communication network linking the gastrointestinal tract and the central nervous system. Among the many microbial metabolites implicated in gut-brain signalling, short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO) have attracted particular interest because of their potential roles in neuroinflammation, vascular dysfunction, and cognitive decline. This narrative review synthesizes current evidence linking SCFAs and TMAO to cognitive health, drawing on human observational studies, experimental animal models, and mechanistic and secondary syntheses. Human data remain limited and largely observational. Altered gut microbiota composition and reduced SCFA levels have been reported in Parkinson's disease and have been associated with disease severity and neurological phenotypes. In parallel, TMAO has been detected in human cerebrospinal fluid and shown to interact with the blood-cerebrospinal fluid barrier, establishing biological plausibility for central nervous system exposure. Observational studies further link circulating TMAO levels with Alzheimer's disease biomarkers, mild cognitive impairment, and dementia-related neuroimaging features. Experimental evidence provides more direct support. TMAO supplementation promotes brain aging, cognitive impairment, and neuropathological changes in mouse and rat models. In contrast, SCFAs, particularly butyrate, exert neuroprotective effects in models of Alzheimer's disease, Parkinson's disease, and systemic inflammation, with improvements in memory and reductions in pathological markers. Mechanistic studies suggest that SCFAs may modulate immune responses, preserve blood-brain barrier integrity, and regulate microglial activity, whereas TMAO has been linked to endothelial dysfunction, oxidative stress, and neurovascular impairment. Taken together, available evidence supports biologically plausible but still preliminary roles for gut-derived metabolites in cognitive health. SCFAs appear broadly neuroprotective, while TMAO shows adverse associations, particularly in preclinical models. Human causality remains unproven, and clinical translation is premature. Well-designed longitudinal and interventional studies are required before these metabolites can be considered reliable biomarkers or therapeutic targets.},
}

@article {pmid41815391,
year = {2026},
author = {Kumar, N and Jangid, K and Kumar, V and Dwivedi, AR and Kumar, V and Devi, B and Arora, T and Parkash, J and Kumar, V},
title = {Synthesis and biological evaluation of N/O-propargylated diarylpyrimidines as dual inhibitors of acetylcholinesterase and monoamine oxidase.},
journal = {RSC advances},
volume = {16},
number = {15},
pages = {13369-13380},
pmid = {41815391},
issn = {2046-2069},
abstract = {Alzheimer's disease is a complex neurological disorder and is becoming a global health concern as the population ages. Considering the complex aetiology of the disease and ineptness of single-targeted drugs, the development of multi-targeted drugs emerges as the most effective strategy for the treatment of the disease. Cholinesterases and monoamine oxidases are amongst the most widely explored targets in Alzheimer's disease, and their dual inhibition offers a promising approach for achieving multipotent therapeutic effects. Herein, we designed and synthesized a series of N/O-propargylated diaryl pyrimidines and evaluated their inhibitory activity against acetylcholinesterase (AChE) and monoamine oxidase (MAO) enzymes. Most of the compounds were found to be active against AChE, MAO-A and MAO-B. Amongst the synthesised derivatives of the series, compounds, compounds NV-1 and NV-9 exhibited a balanced multipotent activity profile against both the targets i.e. acetylcholinesterase and monoamine oxidase. Compounds NV-1 and NV-9 displayed IC50 values of 1.30 µM and 0.88 µM against AChE, 0.232 µM and 9.31 µM against MAO-A and 0.949 µM and 9.23 µM against MAO-B, respectively. In the reversibility inhibition studies, both the compounds were found to be reversible in nature. In kinetic inhibition studies, both NV-1 and NV-9 showed non-competitive inhibition for AChE. Additionally, NV-1 and NV-9 were found to be moderately neuroprotective in nature and exhibit no cytotoxicity at lower compound concentrations. In the partition coefficient studies (octanol/water), the compound NV-9 was found to be lipophilic in nature. Molecular docking studies illustrate their stability within the active cavity of both enzymes. Simulation studies confirmed the thermodynamic stability of these compounds within the cavity for up to 100 ns. Thus, the N/O-propargylated diarylpyrimidines have the potential to be developed as multipotent drugs for the treatment of Alzheimer's disease.},
}

@article {pmid41815099,
year = {2026},
author = {Warren, A},
title = {Loneliness as a sex-specific risk factor for cognitive aging.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1784613},
pmid = {41815099},
issn = {1662-5161},
abstract = {Loneliness has emerged as a robust risk factor for adverse cognitive outcomes, including accelerated cognitive decline and increased dementia risk. However, accumulating evidence suggests that the cognitive consequences of loneliness may be sex-specific, with women experiencing disproportionate exposure, vulnerability, and downstream effects across the life course. This mini-review synthesizes epidemiological, psychosocial, and neurobiological evidence linking loneliness to cognitive aging in women, highlighting sex differences in prevalence, social role exposures (e.g., caregiving, widowhood), stress responsivity, and neuroendocrine and inflammatory pathways. Findings from longitudinal cohort studies are reviewed, demonstrating stronger associations between loneliness and cognitive decline in women, alongside emerging mechanistic research implicating hypothalamic-pituitary-adrenal (HPA) axis dysregulation, immune activation, and hippocampal vulnerability. Critical gaps in aging neuroscience, including limited sex-disaggregated analyses and undermeasurement of relational and social variables, require urgent attention. A sex-sensitive framework for integrating loneliness into cognitive aging research and prevention strategies, emphasizing targeted assessment and intervention approaches that reflect women's lived social contexts, holds promise for advancing precision prevention in women's brain health. Framing loneliness as a modifiable, sex-specific risk factor offers a novel avenue for precision prevention in women's cognitive aging.},
}

@article {pmid41815076,
year = {2026},
author = {Scaramuzzi, GF and Manippa, V and Taurisano, P},
title = {Re-tuning the brain: The promise of 40 Hz sensory stimulation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261429856},
doi = {10.1177/13872877261429856},
pmid = {41815076},
issn = {1875-8908},
abstract = {Growing interest in noninvasive neuromodulation posits 40 Hz sensory stimulation as a potential intervention for Alzheimer's disease. Early studies suggested that 40 Hz visual flicker entrains gamma activity and reduces amyloid pathology; however, later work found either absent entrainment or even increased amyloid burden, revealing strong dependence on disease stage, network integrity, and stimulation parameters. Initial clinical investigations suggest that 40 Hz stimulation is safe, well-tolerated, and capable of modulating cortical network dynamics and improving cognition, despite limited effects on amyloid burden. These findings suggest a shift from molecular pathology to network plasticity as the primary target of gamma stimulation.},
}

@article {pmid41815074,
year = {2026},
author = {Chen, J and Guan, J and Zhang, Y and Xue, S and Lu, X and Zhang, L and Liu, Y and Ji, J and Chang, J},
title = {Association of central adiposity indices with cognitive impairment in elderly populations: Development and validation of a risk prediction nomogram using NHANES and CHARLS cohorts.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261424471},
doi = {10.1177/13872877261424471},
pmid = {41815074},
issn = {1875-8908},
abstract = {BackgroundCognitive impairment is a primary contributor to disability among older adults, with growing evidence identifying central adiposity as an adjustable risk factor for neurodegeneration, but comprehensive predictive models integrating central adiposity indices for mild cognitive impairment (MCI) in aging individuals remain underexplored.ObjectiveThis study aimed to establish and verify a model for predicting the risk of MCI in elderly population by incorporating anthropometric indices.MethodsWe calculated five central adiposity indices using anthropometric measurements from 2464 United States adults aged 60 years or older (National Health and Nutrition Examination Survey, 2011-2014). Cognitive performance was assessed using three standardized neuropsychological tests. A random assignment placed participants into either a training (n = 1725) or a validation (n = 739) set. Furthermore, the data from participants in the 2011 wave of the China Health and Retirement Longitudinal Study served as an external validation cohort (n = 536). LASSO-selected predictors were employed to inform multivariable logistic regression modeling.ResultsPositive linear relationships were found between three anthropometric indices-A Body Shape Index (ABSI), Conicity Index (CoI) and Weight-Adjusted-Waist Index (WWI)-with MCI risk (p < 0.05, p for nonlinearity > 0.05). The nomogram incorporating ABSI demonstrated strong discriminative capacity (training AUC = 0.861; internal validation AUC = 0.826; external validation AUC = 0.798), precise calibration, and good clinical utility.ConclusionsThe risk of MCI was independently linked to central adiposity indices (ABSI, WWI, and CoI). The nomogram incorporating ABSI provided a validated, clinically applicable prediction model for initial screening of MCI in older populations.},
}

@article {pmid41815071,
year = {2026},
author = {Alkam, T and Tarshizi, E and Van Benschoten, AH},
title = {Detecting multimorbidity patterns in Alzheimer's disease using unsupervised machine learning: A nationwide emergency department study (2007-2022).},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430952},
doi = {10.1177/13872877261430952},
pmid = {41815071},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) patients frequently present to emergency departments (EDs) with complex comorbidities that complicate triage and management. Yet, little is known about how these multimorbidity patterns have evolved over time.ObjectiveTo identify temporal shifts in comorbidity-based phenotypes among older adults with AD visiting EDs between 2007 and 2022 using unsupervised clustering methods.MethodsWe analyzed ED visits for adults aged ≥60 with an AD diagnosis from the Nationwide Emergency Department Sample (NEDS) for the years 2007, 2012, 2017, and 2022. Using ICD-9/10 codes, we mapped diagnoses to 30 clinically relevant comorbidities per year and applied the k-means clustering method to identify subgroups based on diagnostic co-occurrence. Heatmaps summarized cluster compositions across timepoints.ResultsOver 15 years, four stable but evolving comorbidity clusters emerged in each year. Earlier cohorts (2007-2012) were dominated by cardiovascular and respiratory clusters (e.g., CHF, CAD, respiratory failure), while more recent cohorts (2017-2022) showed increased prevalence of nonspecific, frailty-related presentations (e.g., fatigue, GERD, general symptoms). Despite rising ED utilization among older adults, the proportion of visits documenting AD declined from 2.59% in 2007 to 1.34% in 2022, potentially reflecting shifts in coding, outpatient management, and diagnostic overshadowing by acute symptoms.ConclusionsThe comorbidity landscape of AD-related ED visits is changing, with a shift toward vaguer syndromes and complex multimorbidity. These findings underscore the need for dementia-aware triage strategies and dynamic phenotyping tools to improve emergency care for cognitively impaired older adults.},
}

@article {pmid41815070,
year = {2026},
author = {Ren, Y and Saleem, K and Patel, PJ and Lee, YH and Feng, J and Yan, Z},
title = {Diminished activity-dependent neuroprotective protein (ADNP) contributes to complement gene elevation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427770},
doi = {10.1177/13872877261427770},
pmid = {41815070},
issn = {1875-8908},
abstract = {BackgroundGene dysregulation is one of the key mechanisms that link pathological abnormalities to cognitive impairment in Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. Our transcriptomic analysis of large-scale postmortem AD human prefrontal cortex (PFC) data revealed that complement genes, a key player in modulating tissue homeostasis and immune surveillance, were prominently upregulated.ObjectiveThe goal of this study is to reveal key transcriptional regulators that contribute to the elevation of complement genes in AD.MethodsTranscriptomic and epigenomic analyses, molecular, biochemical and immunocytochemical assays, and in vivo gene manipulation, were used.ResultsOur epigenomic analysis identified ADNP (activity-dependent neuroprotective protein), a chromatin regulator strongly linked to intellectual disability, as one of the top-ranking transcription factors regulating complement genes. ADNP and its partner HP1γ (Heterochromatin protein 1) were found to be significantly diminished in postmortem AD human PFC. Reduced Adnp expression was also found in PFC of a familial AD mouse model, 5xFAD. Knockdown of Adnp in mice led to the significantly increased levels of complement genes, reminiscent to complement gene elevation in postmortem AD humans and 5xFAD mice. Furthermore, human induced pluripotent stem cell-derived neuronal cultures from AD patients exhibited astrocyte activation, ADNP/HP1γ reduction, and complement gene increase. Manipulation of ADNP levels led to bidirectional changes in complement gene expression.ConclusionsThese data suggest that the diminished ADNP in AD could lead to chromatin dysregulation because of disrupted transcriptional repression, which contributes to the elevation of complement genes. It provides a novel upstream epigenetic modifier for gene dysregulation in AD.},
}

@article {pmid41815069,
year = {2026},
author = {Yang, F and Xu, B and Lin, J and Zheng, D and Lan, S and Luo, K and Yang, G},
title = {Early detection of Alzheimer's disease based on leveraging multimodal features of the clock drawing test.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261423940},
doi = {10.1177/13872877261423940},
pmid = {41815069},
issn = {1875-8908},
abstract = {BackgroundAlthough multi-task handwriting analysis has the potential to improve early detection of Alzheimer's disease (AD), the educational bias inherent in its text-based tasks poses a significant obstacle to its widespread adoption across different regions.ObjectiveUsing the clock drawing test, we aim to design a deep neural network to extract features from static images and process signals to achieve high-precision recognition of early AD.MethodsEarly Detection of Alzheimer's Disease based on Leveraging Multimodal Features of the clock-drawing test (EDADLMF) is proposed. Firstly, to utilize the behavioral features inherent in the clock drawing test task, we propose a Dual Stream Clock Drawing Feature Extraction module,which employs a convolutional neural networks to capture the spatial features of static clock face images, while concurrently employing a multi-layer perceptron to map low-dimensional process signal into a high-dimensional feature space. Furthermore, we propose a Feature Fusion module with the Squeeze-and-Excitation attention mechanism to adaptively enhance key features and fuses complementary information from different modalities. Thirdly, to enhance the model's focus on hard-to-classify samples, a PolyLoss function is introduced to assign greater weights to difficult samples.ResultsComparative experiments on benchmark demonstrated that EDADLMF outperforms the compaired methods on accuracy (92.59%), precision (93.65%), recall (92.65%), and F1-score (92.59%), and the case study indicates that the developed prototype system has well effectiveness.ConclusionsThe clock drawing test, combined with process signals and image data, exhibits better screening accuracy and could serve as a practical alternative to initial MRI scans.},
}

@article {pmid41815067,
year = {2026},
author = {Hada, K and Murata, Y and Ohi, Y and Hashimoto, S and Watanabe, H and Ozeki, K and Saido, TC and Saito, T and Sasaguri, H and Mizoguchi, H and Yamada, K and Wakiya, Y},
title = {Involvement of orexin nerves in early stage of Alzheimer's disease model mice and preventive effect of orexin receptor antagonists.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {110},
number = {2},
pages = {588-604},
doi = {10.1177/13872877261415630},
pmid = {41815067},
issn = {1875-8908},
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/prevention & control/pathology/drug therapy ; *Orexin Receptor Antagonists/pharmacology/therapeutic use ; Mice ; Disease Models, Animal ; *Triazoles/pharmacology/therapeutic use/pharmacokinetics ; *Azepines/pharmacology/therapeutic use/pharmacokinetics ; Amyloid beta-Peptides/metabolism ; Male ; Mice, Transgenic ; *Orexin Receptors/metabolism/genetics ; Mice, Inbred C57BL ; *Orexins/metabolism ; },
abstract = {BackgroundOrexin (OX) levels are elevated in the cerebrospinal fluid of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD).ObjectiveTo investigate the efficacy of dual OX receptor antagonists (suvorexant and lemborexant) in an early-stage AD mouse model (App-KI).MethodsOX receptor gene expression was measured. Additionally, drug distribution and effects on motor activity following single oral administration of suvorexant and lemborexant were assessed. Furthermore, cognitive function, amyloid-β (Aβ) levels and uptake by microglia in the hippocampal CA1 region were evaluated following daily administration of suvorexant and lemborexant for 60 days.ResultsOXR gene expression was highest in the lateral hypothalamus of wild-type mice and was also observed in other brain regions. OX1R gene expression was significantly increased in these brain regions in App-KI mice. In wild-type mice, brain concentrations of suvorexant peaked 20 to 40 min after administration, and those of lemborexant peaked 15 min after administration. Concentrations subsequently declined but remained detectable 24 h after administration. Additionally, motor activity decreased following the administration of either suvorexant or lemborexant; however, no difference in motor activity was observed compared to the control group 24 h later. Notably, the Y-maze test revealed that suvorexant and lemborexant mitigated cognitive impairment in App-KI mice. Furthermore, both drugs suppressed the accumulation of Aβ in the CA1 region of the hippocampus in App-KI mice. This was associated with increased Aβ uptake by activated microglia.ConclusionsThe results suggest that suvorexant and lemborexant effectively suppresses the early stages of AD.},
}

Animals
*Alzheimer Disease/metabolism/genetics/prevention & control/pathology/drug therapy
*Orexin Receptor Antagonists/pharmacology/therapeutic use
Mice
Disease Models, Animal
*Triazoles/pharmacology/therapeutic use/pharmacokinetics
*Azepines/pharmacology/therapeutic use/pharmacokinetics
Amyloid beta-Peptides/metabolism
Male
Mice, Transgenic
*Orexin Receptors/metabolism/genetics
Mice, Inbred C57BL
*Orexins/metabolism

@article {pmid41815049,
year = {2026},
author = {Xu, Y and Huang, T},
title = {Association of the endothelial activation and stress Index (EASIX) with cognitive function in United States older adults: Findings from NHANES 2011-2014.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427767},
doi = {10.1177/13872877261427767},
pmid = {41815049},
issn = {1875-8908},
abstract = {BackgroundCognitive decline poses a significant public health challenge in aging populations. Endothelial dysfunction is increasingly recognized as a key mechanism linking vascular pathology to cognitive impairment. The Endothelial Activation and Stress Index (EASIX), derived from routine laboratory measures, has been associated with vascular outcomes, but its relationship with cognitive function in the general aging population remains unexplored.ObjectiveThis study aimed to investigate the association between EASIX and cognitive performance among community-dwelling older adults.MethodsWe analyzed data from 2143 participants aged ≥60 from NHANES 2011-2014. EASIX was calculated as (creatinine × lactate dehydrogenase) / platelet count. Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease Word Learning (CERAD-WL) and Delayed Recall tests, Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). Survey-weighted linear and logistic regression models were employed to examine associations between EASIX and cognitive outcomes, adjusting for multiple covariates.ResultsEach unit increase in EASIX was significantly associated with lower scores on the DSST (β = -1.94, 95% CI: -2.79 to -1.10), AFT (β = -0.77, 95% CI: -1.04 to -0.50), and CERAD-WL (β = -0.53, 95% CI: -0.94 to -0.13). Higher EASIX was also associated with increased odds of cognitive dysfunction on AFT (OR = 1.22, 95% CI: 1.05-1.42) and DSST (OR = 1.66, 95% CI: 1.09-2.52). Associations remained robust in sensitivity analyses.ConclusionsEASIX is independently associated with domain-specific cognitive decline in older adults, supporting its potential utility as an accessible biomarker of cognitive aging.},
}

@article {pmid41815034,
year = {2026},
author = {Boockvar, KS and Marcantonio, ER and Price, CC and Metzger, ED and Tommet, D and Schmitt, EM and Heine, C and Topper, M and Jones, RN and Fong, TG and Inouye, SK and , },
title = {Gold standard assessment of delirium severity in patients with dementia: Evaluation of an expert panel adjudication process.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261422418},
doi = {10.1177/13872877261422418},
pmid = {41815034},
issn = {1875-8908},
abstract = {BackgroundPatients with Alzheimer's disease and related dementias (ADRD) have an increased risk for delirium and subsequent complications. Rating delirium severity in the presence of co-occurring dementia is challenging due to overlapping features of delirium and ADRD. The multi-site prospective Better ASsessment of ILlness (BASIL)-II study will develop and validate a new delirium severity instrument for use in patients with and without ADRD.ObjectiveDescribe an expert panel process used to rate delirium severity.MethodsClinical assessors conducted standardized cognitive tests. A separate panel of experts independently reviewed assessors' reports, rated delirium severity using a 0-10 scale, and assigned dementia diagnoses using DSM-5 criteria. Panel agreement was defined using a priori criteria. Cases without agreement after initial review were discussed as a group and re-rated using a modified Delphi approach until achieving consensus.ResultsPatients (N = 488) were on average 79 years old, 58% female, and 75% White. After initial review, 80% of cases were in agreement for delirium severity. Kappa was 0.86 (95% CI, 0.78, 0.82) before expert panel discussion and 0.90 (95%CI, 0.89, 0.92) after consensus. Final delirium severity ratings were no delirium (48%); subsyndromal (22%), mild-moderate (25%), or severe (6%). Disagreement in delirium severity was associated with ADRD (OR 3.02), nursing home setting (2.63), and vision impairment (2.42).ConclusionsThis rigorous process provides confidence that delirium severity can be rated accurately in patients with and without ADRD. We will use this expert panel adjudication to provide the reference standard for validation of a future delirium severity instrument.},
}

@article {pmid41814978,
year = {2026},
author = {Gul, G},
title = {Molecular dynamics insights into the interactions of a potential neurotherapeutic peptide with model liposomes.},
journal = {Physical chemistry chemical physics : PCCP},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5cp04834f},
pmid = {41814978},
issn = {1463-9084},
abstract = {Peptide molecules capable of disrupting toxic protein aggregates implicated in neurodegenerative diseases hold significant therapeutic potential; however, their clinical translation is constrained by rapid proteolysis and poor penetration into brain tissue. Lipid-based nanoparticles provide a promising delivery platform due to their ability to encapsulate diverse therapeutic cargos, reduce toxicity, and offer high biocompatibility. Here, therefore, we investigated the interactions of a cationic inhibitor peptide, KR, originally developed against Alzheimer's disease, with PC/PG lipid bilayers containing varying cholesterol concentrations using both atomistic and coarse-grained molecular dynamics (MD) simulations. Atomistic simulations revealed that the membrane response to KR is concentration-dependent: higher peptide loadings enhance lipid mobility and slightly increase the area per lipid, especially in cholesterol-free membranes, where deeper insertion facilitates local membrane loosening. KR peptides were preferentially associated with lipid headgroups through electrostatic and hydrogen-bond interactions, predominantly mediated by C-terminal Arg residues. Cholesterol reduced membrane permeability and, in coarse-grained simulations, strengthened both van der Waals and electrostatic interactions with PG lipids, resulting in peptides forming roughly three times more contacts with PG than with PC lipids. Across all systems, KR could not traverse the hydrophobic membrane core from bulk solution, yet peptides were efficiently encapsulated when partially embedded within the bilayer interior. Our study constitutes one of the first multiscale MD investigations of a potential neurotherapeutic peptide at the molecular level and provides mechanistic insights for designing liposomal nanocarriers for peptide delivery to the brain.},
}

@article {pmid41814803,
year = {2026},
author = {Zhang, YX and Shi, YJ and Li, T and Bai, JM and Shen, YF and Shan, SY and Li, HY and Xiao, HH},
title = {[Shenzao Jiannao Oral Liquid treats Alzheimer's disease by regulating gut microbiota].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {3},
pages = {791-798},
doi = {10.19540/j.cnki.cjcmm.20250725.704},
pmid = {41814803},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/drug therapy/microbiology/metabolism/genetics/psychology ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/administration & dosage ; Mice ; Mice, Inbred C57BL ; Male ; Humans ; Mice, Transgenic ; Disease Models, Animal ; Maze Learning/drug effects ; Administration, Oral ; Memory/drug effects ; Occludin/metabolism/genetics ; },
abstract = {This study investigates the therapeutic effect and mechanism of Shenzao Jiannao Oral Liquid(SZJN) on Alzheimer's disease(AD) from gut microbiota. APP/PS1 double transgenic mice were used to establish the AD model and then allocated into the following groups: model(normal saline of equal volume), positive drug(donepezil hydrochloride, 0.65 mg·kg~(-1)), and low-, medium-, and high-dose(0.3, 1.5, and 7.5 g·kg~(-1), respectively) SZJN. Meanwhile, C57BL/6J mice of the same brood were selected as the blank group(normal saline of equal volume). All groups were treated by gavage for 8 weeks. The Morris water maze was used to evaluate the spatial exploration, learning, and memory abilities. The nesting test was conducted to assess the daily living abilities. Hematoxylin-eosin(HE) staining was employed to examine histopathological damage in the intestinal tissue. AB-PAS staining was performed to reveal the mucus barrier damage in the intestinal tissue. Western blot was conducted to measure the protein levels of zonula occludens-1(ZO-1) and Occludin. Immunofluorescence(IF) was used to analyze the expression of ZO-1, Occludin, and the macrophage marker F4/80. The diversity, species abundance, and correlations of gut microbiota were analyzed by 16S rDNA sequencing. Animal experiments demonstrated that compared with the model group, the high-dose SZJN group exhibited shortened escape latency, increased platform crossings and time spent in the target quadrant, and improved nesting scores. The high-dose SZJN groups showed alleviated intestinal mucosal contraction, improved cellular morphology, reduced intestinal tissue damage, increased mucin content, and increased goblet cells. Additionally, high-dose SZJN groups exhibited upregulated expression of ZO-1 and Occludin in the intestinal tissue, along with reduced F4/80 protein expression. Gut microbiota analysis revealed increased species diversity and richness in the high-dose SZJN groups, with microbiota structures resembling that in the blank group. These results confirm that high-dose SZJN improves the learning and memory abilities, mitigates intestinal pathological damage, and protects the intestinal tissue of AD mice by regulating the gut microbiota.},
}

Animals
*Alzheimer Disease/drug therapy/microbiology/metabolism/genetics/psychology
*Gastrointestinal Microbiome/drug effects
*Drugs, Chinese Herbal/administration & dosage
Mice
Mice, Inbred C57BL
Male
Humans
Mice, Transgenic
Disease Models, Animal
Maze Learning/drug effects
Administration, Oral
Memory/drug effects
Occludin/metabolism/genetics

@article {pmid41814795,
year = {2026},
author = {Xi, H and Yang, WM and Xie, WT and Yang, Y and Wei, WX and Li, H and Zhai, S},
title = {[Construction and evaluation of an animal model of Alzheimer's disease with spleen-kidney deficiency and stagnant phlegm syndrome based on formula test].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {3},
pages = {708-721},
doi = {10.19540/j.cnki.cjcmm.20251110.901},
pmid = {41814795},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/physiopathology/drug therapy ; *Disease Models, Animal ; Male ; Mice ; Mice, Transgenic ; Mice, Inbred C57BL ; Humans ; *Spleen/physiopathology/drug effects ; *Kidney/physiopathology/drug effects ; Brain-Derived Neurotrophic Factor/metabolism/genetics ; },
abstract = {This study aims to establish a standardized mouse model of Alzheimer's disease(AD) with spleen-kidney deficiency and stagnant phlegm syndrome(AD-SKDSP) based on TCM theory, so as to provide a disease-syndrome combined model that aligns with the TCM diagnosis and treatment paradigm of "disease-syndrome-formula-efficacy" for modern research on AD prevention and treatment. Four-month-old male double-transgenic APP/PS1 mice were used as AD model animals. A standardized animal model of AD-SKDSP was constructed by high-sugar and high-fat diet feeding combined with ice-water bath and tail-clamping stimulation. The mice were randomly divided into an AD model group, an AD-SKDSP group, an AD Zhinao Capsule group, and a normal control group consisting of same-litter and age-matched male C57BL/6J mice. Corresponding drug treatments were administered at designated time points. During the eight-week modeling period, the following parameters were measured: physical sign scores, grip strength, body weight, 24-hour food intake, 24-hour fecal water content, female mouse fertility, Morris water maze performance, nose-tongue-collateral-foot color, hippocampus detected by hematoxylin-eosin(HE) staining, Aβ_(1-42) and brain-derived neurotrophic factor(BDNF) detected by immunohistochemistry, whole blood and plasma viscosity, 2-hour D-xylose, testosterone(T), estradiol(E_2), calcium(Ca), phosphorus(P), bone Gla protein(BGP), hippocampal synapsin(SYN) and postsynaptic density protein 95(PSD-95) mRNAs, and SYN, PSD-95, and BDNF proteins. The results showed that by the end of the 4th week, compared with the normal control group, the AD model group, AD-SKDSP group, and AD Zhinao Capsule group exhibited progressively increased physical sign scores and 24-hour fecal water content, and progressively decreased grip strength, body weight, and 24-hour food intake(P<0.05, P<0.01). Compared with the AD model group, the AD-SKDSP group and AD Zhinao Capsule group showed significantly increased physical sign scores and 24-hour fecal water content, along with significantly reduced grip strength, body weight, and 24-hour food intake(P<0.05, P<0.01). From the 5th week onward, compared with the AD-SKDSP group, the AD Zhinao Capsule group demonstrated significant reductions in physical sign scores and 24-hour fecal water content, as well as significant increases in grip strength, body weight, and 24-hour food intake with prolonged intragastric administration of Zhinao Capsule(P<0.05, P<0.01). By the end of the 8th week, compared with the normal control group, the AD model group and AD-SKDSP group exhibited significantly decreased female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E_2, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression. Meanwhile, platform latency, hippocampal Aβ_(1-42) expression, and whole blood and plasma viscosity(low, medium, and high shear rates) were significantly increased, while platform crossings and target quadrant swimming time were markedly reduced(P<0.05, P<0.01). Hippocampal CA1 neurons in these groups displayed partial loss of normal morphology, with pyknotic or swollen nuclei, deep blue staining, disorganized distribution, and a thickness of "3-5" layers. Compared with the AD model group, the AD-SKDSP group showed significant reductions in female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E_2, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression, significant increases in platform latency, hippocampal Aβ_(1-42) expression, and whole blood and plasma viscosity(low, medium, and high shear rates), and significant decreases in platform crossings and target quadrant swimming time(P<0.05, P<0.01). The hippocampal CA1 neurons exhibited irregular shapes, increased nuclear pyknosis, intensified deep blue staining, a thickness of "1-3" layers, and chaotic distribution. Compared with the AD-SKDSP group, the AD Zhinao Capsule group demonstrated significant increases in female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E_2, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression, significant decreases in platform latency, hippocampal Aβ_(1-42) expression, and whole blood and plasma viscosity(low, medium, and high shear rates), and significant increases in platform crossings and target quadrant swimming time(P<0.05, P<0.01). The hippocampal CA1 neuronal pathology was markedly alleviated. In summary, guided by the holistic concept and syndrome differentiation theory of TCM and on the basis of characteristics of "spleen deficiency", "kidney deficiency", and "intermingled phlegm and blood stasis", this study successfully established a standardized AD-SKDSP animal model by combining a high-sugar and high-fat diet with ice-water bath and tail-clamping stimulation for eight weeks. This modeling method exhibits strong controllability, minimal physicochemical stimulation, reproducibility, and verifiability, providing a stable and standardized disease-syndrome combined animal model for future research on the "disease-syndrome-formula-efficacy" paradigm in AD-SKDSP.},
}

Animals
*Alzheimer Disease/genetics/metabolism/physiopathology/drug therapy
*Disease Models, Animal
Male
Mice
Mice, Transgenic
Mice, Inbred C57BL
Humans
*Spleen/physiopathology/drug effects
*Kidney/physiopathology/drug effects
Brain-Derived Neurotrophic Factor/metabolism/genetics

@article {pmid41814765,
year = {2026},
author = {Wu, D and Lai, BX and Wang, ZY and Niu, QX and Cai, YQ and Long, QH},
title = {[Protective effects of Suanzaoren Decoction on hippocampal neuron and its influence on PI3K/Akt signaling pathway in APP/PS1 transgenic mice].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {1},
pages = {173-180},
doi = {10.19540/j.cnki.cjcmm.20250930.701},
pmid = {41814765},
issn = {1001-5302},
mesh = {Animals ; *Hippocampus/drug effects/metabolism/cytology ; Male ; *Signal Transduction/drug effects ; Mice ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Drugs, Chinese Herbal/administration & dosage/pharmacology ; *Phosphatidylinositol 3-Kinases/metabolism/genetics ; *Neurons/drug effects/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism/genetics ; Mice, Transgenic ; Mice, Inbred C57BL ; Amyloid beta-Protein Precursor/genetics/metabolism ; Apoptosis/drug effects ; Humans ; *Neuroprotective Agents/administration & dosage ; Presenilin-1/genetics/metabolism ; },
abstract = {This study explored the mechanism by which Suanzaoren Decoction(SZRD) ameliorates hippocampal neuronal damage in APP/PS1 mice by inhibiting Bax/Bcl-2/caspase-3-mediated apoptosis through the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway. Differentially expressed genes(DEGs) in Alzheimer's disease(AD) were screened using the GEO database, and KEGG and GO enrichment analyses were performed using R software. Thirty 6-month-old APP/PS1 transgenic mice were randomly assigned to three groups: APP/PS1 group, low-dose SZRD group(12.96 g·kg~(-1)), and high-dose SZRD group(25.92 g·kg~(-1)), while ten age-matched male C57BL/6J mice served as the blank control group. The treatment groups received SZRD by gavage for 28 consecutive days. Following treatment, spatial learning and memory were assessed using the Morris water maze test. Neuronal numbers were evaluated by Nissl staining. Immunohistochemistry(IHC) was used to detect neuron-specific nuclear protein(NeuN) and assess amyloid-β(Aβ) deposition in hippocampal neurons. Western blot was performed to measure the expression levels of PI3K/Akt pathway proteins and apoptosis-related markers, including Bcl-2, Bax, caspase-3, and cleaved-caspase-3 in hippocampal tissues. Bioinformatics analysis identified 686 DEGs, with GO enrichment linked to synaptic function and neurotransmitter transport, and KEGG pathways including neuroactive ligand-receptor interaction and PI3K/Akt signaling. In vivo experiments showed that, compared with APP/PS1 mice, both low-and high-dose SZRD groups exhibited improved learning and memory, increased neuronal numbers, and decreased Aβ deposition. Furthermore, hippocampal levels of p-PI3K/PI3K, p-Akt/Akt, and Bcl-2 were upregulated, while Bax and cleaved-caspase-3/caspase-3 levels were downregulated. In conclusion, SZRD may improve hippocampal neuronal damage and cognitive function in APP/PS1 mice by regulating Bax/Bcl-2/caspase-3-mediated apoptosis through the PI3K/Akt signaling pathway.},
}

Animals
*Hippocampus/drug effects/metabolism/cytology
Male
*Signal Transduction/drug effects
Mice
*Alzheimer Disease/drug therapy/genetics/metabolism
*Drugs, Chinese Herbal/administration & dosage/pharmacology
*Phosphatidylinositol 3-Kinases/metabolism/genetics
*Neurons/drug effects/metabolism
*Proto-Oncogene Proteins c-akt/metabolism/genetics
Mice, Transgenic
Mice, Inbred C57BL
Amyloid beta-Protein Precursor/genetics/metabolism
Apoptosis/drug effects
Humans
*Neuroprotective Agents/administration & dosage
Presenilin-1/genetics/metabolism

@article {pmid41814751,
year = {2026},
author = {Liang, LY and Cao, JL and Zhao, ZL and Qi, YF and Wang, YH and Fang, SM and Dong, SB and Wang, YK and Tan, XH and Wei, BQ and Ma, BX and Cui, JQ},
title = {[Research progress in neuroprotective effects of Bacopa monnieri active components and derivatives in neurological disorders].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {1},
pages = {40-49},
doi = {10.19540/j.cnki.cjcmm.20251011.703},
pmid = {41814751},
issn = {1001-5302},
mesh = {*Bacopa/chemistry ; *Neuroprotective Agents/chemistry/pharmacology ; Humans ; *Nervous System Diseases/drug therapy ; Animals ; *Drugs, Chinese Herbal/chemistry/pharmacology ; },
abstract = {Bacopa monnieri, a plant of Scrophulariaceae, has a long history of medicinal use and is recognized as a traditional medicinal herb in multiple countries. Neurological disorders, due to their extensive damage to neural functions, have become a major public health challenge and garnered worldwide attention. In ancient times, B. monnieri was documented for treating cognitive and memory impairments. Recent studies have elucidated its pharmacological mechanisms and therapeutic targets underpinning the neuroprotective effect. However, the molecular mechanisms of its active ingredients have not been systematically summarized. This study is the first to integrate the target sites of its core ingredients across multiple categories of neurological disorders. It summarizes the pharmacological mechanisms of B. monnieri as well as its active ingredients and derivatives in various neurological diseases, which exert neuroprotective effects through multi-target interactions. This paper provides novel strategies for developing botanical drugs targeting diseases like Alzheimer's and epilepsy and aims to offer evidence-based guidance for the development and application of B. monnieri in functional foods, health supplements, and pharmaceuticals.},
}

*Bacopa/chemistry
*Neuroprotective Agents/chemistry/pharmacology
Humans
*Nervous System Diseases/drug therapy
Animals
*Drugs, Chinese Herbal/chemistry/pharmacology

@article {pmid41814705,
year = {2025},
author = {Lai, BX and Wu, D and Niu, QX and Long, QH and He, LL},
title = {[Qiangji Decoction regulates AMPKα/Drp1/Nrf2 pathway to ameliorate neural damage induced by D-galactose by suppressing oxidative stress and neuronal apoptosis].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {24},
pages = {6967-6977},
doi = {10.19540/j.cnki.cjcmm.20250926.801},
pmid = {41814705},
issn = {1001-5302},
mesh = {Animals ; *Apoptosis/drug effects ; *Drugs, Chinese Herbal/administration & dosage/pharmacology ; *NF-E2-Related Factor 2/metabolism/genetics ; *AMP-Activated Protein Kinases/metabolism/genetics ; Mice ; *Oxidative Stress/drug effects ; *Neurons/drug effects/metabolism/cytology ; *Galactose/adverse effects ; Male ; Mice, Inbred C57BL ; *Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology ; Signal Transduction/drug effects ; Humans ; Hippocampus/drug effects/metabolism ; },
abstract = {This study aims to investigate the mechanism by which Qiangji Decoction(QJD) regulates the adenosine 5'-monophosphate(AMP)-activated protein kinase α(AMPKα)/dynamin-related protein 1(Drp1)/nuclear factor E2 related factor 2(Nrf2) pathway to ameliorate oxidative stress and neuronal apoptosis induced by D-galactose. Seventy-two C57BL/6 mice were randomized into the control, model, low-dose Qiangji Decoction(L-QJD), medium-dose Qiangji Decoction(M-QJD), high-dose Qiangji Decoction(H-QJD), and metformin(Met) groups. The mouse model of Alzheimer's disease(AD) was established by subcutaneous injection of D-galactose(0.1 g·kg~(-1)) into the mouse neck for 8 consecutive weeks. The control and model groups received equal volumes of normal saline by gavage at a dose of 20 mL·kg~(-1), and the L-QJD, M-QJD, and H-QJD groups were treated with QJD extract at doses of 12.48, 24.96, and 49.92 g·kg~(-1), respectively. The Met group was administrated with metformin sustained-release tablets by gavage at a dose of 0.2 g·kg~(-1). After 4 weeks of treatment, the Morris water maze test was carried out to evaluate the learning and memory abilities of mice. The pathological changes of the hippocampus were observed via hematoxylin-eosin staining. Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining was employed to detect apoptotic neurons in the hippocampus. Immunofluorescence(IF) staining was employed to detect the expression levels of B cell lymphoma-2(Bcl-2) and Bcl2-associated X protein(Bax) in the hippocampus. Biochemical assay kits were used to measure the levels of malondialdehyde(MDA), total superoxide dismutase(T-SOD), glutathione peroxidase(GSH-PX), and catalase(CAT) in the hippocampal tissue. Western blot was used to determine the expression levels of AMPKα, phosphorylated AMPKα(p-AMPKα-Thr172), Drp1, phosphorylated Drp1(p-Drp1-Ser616), cysteinyl aspartate-specific proteinase-3(caspase-3), cleaved caspase-3, Nrf2, heme oxygenase 1(HO-1), and NAD(P)H quinone oxidoreductase 1(NQO1) in the hippocampal tissue. The results showed that compared with the control group, the model group presented reduced learning and memory abilities, increased neurons with shrinkage or deep staining, increased apoptotic neurons(P<0.01), upregulated expression of Bax, MDA, p-Drp1-Ser616/Drp1, and cleaved caspase-3/caspase-3(P<0.01), and downregulated expression of Bcl-2, T-SOD, GSH-PX, CAT, p-AMPKα-Thr172/AMPKα, Nrf2, HO-1, and NQO1(P<0.01) in the hippocampus. Compared with the model group, the M-QJD, H-QJD, and Met groups showed improved learning and memory abilities, decreased neurons with shrinkage or deep staining and apoptotic neurons(P<0.05, P<0.01), downregulated expression of Bax, MDA, p-Drp1-Ser616/Drp1, and cleaved caspase-3/caspase-3 in the hippocampus(P<0.05, P<0.01), and upregulated expression of Bcl-2, T-SOD, GSH-PX, CAT, p-AMPKα-Thr172/AMPKα, Nrf2, HO-1, and NQO1 in the hippocampus(P<0.05, P<0.01). QJD could alleviate D-galactose-induced cognitive impairment, neuronal apoptosis, and oxidative stress by regulating the AMPKα/Drp1/Nrf2 pathway.},
}

Animals
*Apoptosis/drug effects
*Drugs, Chinese Herbal/administration & dosage/pharmacology
*NF-E2-Related Factor 2/metabolism/genetics
*AMP-Activated Protein Kinases/metabolism/genetics
Mice
*Oxidative Stress/drug effects
*Neurons/drug effects/metabolism/cytology
*Galactose/adverse effects
Male
Mice, Inbred C57BL
*Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology
Signal Transduction/drug effects
Humans
Hippocampus/drug effects/metabolism

@article {pmid41814444,
year = {2026},
author = {Myeong, SH and Lee, NK and Lee, NH and Choi, SJ and Son, HJ and Chang, JW and Kim, HJ and Na, DL},
title = {Intracerebroventricular human mesenchymal stem cells induce MMP9-driven transient inflammation in Alzheimer's disease.},
journal = {Stem cell research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13287-026-04958-x},
pmid = {41814444},
issn = {1757-6512},
support = {RS-2022-KH129480//Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea/ ; SMO1250391//Samsung Medical Center Grant/ ; SMO1264024//Samsung Medical Center Grant/ ; RS-2022-KH127216//the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)/ ; },
abstract = {BACKGROUND: Mesenchymal stem cells (MSCs) are often considered hypoimmunogenic. However, a transient fever observed after intracerebroventricular (ICV) administration in a clinical trial suggests an acute host response. This study examines the mechanisms underlying this reaction, with a focus on MSC migration and the role of matrix metalloproteinase-9 (MMP9).

METHODS: We analyzed cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients treated with saline (n = 3) or human MSCs (hMSCs) (n = 6) using an exploratory protease array, followed by enzyme-linked immunosorbent assay (ELISA). The function of MMP9 was examined further through in-vitro migration and lipopolysaccharide (LPS) stimulation assays in MMP9-silenced hMSCs (siMMP9-hMSCs). In-vivo, siMMP9-hMSCs were delivered ICV into 5xFAD mice to evaluate cell distribution and immune responses.

RESULTS: CSF protease profiling of AD patients revealed that MSC administration increased MMP9 levels. MMP9 knockdown reduced hMSC migration and attenuated LPS induced cytokine increase in the conditioned media (TNF-α and IL-1β) or in the hMSC lysates (IL-1β, IL-6, and CRP) in-vitro. In 5xFAD mice, siMMP9-hMSCs exhibited altered migration and inflammation signatures, characterized by restricted periventricular distribution accompanied by increased CD45 leukocyte accumulation and caspase-3 activity. Naïve hMSCs, on the other hand, dispersed more broadly.

CONCLUSIONS: MMP9 promotes the migration of hMSCs and influences the initial interactions between the host and the graft after ICV delivery. Loss of MMP9 activity limits dispersion and is associated with increased local immune activation. This highlights the importance of MMP9-dependent processes in the early post-transplantation phase. These findings may inform strategies to optimize the safety of central nervous system-directed stem cell therapies.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02054208.},
}

@article {pmid41814439,
year = {2026},
author = {Kitajima, E and Suwanda, A and Jobson, D and Allan, L and Paydar, K and Han, G and Washida, K and Ihara, M and Kalailingam, P and Hase, Y and Sze, SK and Polvikoski, T and Kalaria, RN},
title = {Carotid arteries in cerebral small vessel disease and dementia.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02250-w},
pmid = {41814439},
issn = {2051-5960},
support = {G0500247/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Carotid artery disease (CAD) is a recognised cause of stroke. However, the relationships between CAD, cerebral small vessel disease (SVD) and dementia remain unclear. We hypothesised that CAD in older individuals contributes to cerebral SVD pathology by altering cerebral perfusion. We performed a clinicopathological study in patients from the Cognitive Function After Stroke (CogFAST) study and prospectively recruited patients with various dementia diagnoses and evidence of cerebral SVD. In addition to brain tissues, we collected postmortem samples of the internal carotid arteries (ICA) from these cohorts in the Newcastle Brain Tissue Resource. Standard neuropathological examination was performed for diagnosis and assignment of the cases per current diagnostic criteria for vascular and neurodegenerative dementias, which were assessed for the presence of vascular pathology including the degree of stenosis and sclerosis in vascular tissues. We evaluated a total of 159 ICA samples and brain tissues from all cases with evidence of SVD. Severity of ICA stenosis and sclerotic index correlated strongly with both clinical stroke and brain infarction (P < 0.001). More than 90% of the subjects had one subtype of ICA lesion in the order: intimal thickening > fibrocalcific > fibrous cap (thick) > fibrous cap (thin) > thrombus group with a strong inflammatory reaction in fibrocalcific atheromas. Regression analyses showed that ICA stenosis was positively correlated to both SVD pathology scores (P < 0.034) and the total number of vascular lesions (P < 0.001). ICA stenosis was also related to dementia caused by cerebrovascular disease (P < 0.001) and by mixed pathologies characterised by Alzheimer's disease and SVD (P = 0.025). Severity of stenosis was related to subcortical and white matter (WM) vascular lesions within the anterior circulation. ICA stenosis and sclerosis were moreover correlated with the total intracranial artery pathology scores (P < 0.001). In the CogFAST group analysis, we observed that MMSE and CAMCOG scores were lower in subjects with moderate to severe stenosis scores compared to the mild stenosis group (P < 0.05). In these CogFAST cases, by far the majority of lesions in the WM were small in size (< 5 mm, range 72-91%) but not in the cortex or basal ganglia and thalamus. Linear regression analysis further indicated that there were greater numbers of these small lesions in the WM with increasing severity of ICA stenosis (P < 0.05). Our observations suggest carotid atherosclerosis promotes cerebral SVD types of change within the intracerebral arteries. It is conceivable that extracranial ICA pathology may influence perfusion and integrity of subcortical structures including the deep WM.},
}

@article {pmid41814129,
year = {2026},
author = {Hai-Chao, C and Fu-Lin, G and Jia-Xin, C and Yi-Shu, Z and Lei, W and Jing, YH},
title = {Loss of Pericyte Exacerbates Alzheimer's Disease-Associated Retinal Pathology.},
journal = {Clinical & experimental ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1111/ceo.70103},
pmid = {41814129},
issn = {1442-9071},
support = {81870949//National Natural Science Foundation of China/ ; 21JR7RA452//Natural Science Foundation of Gansu Province/ ; 25JRRA691//Natural Science Foundation of Gansu Province/ ; 2024M751266//China Postdoctoral Science Foundation/ ; lzuyxcx-2022-179//Lanzhou University Medical Research Innovation Capacity Enhancement Program/ ; },
abstract = {BACKGROUND: The retina, part of the central nervous system, reflects brain pathology. In Alzheimer's disease (AD), it shows changes like amyloid beta (Aβ) accumulation and vascular alterations. Pericytes modulate the glymphatic system, crucial for Aβ clearance, but their role in the ocular glymphatic system is unclear. This study explores pericytes' impact on the glymphatic system and AD-related retinal pathology.

METHODS: APP/PS1 mice, a model of progressive Aβ deposition, were crossed with Pdgfr-β[+/-] mice, which exhibit pericyte dysfunction due to haploinsufficiency of platelet-derived growth factor receptor β (Pdgfr-β), generating four littermate genotypes: wild type, Pdgfr-β[+/-], APP/PS1 and APP/PS1:Pdgfr-β[+/-]. Retinal pericytes were assessed by PDGFR-β and NG 2 labelling, vascular complexity by OCTA and CD31 immunostaining and glymphatic-related regulation by laminin-211 and perivascular aquaporin-4 (AQP-4) expression. Retinal Aβ and p-Tau pathology was evaluated by immunofluorescence. Retinal Aβ clearance was assessed in wild type and Pdgfr-β[+/-] mice using intravitreal FAM-Aβ (1-42) injection followed by quantification of tracer efflux along the optic nerve to the deep cervical lymph nodes.

RESULTS: Pdgfr-β knockdown exacerbated retinal pericyte loss, leading to reduced laminin-211 expression, disrupted perivascular AQP-4 polarisation and impaired ocular glymphatic Aβ clearance. Consequently, this disruption is associated with increased Aβ and p-Tau pathology, reduced vascular complexity and thinning of the retinal layers in APP/PS1 mice.

CONCLUSIONS: The loss of retinal pericytes is one of the major factors in retinal pathology associated with AD. It exacerbates Aβ and p-Tau pathology and causes retinal vascular and structural damage by affecting the function of the ocular glymphatic system.},
}

@article {pmid41814083,
year = {2026},
author = {Akbar, F and Alkhrijah, Y and Usman, SM and Khalid, S and Ihsan, I and Alawad, MA},
title = {A deep-SVM hybrid framework with enhanced EEG feature engineering and SHAP-based explainability for Alzheimer's classification.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-43431-w},
pmid = {41814083},
issn = {2045-2322},
support = {IMSIU-DDRSP2601//Deanship of Scientific Research, Imam Mohammed Ibn Saud Islamic University/ ; },
abstract = {Accurate classification among Alzheimer's Disease (AD), Fronto Temporal Dementia (FTD), and Cognitively Normal (CN) adults from EEG remains challenging. We propose a multi-class classification method that fuses interpretable spectral/connectivity biomarkers (band power, spectral entropy, α-coherence) with compact temporal embeddings from a customized lightweight one Dimensional Convolutional Neural Network (1D-CNN). The fused features are reduced by Principal Component Analysis (PCA) and classified with Support Vector Machine (SVM). All data-dependent steps like Synthetic Minority Over Sampling Technique (SMOTE), z-scoring and PCA are fit strictly on training folds to prevent leakage. Hyperparameters including PCA dimensionality and SMOTE neighbors were selected via inner-loop grid sweeps that maximized macro-F1; full grids and class distributions before/after SMOTE (inner-train only) are reported in the Supplement. On OpenNeuro ds004504 (eyes-closed; [Formula: see text]; 36 AD/23 FTD/29 CN) the model achieved 94.5% accuracy, macro-F1 [Formula: see text], and AUC [Formula: see text]. Robustness was examined on two public datasets using the identical preprocessing/segmentation: (i) cross-condition testing on ds006036 (eyes-open recordings from the same participants) and (ii) zero-shot transfer to an independent OSF dataset with different instrumentation and demographics. SHapley Additive exPlanations (SHAP) analyses provided global, class-wise, and subject-level attributions aligned with known electrophysiology (e.g., reduced α-coherence, elevated θ), supporting clinical interpretability. These results indicate that a transparent hybrid feature design can deliver accurate, leakage-safe, and explainable EEG-based differentiation of AD, FTD, and CN with preliminary external checks.},
}

@article {pmid41814022,
year = {2026},
author = {Blujdea, ER and van Bokhoven, P and Martino-Adami, PV and Marshe, VS and Vromen, EM and Hok-A-Hin, YS and Boiten, WA and Irwin, DJ and Chen-Plotkin, AS and Lemstra, AW and Pijnenburg, Y and van der Flier, WM and Peters, O and Hellmann-Regen, J and Priller, J and Schneider, A and Wiltfang, J and Jessen, F and Düzel, E and Buerger, K and Perneczky, R and Teipel, S and Laske, C and Brosseron, F and , and Del Campo, M and Wijdeven, R and Visser, PJ and Tijms, BM and De Jager, PL and Ramirez, A and Teunissen, CE and Vermunt, L},
title = {Microglia protein profiles in CSF across Alzheimer's disease clinical stages.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {41814022},
issn = {2662-8465},
support = {WE.03-2018-05//Alzheimer Nederland (Alzheimer Netherlands)/ ; WE.03-2018-05//Alzheimer Nederland (Alzheimer Netherlands)/ ; },
abstract = {Microglia are implicated in the progression of Alzheimer's disease (AD) pathology from its earliest stages, suggesting that cerebrospinal fluid (CSF) microglia profiling across clinical AD stages can aid in treatment development and monitoring. We analyzed two CSF cohorts (n = 834) that span from unimpaired controls to preclinical and dementia AD stages, identifying 109 dysregulated microglia-related proteins. Enrichment analyses revealed innate immune processes and cellular recruitment in preclinical AD, whereas AD dementia revealed adaptive immunity and macrophage responses. Next, we aligned the in vivo microglia protein profiles with ex vivo-derived microglial transcriptomic signatures, such as disease-associated microglia phenotypes. Transcriptomic signatures were not specific to either clinical stage but spanned both. We classified an 18-protein panel highlighting distinct changes between the preclinical and dementia stages. Our findings underscore the potential of microglia-based biomarker research for AD staging, offering insights into microglia dynamics in clinical AD stages and how transcriptomic signatures translate to proteomic profiles.},
}

@article {pmid41814005,
year = {2026},
author = {Kaeser, SA and Schultz, SA and Hofmann, A and Häsler, LM and Xu, Y and Lambert, M and Obermüller, U and Brockmann, K and Bijzet, J and Nienhuis, H and Nuvolone, M and Obici, L and Palladini, G and Hegenbart, U and Schönland, SO and Jucker, M},
title = {Blood phosphorylated tau elevation as a biomarker in immunoglobulin light chain and transthyretin amyloidosis.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {41814005},
issn = {1546-170X},
abstract = {Elevated blood levels of phosphorylated tau (p-tau) are diagnostic of Alzheimer disease and are associated with the deposition of amyloid-β in the cerebral neuropil. Elevated p-tau levels have also been associated with cerebral deposition of Danish amyloid and prion protein amyloid. Here we analyzed p-tau in serum from four different cohorts of people with the most common types of systemic amyloidosis, transthyretin (ATTR) amyloidosis and immunoglobulin light chain (AL) amyloidosis. We found higher levels of serum p-tau181 in the AL and ATTR groups than in controls. Subsequent analyses revealed that these effects were more pronounced in the presence of polyneuropathy (PNP) and in AL compared to ATTR amyloidosis. Individuals with different forms of PNP that were not due to amyloidosis did not exhibit elevated p-tau181 levels. In cases of presymptomatic (genetic) ATTR, p-tau181 levels increased as a function of predicted years from symptom onset. Additional measurement of p-tau217 in one cohort revealed similar increases, and discriminated people with AL and those with ATTR from controls equally as well as p-tau181. These findings suggest that elevated serum p-tau levels are not specific to Alzheimer disease and may also serve as a diagnostic tool of ATTR and AL amyloidosis, with potential utility in distinguishing amyloidosis-related PNP from PNP of other etiologies.},
}

@article {pmid41813802,
year = {2026},
author = {Kumar, S and Sinclair, JA and Shi, T and Chuang, HS and Senapati, S and Chang, HC},
title = {Rapid and sensitive detection of cancer-derived small extracellular vesicles using Janus particles.},
journal = {Nature biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {41813802},
issn = {2157-846X},
support = {1UH3CA241684-01//U.S. Department of Health & Human Services | NIH | Office of Strategic Coordination (OSC)/ ; 1UH3CA241684-01//U.S. Department of Health & Human Services | NIH | Office of Strategic Coordination (OSC)/ ; 1UH3CA241684-01//U.S. Department of Health & Human Services | NIH | Office of Strategic Coordination (OSC)/ ; },
abstract = {Detecting small extracellular vesicles is critical for understanding disease biology and developing diagnostic tools, yet current methods require lengthy isolation steps and lack sensitivity owing to interference from abundant proteins. Here we report on an assay that uses Janus particles that enable rapid, isolation-free detection by exploiting Brownian rotation-induced blinking changes. When vesicles bind, their size significantly alters the blinking frequency, while smaller proteins produce no signal, ensuring selectivity. Using less than 10 μl of sample, the assay detects approximately 200 vesicles per microlitre and works directly on plasma, serum, urine and cell media in under 1 h. In a blind study of 87 subjects with colorectal cancer, pancreatic ductal adenocarcinoma, glioblastoma, Alzheimer's disease and healthy controls, the method identified disease type with an area under the curve of 0.90-0.99. Compared with ultracentrifugation combined with surface plasmon resonance, which requires 24 h, our approach delivers 2 orders of magnitude better sensitivity and dynamic range, offering a fast and robust platform for clinical and research applications.},
}

@article {pmid41813747,
year = {2026},
author = {Omar, MA and Al-Ashmawy, AAK and Abd El Salam, HA and El-Shiekh, RA and Aboulthana, WM and Srour, AM},
title = {New benzimidazole-alkanesulfonate conjugates as cholinesterase inhibitors with in vitro and in silico validation.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-39534-z},
pmid = {41813747},
issn = {2045-2322},
abstract = {Alzheimer's disease, the leading cause of dementia, is strongly associated with impaired cholinergic neurotransmission due to excessive acetylcholine degradation by acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Because current medications provide only symptomatic relief without modifying disease progression, there is an urgent need for more effective therapeutic agents. Dual inhibitors targeting both AChE and BChE represent a promising strategy. In this study, we designed and synthesized a novel series of benzimidazol-alkanesulfonate conjugates (4a-r) and evaluated their dual inhibitory activity against AChE and BChE. The results indicated that most compounds exhibited moderate to high inhibitory activity toward the target enzymes; however, derivatives 4b, 4h, 4i, 4q, and 4r showed promising AChE inhibitory activity with IC50 values of 0.91 ± 0.02, 0.89 ± 0.02, 0.54 ± 0.05, 0.37 ± 0.01, and 0.41 ± 0.009 µM, respectively, comparable to that of the reference drug donepezil (IC50 = 0.67 ± 0.00 µM). The antioxidant potency (represented by TAC and IRP) and scavenging activity (represented by DPPH, ABTS, NO, OH, and H2O2) revealed that compounds 4q and 4r possess remarkable antioxidant potential, comparable to the reference antioxidant ascorbic acid. Furthermore, in silico ADME prediction and molecular docking studies were performed to predict their binding modes and interactions in the AChE binding pocket; the results revealed that derivatives 4q and 4r showed the highest binding affinity among the tested series and the reference drug donepezil, which validated the obtained in vitro results.},
}

@article {pmid41813741,
year = {2026},
author = {Aboulthana, WM and El-Feky, AM and Omar, NI and El-Sayed, AEB},
title = {The influence of algal biostimulator and nitrogen source on the phytochemical composition and biological properties of Corchorus olitorius leaves and stems.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-39774-z},
pmid = {41813741},
issn = {2045-2322},
abstract = {The present study aimed to evaluate the impact of different nitrogen sources combined with an algal biostimulant on the biochemical composition and biological activities of Corchorus olitorius (Mulukhiyah) grown under saline irrigation. A pot experiment was conducted during the summer season of 2023 at the Algal Biotechnology Unit, National Research Centre, Cairo, Egypt. Seeds were soaked in algal slurry and cultivated in sandy soil, irrigated with Pandorina sp. slurry (3846.4 ppm on average), and supplemented with an in situ algal biostimulator applied as a foliar spray (1.0 mL L[-1]) in combination with nitrogen, phosphorus, and potassium (NPK) fertilization. Phytochemical analyses revealed that leaves consistently accumulated higher levels of sterols, terpenes, fatty acids, pigments, polyphenols, tannins, and flavonoids compared with stems. Among the three fertilization regimes, ammonium nitrate, in combination with the biostimulant, produced the highest concentrations of sterols (1.03% in leaves), terpenes (0.93%), fatty acids (3.05%), chlorophylls (4.16 mg/g), carotenoids (3.79 mg/g), polyphenols (252.76 mg/100 g), condensed tannins (101.10 μg/mL), and flavonoids (6.19 mg/g). HPLC profiling confirmed the presence of diverse phenolic and flavonoid compounds, including gallic acid, chlorogenic acid, caffeic acid, rutin, quercetin, and kaempferol, with leaves exhibiting a broader and higher profile than stems. In vitro biological assays demonstrated that ammonium nitrate-treated extracts exhibited superior antioxidant activity (total antioxidant capacity: 129.6 ± 2.3 mg GAE/g; DPPH scavenging IC50: 41.8 ± 1.2 µg/mL), anti-Alzheimer activity (AChE inhibition: 67.4% at 200 µg/mL), anti-diabetic activity (α-amylase IC50: 72.3 ± 1.5 µg/mL), and cytotoxic effects, particularly against Caco-2 cells (IC50: 50.65 ± 2.84 µg/mL). Conversely, no significant enhancement was observed in anti-inflammatory and anti-arthritic properties, where all extracts showed comparable inhibition (~ 48-52%) relative to the standard drug diclofenac. Overall, the findings indicate that the combined application of ammonium nitrate fertilizer and algal biostimulant enhances the accumulation of bioactive phytochemicals in C. olitorius, which translates into improved pharmacological potential, particularly antioxidant and cytotoxic activities. These results support the use of optimized fertilization strategies for improving the nutraceutical and medicinal value of C. olitorius under saline conditions.},
}

@article {pmid41796200,
year = {2026},
author = {Jang, KB and Kang, DM and Lee, MH and Lukianenko, N and Kim, YK and Lim, S and Kim, S and Cho, HJ},
title = {GV1001 reduces pathological 4R tau and functional deficits in models relevant to progressive supranuclear palsy.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41796200},
issn = {2045-2322},
abstract = {UNLABELLED: GV1001, a peptide drug derived from human telomerase reverse transcriptase, has showed the therapeutic effect in the animal model of Alzheimer’s disease (AD), a representative chronic neurodegenerative disease having impaired learning and memory. In our previous studies, GV1001 has showed the multi-functions including anti-apoptosis, anti-oxidative stress, and anti-neuroinflammation in AD-related in vitro and in vivo systems. Here, in addition to these previously reported functions, GV1001 was discovered to reduce the protein level of 4R tau isoform in the pathological condition. There is no studies providing the potential of GV1001 as a therapeutic drug for neurodegenerative movement disorders. Progressive supranuclear palsy (PSP) is a rare atypical Parkinsonism in the midbrain region, leading to more severe motor symptoms and very rapid pathological progression. Increased 4R tau isoform in an affected brain region of the primary 4R tauopathy is a distinct pathological character in PSP patients. In this study, GV1001 down-regulated the protein level of 4R tau specifically in an annonacin-induced PSP in vitro neuronal model as well as in vivo study using 4R TauP301L-BiFC mouse model. These findings suggest a novel role of GV1001 in 4R tauopathy and support its disease-modifying potential within the context of 4R tau–driven neurodegenerative models, including PSP.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-42195-7.},
}

@article {pmid41698978,
year = {2026},
author = {Pilotto, A and Pelucchi, S and Trasciatti, C and Ferullo, L and Poli, L and Tolassi, C and Catanese, A and Girotto, I and Labella, B and Gorla, F and D'Andrea, L and Stringhi, R and Di Luca, M and Marcello, E and Padovani, A},
title = {Synaptic and cytoskeletal CSF signatures of motor neuron disease: the role of cyclase-associated protein 2.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41698978},
issn = {2045-2322},
support = {2017MYJ5TH//Ministero dell'Università e della Ricerca/ ; ID853981//Innovative Medicines Initiative/ ; PNRR-MAD-2022-12376110//Ministero della Salute/ ; AGYR2021 Life-Bio//Airalzh Foundation/ ; ID853981//DIGI-BRAIN the H2020 IMI IDEA-FAST/ ; RF-2018-12366209//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; PRIN 20202THZAW//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; PRIN202039WMFP//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; PRIN COCOON (2017MYJ5TH)//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; 022343//Michael J. Fox Foundation for Parkinson's Research/ ; PE0000006//MNESYS/ ; PSR2023_SPELU//Piano di Sostegno alla Ricerca, Università degli Studi di Milano/ ; CA 2915/4-1//Deutsche Forschungsgemeinschaft/ ; FIS00000560//Fondo Italiano per la Scienza/ ; ID853981//H2020 IMI IDEA-FAST/ ; NRRP M6C2//NextGenerationEU/ ; },
abstract = {UNLABELLED: Cyclase-associated protein 2 (CAP2) is a synaptic actin-binding protein involved in cofilin-mediated spine remodelling, Alzheimer’s Disease synaptic failure and myofibril maintenance, indicating its potential involvement in motor neuron disease (MND). This study examined cerebrospinal fluid (CSF) levels of CAP2 in 60 patients with MND and 40 healthy controls (HC) to assess its diagnostic and prognostic value and its relationship with neuronal, glial and synaptic markers. Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated and total tau (p-Tau 181, t-Tau), CAP2 and synaptosomal-associated protein 25 (SNAP-25) were quantified using ELISA, Lumipulse and SIMOA platforms. MND patients displayed increased GFAP, NfL, t-Tau, p-Tau 181 levels and CAP2 while SNAP-25 was reduced. CAP2 correlated with tau markers, but not with NfL or GFAP. Unlike NfL, which was higher in upper motor neuron–predominant cases and predicted faster progression and poorer survival, CAP2 did not vary with disease subtypes or severity. The study showed that CAP2 is associated with MND independently from neuronal, glial and presynaptic dysfunction. Integrating CAP2 into multi-marker panels could enhance understanding of synaptic pathology in MND.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-39274-0.},
}

@article {pmid41680411,
year = {2026},
author = {Minta, K and Colombo, G and Tee, M and Low, M and Grübel, J and Wiener, J and Chen, CP and Hilal, S and Schinazi, VR},
title = {SPACE: A novel digital tool for assessing hippocampal structural integrity in older adults.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41680411},
issn = {2045-2322},
support = {NRF2022-ITS010-0006//Intra-CREATE Seed Collaboration Grant/ ; },
abstract = {UNLABELLED: Hippocampal atrophy is a hallmark of Alzheimer’s disease and is linked to deficits in navigation. We investigated whether performance in a novel digital assessment, the Spatial Performance Assessment for Cognitive Evaluation (SPACE), is associated with hippocampal volume beyond traditional neuropsychological tests in older adults. Forty older adults (Mage = 67, SD = 6) underwent structural MRI and completed the spatial and navigation tasks in SPACE along with a battery of neuropsychological tests typically used to detect cognitive impairment. Regression analyses revealed that poorer performance in the path integration and mapping tasks was associated with smaller hippocampal volume after accounting for age, education, and neuropsychological test performance. Notably, individuals who accurately completed the path integration task and successfully learned the spatial configuration of landmarks required for subsequent reconstruction in the mapping task exhibited larger hippocampal volumes. Together, these findings suggest that SPACE may capture aspects of spatial cognition closely linked to hippocampal structural integrity and may complement existing cognitive assessments by providing increased sensitivity to hippocampal variation in non-clinical older adults.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-39628-8.},
}

@article {pmid41813153,
year = {2026},
author = {Panek, S and Van Baelen, AC and Volta, BD and Dutta, SB and Hericks, L and Karoui, R and Vortmeyer, E and Hannappel, Y and Dodero, VI and Huser, T and Servent, D and Lequin, O and Kapurniotu, A and Sewald, N and Tonali, N},
title = {Cyclopeptide-Based Fluorescent Conjugates for Monitoring Prefibrillar Aβ Nanostructures.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.6c00059},
pmid = {41813153},
issn = {1520-4804},
abstract = {Amyloid-β (Aβ1-42) prefibrillar aggregates are considered the most neurotoxic amyloid species, yet their transient and heterogeneous nature makes selective detection challenging. Many fluorescent probes also fail to discriminate Aβ from homologous peptides such as IAPP, leading to poor specificity. We report a peptide-guided late-stage diversification strategy to generate BODIPY-based probes highly selective for prefibrillar Aβ1-42. A rationally engineered cyclic peptide derived from the C-terminal region of Aβ1-42 provides conformational rigidity and precise molecular recognition. Conjugation to BODIPY fluorophores afforded peptide-dye hybrids systematically evaluated for selectivity and photophysical response. A controlled aggregation protocol enabling reproducible generation of prefibrillar Aβ species was established to validate probe performance. A Sonogashira-derived conjugate (probe 8) showed strong fluorescence turn-on and selective affinity for prefibrillar Aβ1-42, with no response to IAPP aggregates. In neuronal cells, probe 8 outperformed conventional antibodies, supporting its potential for mechanistic studies and early Alzheimer's disease diagnostics.},
}

@article {pmid41813040,
year = {2026},
author = {Araujo, AQC},
title = {The corporate takeover of Alzheimer's treatment: a crisis in neurological autonomy?.},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {3},
pages = {1-5},
doi = {10.1055/s-0046-1817020},
pmid = {41813040},
issn = {1678-4227},
abstract = {The recent approval of monoclonal antibodies for the treatment of Alzheimer's disease represents a significant advancement in neurology. This accomplishment coincides with a worrisome trend: the increasing hegemony of large corporate healthcare organizations and commercial laboratory corporations in the supply of these new medications. This editorial examines how corporate influence undermines the traditional physician-patient relationship, diminishes neurologist autonomy, and signals a broader incursion into neurological practice by nonspecialists. The current situation in Brazil, compared with the United States and Europe, including the United Kingdom, is discussed, and strategies are proposed to maintain the integrity of neurological therapy amid growing corporate influence in the medical field.},
}

@article {pmid41813037,
year = {2026},
author = {Ribeiro, IC and Gonçalves, BC and Aventurato, ÍK and Silva, MCRD and Rizzi, L and Rochetti, ALG and Fernandes, GBP and Cendes, F and Balthazar, MLF},
title = {Differences in cognitive performance and neuroanatomy according to Alzheimer's disease pathophysiology.},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {3},
pages = {1-9},
doi = {10.1055/s-0046-1817040},
pmid = {41813037},
issn = {1678-4227},
mesh = {Humans ; *Alzheimer Disease/physiopathology/pathology/diagnostic imaging ; Male ; Female ; Aged ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/physiopathology/diagnostic imaging/pathology ; Neuropsychological Tests ; *Cognition/physiology ; Biomarkers/cerebrospinal fluid ; Aged, 80 and over ; Disease Progression ; Middle Aged ; Brain/pathology ; Reference Values ; },
abstract = {The diagnosis of predementia stages indicates an increased risk of progression to dementia. The Amyloid, Tau, and Neurodegeneration AT(N) classification considers measurements of altered proteins and the presence of neurodegeneration to classify the risk groups regarding the pathophysiology of Alzheimer's disease (AD). The cognitive and anatomical characteristics of the patients in the predementia stage according to the AT(N) classification are not fully understood.To investigate whether there are differences in the clinical and anatomical profiles among older adults in the predementia stage according to the ATN classification, and to investigate the associations involving cognition and cortical thickness and subcortical volume in the AT(N) groups.In total, 72 older adults with subjective cognitive decline and mild cognitive impairment were allocated to groups according to the AT(N) classification (AD continuum: n = 37; suspected non-AD pathophysiology: n = 8; normal biomarkers: n = 27). The participants were investigated through cognitive tests, magnetic resonance imaging scans, and cerebrospinal fluid analyses. We used multivariate and univariate analyses with post-hoc testing to verify differences among groups. In addition, linear regressions were performed to verify the interactions involving cognition and gray matter metrics.The suspected non-AD pathophysiology group showed worse performance in attention/executive function than the AD continuum and normal biomarkers groups (p = 0.04). However, the ATN classification groups did not differ in terms of cortical thickness (p > 0.05). In addition, in the AD continuum group, memory was associated with left fusiform gyrus thickness (p = 0.000 uncorrected; r = 0.238).Cognition, but not gray matter metrics, differs among AT(N) classification groups. Memory is associated with cortical thickness in patients with positive amyloid Beta (AD continuum).},
}

Humans
*Alzheimer Disease/physiopathology/pathology/diagnostic imaging
Male
Female
Aged
Magnetic Resonance Imaging
*Cognitive Dysfunction/physiopathology/diagnostic imaging/pathology
Neuropsychological Tests
*Cognition/physiology
Biomarkers/cerebrospinal fluid
Aged, 80 and over
Disease Progression
Middle Aged
Brain/pathology
Reference Values

@article {pmid41812941,
year = {2026},
author = {Wang, M and Niu, D and Zhang, Q and Tang, Y and Zhao, Y and Chen, F},
title = {CRISPR-based correction of apolipoprotein E4 in Alzheimer's disease: Therapeutic strategies and macromolecular delivery innovations.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {151352},
doi = {10.1016/j.ijbiomac.2026.151352},
pmid = {41812941},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide, with substantial unmet clinical needs. The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late onset AD, with each copy increasing risk approximately two- to three-fold, and homozygous carriers facing up to a 10- to 15-fold higher risk compared to APOE3 carriers. APOE4 contributes to diverse pathogenic mechanisms including lipid dysregulation, neuroinflammation, synaptic dysfunction, and vascular compromise. The precise, allele-specific correction of APOE4 therefore holds transformative therapeutic potential. CRISPR-based genome editing technologies, including nuclease disruption, base editing, and prime editing, offer unprecedented opportunities to directly modify APOE4 at its genomic source. Here, we review mechanistic underpinnings of APOE4 pathology, summarize current gene editing platforms for APOE4 correction, evaluate relevant in vitro and in vivo model systems, and assess delivery strategies with an emphasis on nanoparticle and exosome based approaches. We highlight recent breakthroughs in exosome mediated APOE4 editing while addressing ongoing technical hurdles in allele specificity and translational barriers such as Cas nuclease immunogenicity, limited delivery efficiency across the blood brain barrier (BBB), and concerns over long term genomic safety. This review concludes that overcoming BBB constraints remains the most significant challenge for clinical translation, and that innovations in exosome and nanoparticle based delivery platforms represent the most promising strategies for advancing CRISPR therapeutics for AD.},
}

@article {pmid41812935,
year = {2026},
author = {Chauhan, P and Wadhwa, K and Singh, G},
title = {Rosa × damascena Herrm. and Commiphora wightii (Arn.) Bhandari. combination therapy ameliorates cognitive, neurobehavioral and metabolic impairments in a rat model of Alzheimer's disease through restoration of mitochondrial functions, regulation of neurotransmitter balance and attenuation of pro-inflammatory cytokine levels.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121509},
doi = {10.1016/j.jep.2026.121509},
pmid = {41812935},
issn = {1872-7573},
abstract = {Rosa × damascena Herrm. has been widely employed in Iranian traditional medicine as a nerve tonic to treat anxiety, depression, headache, and other neurological disorders. Additionally, Commiphora wightii (Arn.) Bhandari. (Guggul) is also well recognized in both Ayurvedic and Unani systems, used to treat lipid disorders, obesity, facial paralysis, tremors, and memory loss.

AIM OF THE STUDY: Although traditionally used individually, the combination represents a rational multi-target strategy to simultaneously address metabolic and neurodegenerative components associated with Alzheimer's disease (AD). Thus, the present study explored the neuroprotective, metabolic, and behavioral effects of R. damascena and C. wightii combination therapy in a streptozotocin (STZ)-induced rat model of AD.

MATERIAL AND METHODS: Adult Wistar rats were administered intracerebroventricular STZ to induce AD-like pathology. A dose-response and combination screening study was initially performed to identify an optimal R. damascena - C. wightii dose pair using normalized escape latency and interaction analysis. The best identified combination and its associated per se doses were then subsequently subjected to detailed behavioral and biochemical evaluations.

RESULTS: The interaction-guided analysis identified R. damascena 600 mg/kg + C. wightii 400 mg/kg as the most effective combination and utilized further. While both extracts alone exerted significant protective effects, their combined intervention was more effective in restoring metabolic homeostasis, enhancing motor coordination and exploratory activity, reducing anxiety-like behavior, and improving spatial learning and memory compared to monotherapy, primarily through attenuation of oxidative stress, inhibition of TNF-α-associated neuroinflammatory cascades, restoration of mitochondrial function, and normalization of glutamatergic and cholinergic neurotransmission.

CONCLUSION: The findings support this combination as a promising herbal strategy for further investigation in the management of metabolic and cognitive disturbances associated with AD.},
}

@article {pmid41812924,
year = {2026},
author = {Shi, Z and Hao, M and Chen, G and Li, F and Zhou, Y and Zhou, JC},
title = {Phosphatidylethanolamine: Its biological significance and responses to nutritional factors for neurohealth.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {101468},
doi = {10.1016/j.tjnut.2026.101468},
pmid = {41812924},
issn = {1541-6100},
abstract = {Phosphatidylethanolamine (PE) is a major component of biological membranes, pivotal to numerous life processes. Inhibition of its synthesis via either the CDP-ethanolamine (Kennedy) pathway or the phosphatidylserine decarboxylation pathway can be lethal. PEs derived from different organelles have different functions and biological significance, so they are not fully interchangeable. From a biological perspective, PE is involved in constructing membranes and plays a crucial part in mitochondrial biogenesis, ferroptosis, cell autophagy, cell division, synthesis of biomolecules, and other processes. Furthermore, PE acts as the essential substrate for glycosylphosphatidylinositol anchor biosynthesis, thereby governing processes such as immune response, signal transduction, and embryonic development. Notably, PE is highly enriched in neural tissues and is closely implicated in the pathology of multiple neurological disorders, including hereditary spastic paraplegia, Liberfarb syndrome, Alzheimer's disease, Parkinson's disease, and sepsis-associated encephalopathy. Given that the levels, composition, and functions of PE can be modulated by dietary and nutritional factors, including polyunsaturated fatty acids, specific minerals and vitamins, and dietary patterns, targeting PE metabolism represents a promising and translatable strategy for supporting neurological health. This approach holds potential not only for populations with or at risk for neurodegenerative disorders but also for developing fetuses and newborns during critical nervous system development. This review summarizes recent advances in these areas, updates our understanding of PE's basic biology, and explores novel strategies for neuroprotection and health promotion.},
}

@article {pmid41812842,
year = {2026},
author = {Jali, V and Li, L and Qi, TA and Tanaka, T and Hilal, S and Gyanwali, B and Chen, CL and Ngam, PI},
title = {Comparative Analysis of Heuron Brain PET and FreeSurfer Software in Automated Amyloid Quantification: Toward Reproducible and Clinically Applicable Brain PET Imaging.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121844},
doi = {10.1016/j.neuroimage.2026.121844},
pmid = {41812842},
issn = {1095-9572},
abstract = {PURPOSE: Beta-amyloid (Aβ) plaque accumulation is a hallmark of Alzheimer's disease (AD) and can be evaluated using positron emission tomography (PET). While visual assessment is standard in clinical settings, quantitative methods such as standardized uptake value ratios (SUVR) may improve diagnostic accuracy and reproducibility. This study aimed to compare the quantification and diagnostic performance of Heuron Brain PET, a recently developed clinical tool, with FreeSurfer, a well-validated research platform, in assessing Aβ deposition.

METHODS: A total of 205 amyloid PET scans (176 [¹¹C]PiB + 29 [¹⁸F]Flutafuranol) were analyzed using both Heuron Brain PET and FreeSurfer. SUVRs were calculated using cerebellar grey matter as the reference region. Diagnostic thresholds were determined, and regional/global SUVRs were compared using paired t-tests and correlation analysis. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. Reproducibility was assessed on a randomly selected subset (n=50) using intraclass correlation coefficients (ICC).

RESULTS: For [¹¹C]PiB, Heuron Brain PET yielded slightly lower global SUVRs than FreeSurfer (1.32 ± 0.34 vs. 1.40 ± 0.41; p < 0.001), but showed very strong correlation (r = 0.960, p < 0.001). AUCs were comparable (Heuron: 0.988; FreeSurfer: 0.979; p = 0.401). ICC for reproducibility was perfect across all regions (ICC = 1.00, 95% CI [1.00, 1.00], p < 0.001). Results for [¹⁸F]Flutafuranol were less consistent due to small sample size.

CONCLUSION: Heuron Brain PET demonstrates comparable SUVR quantification and diagnostic performance to FreeSurfer for [¹¹C]PiB PET, with excellent reproducibility and rapid analysis, supporting its potential for routine clinical application.},
}

@article {pmid41812815,
year = {2026},
author = {Shen, X and Dong, X and Nao, J},
title = {Harmine and its derivatives: A promising multi-target therapeutic avenue for Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.03.006},
pmid = {41812815},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, and cholinergic dysfunction. Currently, no disease-modifying drugs are available, and existing symptomatic treatments offer limited efficacy while posing safety concerns, highlighting the urgent need for multi‑target therapeutic strategies. The natural β‑carboline alkaloid harmine has attracted considerable attention due to its favorable blood-brain barrier penetration and multi‑target profile. Accumulating preclinical evidence indicates that harmine can concurrently modulate several core pathological processes of AD. Mechanistically, it potently inhibits dual‑specificity tyrosine phosphorylation‑regulated kinase 1A (DYRK1A), thereby reducing tau hyperphosphorylation, suppressing aberrant amyloid precursor protein processing, and enhancing neprilysin‑mediated Aβ clearance. Concurrently, harmine attenuates neuroinflammation via negative regulation of the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF‑κB) and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathways, improves cholinergic neurotransmission through acetylcholinesterase inhibition, and alleviates glutamate excitotoxicity by upregulating astrocytic glutamate transporter 1/excitatory amino acid transporter 2 (GLT-1/EAAT2) expression. Structurally optimized harmine derivatives have demonstrated enhanced dual inhibitory activity and improved cognitive outcomes in preclinical models. Despite these promising findings, challenges such as pharmacokinetic limitations, insufficient target selectivity, and a lack of clinical data remain. In conclusion, the harmine scaffold represents a mechanistically grounded and promising direction for the development of multi‑target therapeutics for AD.},
}

@article {pmid41812704,
year = {2026},
author = {Wang, J and Wang, B and Zhu, K and Zhang, J and Zhang, G and Liu, S and Dasun Vimukthi, WP and Zhang, Y and Cao, F and Yang, C and Sun, X},
title = {Indoor aerosols induced blood-brain barrier leakiness and β-amyloid1-42 aggregation.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.03.015},
pmid = {41812704},
issn = {2090-1224},
abstract = {INTRODUCTION: Exposure to indoor aerosols that include fine particulate matter 2.5 (PM2.5) and microorganisms has been implicated in various health issues, including neurodegenerative diseases.

OBJECTIVES: The major components of indoor aerosols could induce the blood-brain barrier (BBB) leakiness and β amyloid (Aβ) aggregation, potentially exacerbating Alzheimer's disease (AD) pathology.

METHODS: The main components of aerosols were collected by an intelligent sampler and an airborne microorganism sampler, respectively. The PM2.5 was characterized with SEM and UV-vis spectrophotometer. The microorganisms were identified by 16S rRNA gene sequencing. The Aβ aggregation was studied by thioflavin T kinetic assay and circular dichroism spectroscopy. The BBB models were constructed by seeding astrocytes and human brain microvascular endothelial cells on the membrane of transwell inserts. Moreover, the BBB leakiness induced by PM2.5, Staphylococcus aureus (S. aureus), and the Aβ aggregates was evaluated by immunofluorescence imaging and transwell assay both in vitro and in vivo.

RESULTS: The PM2.5 owns the size of 112 ± 35.41 nm and the surface charge of -0.125 mV. PM2.5 and S. aureus can independently disrupt the BBB integrity both in vitro and in vivo by down-regulating adherens and tight junction proteins including zonula occludens-1, VE-cadherin, occludin, and claudin-5. Furthermore, PM2.5 and S. aureus accelerated Aβ aggregation into neurotoxic oligomers and fibrils. In combined exposures, PM2.5 + Aβ or S. aureus + Aβ act synergistically to exacerbate BBB permeability and cytotoxicity of endothelial cells, astrocytes, and neuron cells, creating a vicious cycle of the BBB dysfunction and neurodegeneration.

CONCLUSIONS: These findings establish PM2.5 and S. aureus as dual environmental drivers of BBB compromise and Aβ pathology, offering novel mechanistic insights and emphasizing the urgent need for strategies to mitigate indoor aerosol-related health risks for AD patients.},
}

@article {pmid41812658,
year = {2026},
author = {Turnbull, A and Gross, JJ and Vankee-Lin, F},
title = {The emergence of neuropsychiatric symptoms in preclinical Alzheimer's disease: An emotion regulation perspective.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.01.022},
pmid = {41812658},
issn = {1097-4199},
abstract = {Preclinical Alzheimer's disease (AD) is associated with distressing neuropsychiatric symptoms (NPSs) that may accelerate progression toward dementia. Existing approaches probe the symptom-level domain-general or domain-specific neural correlates of NPSs. However, the field lacks process-oriented models of symptom emergence for targeted treatment. We propose one pathway for symptom emergence involving the disruption of emotion regulation (ER) systems by early AD pathology. AD pathology in the ventral anterior cingulate cortex-ventromedial prefrontal cortex disrupts model-free ER that modulates negative valuations using experience-dependent reinforcement learning (e.g., fear extinction), leading to increased negative valuations and negative affect. We further propose that model-based ER competes for overtaxed executive resources and is less successful in preclinical AD, particularly in demanding real-world contexts. These changes lead to a shift toward negative affect, leading to divergent trajectories of NPSs depending on critical moderators. We discuss implications for intervention to improve NPSs and potentially slow dementia progression.},
}

@article {pmid41812391,
year = {2026},
author = {Yilmaz, S and Aslam, S and Sillau, S and Katz, M and Kluger, B},
title = {Bridging the gap: Evaluating a community-based palliative care intervention for underserved patients with Parkinson's disease.},
journal = {Parkinsonism & related disorders},
volume = {146},
number = {},
pages = {108262},
doi = {10.1016/j.parkreldis.2026.108262},
pmid = {41812391},
issn = {1873-5126},
abstract = {BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative illness with a profound impact on quality of life (QOL). While palliative care has demonstrated benefits in PD, reach and evidence of effectiveness in underserved populations remain limited. The goal of this study was to evaluate the effect of a novel palliative care intervention on QOL among underserved patients with PD.

METHODS: We conducted a secondary analysis of data from a stepped-wedge, pragmatic clinical trial (NCT03076671) among 322 participants with PD. We created an "underserved demographic" composite variable based on rural residency, low income (<$50,000/year), and race/ethnicity (non-White or Hispanic). QOL was measured using the Quality of Life in Alzheimer's Disease Scale (QOL-AD) at baseline, 6 months, and 12 months. We used t-tests for group comparisons at baseline and linear mixed-effects models for longitudinal analyses.

RESULTS: A total of 129 participants were identified as underserved. The intervention showed significant improvement in QOL over time for non-underserved participants at 6 months (p = 0.06) and 12 months (p = 0.04). While overall improvements among underserved participants were not observed at earlier time points, we found a statistically significant time and group interaction effect suggesting a meaningful QOL improvement in the underserved group at 12 months compared to baseline (estimate = 2.39, 95% CI: 0.33-4.46, p = 0.05).

CONCLUSIONS: Findings suggest that this community-based palliative care intervention may help support improvements in QOL over time among underserved patients with PD. Tailored, longitudinal palliative care approaches may help bridge disparities in neurologic care.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03076671.},
}

@article {pmid41812151,
year = {2026},
author = {Yang, M and Li, Z and Xinhong Ye, K and Guo, J and Lee, TS and Cao, L and Wang, Y and Ye, R and Maier, AB and Feng, L and Chen, C},
title = {Dietary Factors and Cognitive Health in Ethnic Chinese: A Systematic Review and Meta-analysis.},
journal = {Nutrition reviews},
volume = {},
number = {},
pages = {},
doi = {10.1093/nutrit/nuag026},
pmid = {41812151},
issn = {1753-4887},
support = {2023HWYQ-017//Distinguished Young Scholars of the Natural Science Foundation of Shandong Program (Overseas)/ ; },
abstract = {CONTEXT: Dementia is a group of neurological disorders affecting millions worldwide, placing substantial strain on healthcare systems. Although diet has been identified as a modifiable risk factor for cognitive health in aging, there is limited research on how dietary patterns affect cognitive outcomes in ethnic Chinese populations. Chinese populations, primarily in Mainland China, Hong Kong, Macao, Taiwan, and Singapore, have distinct genetic profiles and diverse dietary traditions. These genetic and cultural dietary factors may interact in specific ways to influence cognitive health.

OBJECTIVE: This systematic review and meta-analysis critically evaluated the evidence on the dietary factors and cognitive health in the ethnic Chinese population.

DATA SOURCES: A systematic search of PubMed, Web of Science, Scopus, and CNKI were conducted according to the PRISMA criteria.

DATA EXTRACTION: Two reviewers independently extracted data using a standardized data extraction template. Information collected included study characteristics, participant demographics, dietary exposures or patterns, cognitive outcomes, and key findings. Study quality was assessed using the National Institutes of Health criteria for observational studies. Extracted data, including reported odds ratios (ORs) and corresponding 95% CIs, were summarized and used for subsequent analyses.

DATA ANALYSIS: Meta-analyses were performed using random-effects models to pool ORs with corresponding 95% CIs. Between-study heterogeneity was assessed using τ2 and I2 statistics, with I2 values >50% indicating substantial heterogeneity. Statistical significance was set at P < .05.

CONCLUSION: Evidence from observational studies suggests that dietary patterns rich in vegetables, fruits, fish, and plant-based foods are associated with a lower risk of cognitive decline in ethnic Chinese adults, potentially influenced by unique genetic variations, traditional dietary practices, and cultural factors. Adherence to the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets, as well as higher consumption of mushrooms and tea, was linked to better cognitive health, whereas diets high in red meat and low in fish and legumes were associated with increased risk. Meta-analysis showed a protective association for plant-based diets (OR: 0.78; 95% CI: 0.69-0.87).

PROSPERO NO. CRD42024575522.},
}

@article {pmid41811933,
year = {2026},
author = {El-Sabbagh, NA and Ellakwa, DE},
title = {AMP-activated protein kinase as a therapeutic target: effects of nano-selenium and thymoquinone in Alzheimer's disease.},
journal = {Archives of physiology and biochemistry},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13813455.2026.2640885},
pmid = {41811933},
issn = {1744-4160},
abstract = {CONTEXT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and complex multifactorial pathogenesis. AMP-activated protein kinase (AMPK) has been identified as a promising molecular target in AD due to its neuroprotective functions, particularly in energy regulation.

OBJECTIVE: To evaluate the effects of nano-selenium and thymoquinone (TQ) on AMPK gene expression in an AD rat model.

SUBJECTS AND METHODS: Fifty male albino rats were divided into five groups. Four groups were induced with AD via lipopolysaccharide (LPS) injection, while the control group remained untreated. The experimental groups received nano-selenium, TQ, or a combination of both treatments. AMPK gene expression in brain tissue was measured using real-time PCR analysis.

RESULTS: Treatment with nano-selenium, TQ, or their combination significantly upregulated AMPK expression in brain tissue compared to untreated AD rats (p<0.001). The combination therapy produced the highest increase in AMPK expression.

DISCUSSION AND CONCLUSION: Nano-selenium and TQ enhance AMPK gene expression in AD, suggesting a potential therapeutic mechanism involving AMPK-related pathways.},
}

@article {pmid41811929,
year = {2026},
author = {Henao Isaza, V and Aguillon, D and Tobón-Quintero, CA and Lopera, F and Ochoa-Gómez, JF},
title = {Comprehensive methodology for sample enrichment in EEG biomarker studies for Alzheimer's risk classification.},
journal = {PloS one},
volume = {21},
number = {3},
pages = {e0343722},
doi = {10.1371/journal.pone.0343722},
pmid = {41811929},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology/genetics ; *Electroencephalography/methods ; Biomarkers ; Male ; Female ; Aged ; Middle Aged ; Presenilin-1/genetics ; Propensity Score ; },
abstract = {OBJECTIVE: Dementia, particularly Alzheimer's disease (AD), constitutes a major global health concern, with AD accounting for approximately 70% of all cases. EEG-based biomarkers hold promise for early identification of individuals at risk; however, small and heterogeneous samples frequently limit generalizability.

METHODS: An EEG-based sample enrichment framework was developed by integrating advanced signal processing, component-level feature extraction, data harmonization (neuroHarmonize), and Propensity Score Matching (PSM). EEG data from four independent cohorts were harmonized to reduce site-related variability while preserving covariates such as age and sex. Features including power, entropy, coherence, synchronization likelihood, and cross-frequency coupling were extracted from independent components. PSM was applied at 2:1, 5:1, and 10:1 ratios to expand and balance the control group (HC) relative to the Alzheimer's risk group (ACr), composed of PSEN1-E280A mutation carriers without cognitive symptoms.

RESULTS: Sample enrichment through PSM improved classification accuracy, with decision tree models yielding values between 0.91 and 0.96. Higher enrichment ratios enhanced model stability and generalizability, as shown by learning curves and confusion matrices. Feature selection was based on model performance and effect sizes (Cohen's d).

CONCLUSIONS: The proposed framework addresses sample size and variability constraints in EEG-based AD risk classification.

SIGNIFICANCE: Harmonization and statistical balancing provide a replicable strategy for multicenter EEG studies targeting early AD detection.},
}

Humans
*Alzheimer Disease/diagnosis/physiopathology/genetics
*Electroencephalography/methods
Biomarkers
Male
Female
Aged
Middle Aged
Presenilin-1/genetics
Propensity Score

@article {pmid41811667,
year = {2026},
author = {Li, D and Li, Y and Wen, L and Chen, Z and Gao, F and Shen, Y and Wang, Q},
title = {Astrocyte-Specific Upregulation of Tumor Necrosis Factor Receptor II Ameliorates Pathological Phenotypes in APP[NL-F/NL-F] Mice.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41811667},
issn = {1995-8218},
abstract = {Our earlier research showed that deletion of tumor necrosis factor-α receptor II (TNFRII) exacerbated Alzheimer's disease (AD) associated pathology in the AD mouse model. Previous studies have demonstrated that TNFRII was mainly expressed in astrocytes. However, whether AD-associated pathology can be modified by targeting TNFRII in astrocytes remains unknown. Here, we showed that TNFRII was decreased in astrocytes in AD brains. Then, we developed transgenic mouse models (astrocyte-specific expression of human TNFRII mice, TNFRII[GFAP] mice) and crossed TNFRII[GFAP] mice with a mouse model of AD (humanized APP knock-in mice, APP[NL-F/NL-F] mice). We found that increased expression of TNFRII in astrocytes rescued learning and memory deficits, decreased amyloid burden, and reactive astrocytes in APP[NL-F/NL-F] mice. Mechanistically, APP[NL-F/NL-F]-TNFRII[GFAP] mice displayed increased microgliosis, higher expression of plaque-associated microglial cluster of differentiation 68 (CD68), and enhanced microglial amyloid-β (Aβ) phagocytosis. In vitro assays confirmed that TNFRII upregulation in astrocytes enhanced phagocytosis of Aβ in BV2 murine microglial cell line (BV2) cells. Our study implicates that increased expression of TNFRII in astrocytes ameliorates pathology and behavioral deficits in APP[NL-F/NL-F] mice and provides new therapeutic options for AD.},
}

@article {pmid41811541,
year = {2026},
author = {Houfkova, A and Schmidt, M},
title = {Amyloid-β and Mitochondrial Membranes: A Missing Link in Alzheimer's Pathogenesis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41811541},
issn = {1559-1182},
support = {SV2112/2024//Univerzita Hradec Králové, Czechia/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline, predominantly in the elderly (Alzheimer Disease International et al., 2015). Although amyloid-β peptide (Aβ), particularly in its oligomeric forms, has long been linked to AD pathogenesis (Chen 9:1205-1235 2017, Gaspar 2 394-400 2010), the mechanisms underlying its cellular toxicity remain unclear. Mitochondrial dysfunction is a consistent feature of AD (D'Alessandro 107:102713 2025), yet how Aβ drives these alterations is not fully understood. This review integrates recent evidence showing that Aβ accumulates on mitochondrial membranes (Cenini 21:3257-3272 2016, Manczak 23:5131-5146 2006, Sirk 5:1989-2003 2007), providing a mechanistic link between amyloid pathology and mitochondrial damage. We discuss how membrane-associated Aβ disrupts mitochondrial protein import by impairing the translocase of the outer membrane (TOM) complex (Cenini 21:3257-3272 2016, Sirk 5:1989-2003 2007) and interferes with voltage-dependent anion channel 1 (VDAC1) (Smilansky 52:30670-30683 2015), a key regulator of metabolite exchange and apoptosis. We further emphasize the role of mitochondria-associated membranes (MAMs) as critical sites for Aβ generation and transfer to mitochondria, where dysregulated cholesterol metabolism may amplify MAM activity and Aβ accumulation (Area-Gomez and Schon 38:90-96 2017, Monaghan 2:240287 2025). Altogether, we propose that mitochondrial membrane localization of Aβ is a central mechanism linking amyloid pathology to mitochondrial dysfunction in aging, highlighting new directions for mitochondria-targeted therapeutic strategies in AD.},
}

@article {pmid41811516,
year = {2026},
author = {Ting, SKS and Asahara Thio, S and Cao, K and Hameed, S and Li, W and Mukesh Shah, J and Lin, S and Sim, J and Chiew, HJ and Ng, KP and Ng, ASL},
title = {Early clinical characteristics of pathologically confirmed progressive supranuclear palsy and corticobasal degeneration.},
journal = {Journal of neurology},
volume = {273},
number = {3},
pages = {},
pmid = {41811516},
issn = {1432-1459},
support = {U24 AG072122/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Supranuclear Palsy, Progressive/pathology/diagnosis/complications/physiopathology ; Male ; Female ; Aged ; *Corticobasal Degeneration/diagnosis/pathology/physiopathology/complications ; Aged, 80 and over ; Middle Aged ; Depression/etiology ; },
abstract = {OBJECTIVES: Although the clinical features of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are well documented, their early clinical presentations from the perspective of initial clinical consultation remain less well understood. This study aimed to characterize the early clinical features of PSP and CBD to inform clinicians on diagnostic assessment and management strategies.

METHODS: Data were obtained from the National Alzheimer's Coordinating Center (NACC) database (2005-March 2025 data freeze). Neuropathologically confirmed cases of PSP (n = 278) and CBD (n = 149) were included. Analyses were restricted to first clinical visits, focusing on demographic, neuropsychiatric, neurological, and neuropsychological variables.

RESULTS: Memory symptoms were reported in more than half of both groups, whereas language impairment was more common in CBD (> 70%) and associated with higher odds of CBD diagnosis. Depression was frequent (~ 50%), with PSP showing higher odds for depressive symptoms but lower odds for disinhibition. Although 20-30% of both PSP and CBD patients exhibited no parkinsonian signs at presentation, gait disturbance, falls, and slowness were common and strongly associated with PSP. Approximately half of both groups presented with cognitive-predominant onset, and nearly one-fifth were initially misdiagnosed as Alzheimer's disease.

CONCLUSIONS: A substantial proportion of PSP and CBD patients lack parkinsonian signs at first presentation, and cognitive-onset presentations are frequent, leading to early diagnostic uncertainty. Clinicians should recognize these overlapping features when evaluating early atypical parkinsonian or cognitive syndromes.},
}

Humans
*Supranuclear Palsy, Progressive/pathology/diagnosis/complications/physiopathology
Male
Female
Aged
*Corticobasal Degeneration/diagnosis/pathology/physiopathology/complications
Aged, 80 and over
Middle Aged
Depression/etiology

@article {pmid41811463,
year = {2026},
author = {Zhang, T and Nie, B and Liu, H and Mao, G and OuYang, C and Jiang, X and Shan, B},
title = {Prediction of alzheimer's disease time to dementia onset using cross-sectional data from spatiotemporal biomarker progression patterns.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {41811463},
issn = {1619-7089},
support = {12205329//National Natural Science Foundation of China/ ; 12175268//National Natural Science Foundation of China/ ; X21520603//Ye Ming Han Fund/ ; E4545AU210//the Innovation Fund of the Institute of High Energy Physics, Chinese Academy of Sciences/ ; },
}

@article {pmid41811103,
year = {2026},
author = {Chen, Y and Ji, X and Zhao, J and Bao, Z and Huang, Y},
title = {SLC38A9 Regulation Affects Hippocampal Neuronal Autophagy: A Potential Alzheimer's Therapeutic Approach by Suppressing Alzheimer's Disease-Related Protein Deposition.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {3},
pages = {e70823},
doi = {10.1002/cns.70823},
pmid = {41811103},
issn = {1755-5949},
support = {82071581//National Natural Science Foundation of China/ ; 2022002//Shanghai Leading Talent Program/ ; 2023ZDFC0402//Shanghai Municipal Health Commission Key Support Discipline Program/ ; //China Youth Medical Innovation Research Project/ ; },
abstract = {AIMS: Impaired autophagy-mediated clearance of Alzheimer's disease (AD)-related proteins is a critical event in AD pathogenesis. SLC38A9, a member of the Solute Carrier 38 family, acts as an arginine sensor and plays an important role in regulating autophagy. Although the activation of autophagy regulated by the SLC38A9 may have a mitigating effect on AD, this aspect still awaits further exploration.

METHODS: APP/PS1 mouse models and HT22 cells treated with amyloid-β 25-35 (Aβ25-35) were transduced with vectors to evaluate the effect of SLC38A9 in AD.

RESULTS: We show that decreasing SLC38A9 could promote the hippocampal neuronal autophagic clearance of AD-related proteins, reduce neuronal apoptosis, and improve cognitive function.

CONCLUSION: Our results demonstrate SLC38A9 is involved in AD-related pathology and its cognitive impairment, and may offer new therapeutic targets to AD.},
}

@article {pmid41810694,
year = {2026},
author = {Yu, L and Yokomizo, S and Doan, TH and Zhao, Q and Ganne, A and Balasubramaniam, M and Kastanenka, KV},
title = {Zolpidem restores sleep and decreases amyloid in a mouse model.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71175},
doi = {10.1002/alz.71175},
pmid = {41810694},
issn = {1552-5279},
support = {R01AG066171/NH/NIH HHS/United States ; //Cure Alzheimer's Fund/ ; //Chan Zuckerberg Initiative DAF Fund/ ; //BrightFocus Foundation/ ; 202360054//Japan Society for the Promotion of Science/ ; PYJH2024314//Affiliated Hospital of Xuzhou Medical University/ ; },
mesh = {Animals ; *Zolpidem/pharmacology ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Alzheimer Disease/drug therapy ; *Sleep/drug effects ; *Plaque, Amyloid/pathology/drug therapy ; Electroencephalography ; Amyloid beta-Protein Precursor/genetics ; Brain/drug effects/metabolism ; Presenilin-1/genetics ; Male ; },
abstract = {INTRODUCTION: Deficits in non-rapid eye movement (NREM) sleep facilitate Alzheimer's disease (AD) progression. Enhancing gamma-aminobutyric acid-ergic (GABAergic) signaling can restore sleep. Unbiased computational analysis identified zolpidem as high-affinity GABA receptor modulator facilitating chloride transport that could slow AD.

METHODS: Zolpidem's effects on sleep and Alzheimer's progression were evaluated in young APP/PS1 (amyloid precursor protein/presenilin 1) mice. Sleep was monitored with electroencephalography/electromyography (EEG/EMG) telemetry. Wide-field imaging with voltage-sensitive dyes (VSDs) was used to track sleep-dependent brain rhythms. Multiphoton microscopy allowed assessments of amyloid plaque load and basal neuronal calcium levels. Behavioral assays were used to measure memory and cognitive function.

RESULTS: Zolpidem restored NREM sleep and rescued sleep-dependent brain rhythm, slow oscillation. Zolpidem administration reduced cortical amyloid plaque burden, mitigated neuronal calcium overload, and enhanced sleep-dependent contextual recall without adverse effects on locomotion.

DISCUSSION: Zolpidem effectively decreased amyloid in young APP/PS1 mice. This supports zolpidem's therapeutic promise as an intervention strategy at early stages of AD.

HIGHLIGHTS: Zolpidem treatment improves non-rapid eye movement (NREM) sleep stability and reduces sleep fragmentation. Zolpidem restores slow oscillation in young APP/PS1 (amyloid precursor protein/presenilin 1) mice. Zolpidem treatment reduces amyloid plaque burden and calcium overload in neurons. Zolpidem-treated mice show improved sleep-dependent memory consolidation. Sleep rhythm enhancement shows promise for Alzheimer's therapy.},
}

Animals
*Zolpidem/pharmacology
Mice
Disease Models, Animal
Mice, Transgenic
*Alzheimer Disease/drug therapy
*Sleep/drug effects
*Plaque, Amyloid/pathology/drug therapy
Electroencephalography
Amyloid beta-Protein Precursor/genetics
Brain/drug effects/metabolism
Presenilin-1/genetics
Male

@article {pmid41810373,
year = {2026},
author = {Vellone, D and Guan, DX and Goodarzi, Z and Forkert, ND and Smith, EE and Ismail, Z},
title = {Apathy in Mild Behavioural Impairment: Associations with Cortical Thickness and Grey Matter Volume.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.25.26347107},
pmid = {41810373},
abstract = {Mild Behavioural Impairment (MBI) is defined by later-life onset of persistent behavioural changes and is recognized as a risk marker for cognitive decline and dementia. Apathy, a core MBI domain characterized by diminished interest, initiative, and emotional reactivity, can emerge before dementia and is hypothesized to be associated with structural brain changes. While previous studies have explored Alzheimer disease (AD)-related neuroanatomical substrates of apathy in the dementia clinical stage, few have investigated these associations in cognitively normal (CN) or mild cognitive impairment (MCI) individuals with persistent apathy consistent with MBI. Thus, this study explores structural brain differences between individuals with MBI-apathy and those without neuropsychiatric symptoms (no-NPS). Participants (n = 446; mean age = 69.6 years; 79.8% CN; 62.8% female) were drawn from the National Alzheimer's Coordinating Center and categorized into MBI-apathy (n = 59) and no-NPS (n = 387) groups. Linear regressions were used to model associations between NPS group and regional brain measures, with adjustments for age, sex, years of education, apolipoprotein E4 carrier status, intracranial volume, and Mini-Mental State Examination score, with false discovery rate (FDR) correction for multiple comparisons. Primary outcomes included two predefined AD meta-regions-of-interest (ROIs): 1) thickness: a composite measure of mean cortical thickness across the entorhinal cortex, inferior temporal gyrus, middle temporal gyrus, inferior parietal lobule, fusiform gyrus, and precuneus; and 2) volume: a composite measure of mean cortical and subcortical grey matter volume across the hippocampus, entorhinal cortex, amygdala, middle temporal gyrus, inferior parietal lobule, and precuneus. Primary outcomes also included cortical thickness and grey matter volume among individual ROIs including the ventral striatum (VS), anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), ventrolateral prefrontal cortex (vlPFC), and dorsolateral prefrontal cortex (dlPFC). MBI-apathy status was associated with significantly lower AD-meta-ROI cortical thickness (Z -score difference [95% CI]; FDR-corrected p -value, -0.43 [-0.73 - [-0.12]]; 0.025) and lower AD meta-ROI grey matter volume (-0.50 [-0.71 - [-0.30]]; <0.001). MBI-apathy was also associated with significantly lower dlPFC thickness (-0.40, [-0.70 - [-0.09]]; 0.02) and volume (-0.28 [-0.50- [-0.06]]; 0.026) and lower OFC volume (-0.32, [-0.57 - [-0.07]]; 0.026) compared to the no-NPS group. Within a non-dementia sample, MBI-apathy was more strongly associated with established AD-vulnerable regions than with regions that have been traditionally implicated in apathy in dementia. Results suggests that during CN and MCI stages, MBI-apathy may reflect early AD-related neurodegeneration, with conventional apathy-related structural changes becoming more prominent as disease progresses.},
}

@article {pmid41810132,
year = {2026},
author = {Parnetti, L and Gaetani, L},
title = {Anti-amyloid therapies as a stress test for the effectiveness and sustainability of health systems engaged against Alzheimer's disease.},
journal = {The Lancet regional health. Europe},
volume = {64},
number = {},
pages = {101631},
pmid = {41810132},
issn = {2666-7762},
}