@article {pmid42541674,
year = {2026},
author = {Kewal, A and Rajput, MS and Shah, J and Gandhi, D},
title = {Valorization of 2-aminoethoxydiphenyl borate as a neurotherapeutic agent: modulation of calcineurin, TRPC1 and MARK2/GSK-3β signaling in scopolamine-triggered tauopathy.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42541674},
issn = {1568-5608},
support = {(IP/2023-24/68)//Nirma University Funded Minor Research Project Scheme. Directorate of Research, Nirma University, Ahmedabad, India/ ; },
abstract = {In Alzheimer's disease (AD), amyloid beta (Aβ) plaques and hyperphosphorylated tau tangles drive neurodegeneration and cognitive decline. Disrupted calcium homeostasis-particularly via transient receptor potential canonical-1 (TRPC1) channels-contributes to tauopathy and disease progression. This study investigated the therapeutic potential of 2-aminoethoxydiphenyl borate (2-APB), a modulator of TRP channels, in a scopolamine-induced rat model of AD. Adult Wistar rats were assigned to six groups: normal control, disease control (scopolamine 2.5 mg/kg), three 2-APB treatment groups (2.5, 5.0 and 10.0 mg/kg) and a donepezil group (5.0 mg/kg), each with six animals. Treatments lasted three weeks. Cognitive performance was assessed using the Morris water maze, memory consolidation and open field tests. Biochemical assays measured acetylcholinesterase (AChE), calcineurin, oxidative stress markers (GSH, MDA) and inflammatory cytokines (TNF-α, IL-6, IL-1β). Protein and gene expression analyses (Western blot, qRT-PCR) evaluated tau, GSK-3β, TRPC1, MARK2, and calcineurin A/PPP3CA, alongside histopathological and immunohistochemical studies. 2-APB treatment significantly reduced pro-inflammatory cytokines, alleviated neuroinflammation, and decreased oxidative stress. Cognitive function improved, correlating with normalized AChE activity and preserved neuronal structure. At the molecular level, 2-APB reduced tau hyperphosphorylation at Ser396 and Thr231, likely through suppression of TRPC1-associated calcium entry and consequent modulation of calcium-dependent kinases (MARK2) and phosphatases (calcineurin), as well as the GSK-3β pathway. However, given that 2-APB is a broad-spectrum calcium signaling modulator - known to act on IP3 receptors, SOCE/ORAI pathways, and multiple TRPC subtypes in addition to TRPC1-the present findings provide supportive evidence linking TRPC1 modulation to the observed neuroprotective effects. Although, the involvement of additional interconnected signaling mechanisms cannot be excluded and these findings should be interpreted within the context of 2-APB's pleiotropic pharmacological profile. Downregulation of TRPC1 and calcineurin A/PPP3CA gene expression supported 2-APB's role in restoring calcium balance and mitigating tau pathology. These results highlight 2-APB's potential in addressing key AD features-tauopathy, oxidative stress, neuroinflammation and cognitive impairment-warranting further preclinical and clinical research as a potential therapeutic for AD and related tauopathies.},
}

@article {pmid42541877,
year = {2026},
author = {Salama, RS and Hulshizer, CA and Crowson, CS and Lennon, RJ and Rocca, WA and George, RJ and Frechette, N and Allen, M and Myasoedova, E},
title = {Menopause status and its role in incident Alzheimer's disease and related dementias, rheumatoid arthritis (RA) disease severity, and overall mortality in women with RA.},
journal = {Seminars in arthritis and rheumatism},
volume = {80},
number = {},
pages = {153051},
doi = {10.1016/j.semarthrit.2026.153051},
pmid = {42541877},
issn = {1532-866X},
abstract = {INTRODUCTION/OBJECTIVES: We aimed to investigate associations between menopausal characteristics, including age at menopause and cause (natural vs. artificial), with long-term outcomes in women with rheumatoid arthritis (RA), incident Alzheimer's disease and related dementias (ADRD), RA severity, and overall mortality. We hypothesized that atypical menopausal characteristics increase ADRD risk and disease severity.

METHODS: Women with incident RA in 1980-2014 who were ≥50 years of age at RA incidence were included. Menopause cause and age at menopause (categorized as <45, 45-54, ≥55 years) were abstracted from medical records. Associations between menopausal characteristics and ADRD, extra-articular manifestations (ExRA), erosions, cardiovascular events, and mortality were evaluated using Cox models. Associations with clinic visits for flares and remissions were assessed using mixed-effects models. Data were collected using the Rochester Epidemiology Project medical records-linkage system.

RESULTS: Both early/premature and late menopause were associated with nonsignificant near two-fold increases in ADRD risk. In addition, early/premature (HR 2.40; 95% CI 1.15-5.01) and late menopause (HR 2.17; 95% CI 1.01-4.66) significantly increased severe ExRA risk. Menopausal characteristics were not associated with presence of erosions or mortality. Artificial menopause was associated with fewer cardiovascular events and fewer visits for RA remission. Early/premature menopause was associated with fewer remission visits (OR 0.50; 95% CI 0.29-0.87).

CONCLUSION: Women with early/premature and late menopause had nonsignificant, increased risk of incident ADRD. Menopausal characteristics had significant associations with RA severity and cardiovascular events, and may be relevant contextual factors in long-term risk assessment for women with RA.},
}

@article {pmid42541965,
year = {2026},
author = {Vanderlip, CR and Lingad, JN and Treadwell, Z and Loritsch, JM and Illeck, CL and Ubele, MF and Boaz, K and Mefford, JL and Jones, ED and Perpich, JA and McCarty, K and Meacham, B and Bembenek Bailey, SA and Puskás, LG and Bresch, F and Powell, DK and Norris, CM and Head, E and Stark, CEL},
title = {Amyloid-associated cognitive trajectories in aging dogs mirror early changes in humans.},
journal = {Neurobiology of aging},
volume = {168},
number = {},
pages = {99-108},
doi = {10.1016/j.neurobiolaging.2026.07.009},
pmid = {42541965},
issn = {1558-1497},
abstract = {Amyloid-β (Aβ) accumulation begins many years before the onset of clinical symptoms in Alzheimer's disease (AD). Studies in humans suggest that unimpaired individuals with elevated Aβ exhibit subtle changes in cognitive trajectories over time, particularly in memory. Identifying animal models that recapitulate these early changes is critical for translational research on preclinical AD. Here, we hypothesized that aging dogs, which naturally accumulate Aβ, show similar patterns to those observed in humans. Forty-three beagles underwent longitudinal cognitive testing on tasks assessing spatial memory, landmark discrimination, and reversal learning, while Aβ burden was measured using cerebrospinal fluid Aβ42/40. Parallel analyses were conducted in cognitively unimpaired older adults from the Harvard Aging Brain Study (n = 287) using Aβ PET imaging and neuropsychological assessments. Despite no baseline differences, dogs with lower CSF Aβ42/40 showed worse longitudinal trajectories on a spatial memory task. No comparable effects were observed for landmark discrimination or reversal learning. Using a data-driven approach, Low CSF Aβ42/40 dogs were more likely to be classified in the Lower trajectory group than High CSF Aβ42/40 dogs. A similar pattern emerged in humans: Aβ+ individuals showed lower memory trajectories compared to Aβ- individuals. Across species, memory deficits were characterized by reduced benefits of practice effects rather than abrupt decline. Together, these findings suggest that aging dogs show Aβ-associated memory trajectories that parallel patterns observed in cognitively unimpaired older adults and support the canine model as a valuable translational platform for studying the earliest stages of AD.},
}

@article {pmid42542073,
year = {2026},
author = {Oriquat, G and Rizaev, J and Abdulqader, AF and Kadhim, AA and Jamuna, KV and Singhal, D and Bainsal, N and Mansurova, N},
title = {Gut microbiota and brain health: Disease-specific pathways and emerging therapeutic strategies.},
journal = {Multiple sclerosis and related disorders},
volume = {113},
number = {},
pages = {107407},
doi = {10.1016/j.msard.2026.107407},
pmid = {42542073},
issn = {2211-0356},
abstract = {The microbiota-gut-brain axis (MGBA) has emerged as a dynamic, bidirectional communication system linking the gastrointestinal tract and the central nervous system (CNS) through neural, immune, endocrine, and metabolic mechanisms. Increasing evidence indicates that alterations in gut microbial communities are associated with a wide range of neurological disorders; however, the strength of this association varies across diseases, and many mechanistic observations still rely predominantly on experimental models rather than human studies. This review provides an overview of current evidence regarding the role of the gut microbiota in maintaining CNS homeostasis, with particular emphasis on intestinal barrier function, immune modulation, vagal and enteric communication, and the generation of biologically active microbial metabolites, including short-chain fatty acids, bile acids, and neurotransmitter-related compounds. Studies in both clinical and experimental settings have reported disease-specific microbial signatures in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorders, and amyotrophic lateral sclerosis. In parallel, microbiota-directed interventions-including probiotics, prebiotics, dietary approaches, fecal microbiota transplantation, and strategies targeting microbial metabolites-have produced encouraging findings in preclinical studies and early-stage clinical investigations. Nevertheless, considerable heterogeneity in study populations, experimental methodologies, and therapeutic protocols continues to limit the translation of these findings into routine clinical practice. Collectively, current evidence supports the MGBA as a valuable framework for understanding neurological diseases while underscoring the need for rigorously designed longitudinal studies and well-controlled clinical trials to define its therapeutic relevance better.},
}

@article {pmid42542107,
year = {2026},
author = {Sui, JZ and Yin, WW and Yu, HH and Hu, H and Wei, LL and Zhang, JS and Wang, FY and Tan, L and Xue, M and Zhao, B and , },
title = {Trajectories of sleep disturbance in older adults and their associations with clinical and pathological outcomes in AD: A longitudinal study.},
journal = {Sleep medicine},
volume = {147},
number = {},
pages = {109168},
doi = {10.1016/j.sleep.2026.109168},
pmid = {42542107},
issn = {1878-5506},
abstract = {BACKGROUND: Sleep disturbance is a core feature of affective and neurodegenerative disorders. This study tracks long-term sleep disturbance trajectories and their links to incident Alzheimer's disease (AD) and longitudinal clinical and pathological changes.

METHODS: A total of 774 non-demented participants from the ADNI cohort were included. Sleep disturbance (NPI sleep item) trajectories over 8 years were identified via group-based trajectory modeling. Cox proportional hazards regression was used to estimate the risk of incident AD. Linear mixed-effects models were used to assess longitudinal changes in cognition, structural magnetic resonance imaging, amyloid-β positron emission tomography (Aβ-PET), fluorodeoxyglucose (FDG)-PET, and cerebrospinal fluid (CSF) biomarkers.

RESULTS: Three trajectories emerged: "Low-stable" (37.2%), "High-peaked" (21.0%), and "Moderate-increasing" (41.8%). Compared to those without sleep disturbance, a significantly elevated risk of incident AD was associated with "High-peaked" (hazard ratio [HR] = 3.28; 95% confidence interval [CI] = 1.89-5.70; p < 0.001) and "Moderate-increasing" trajectories (HR = 2.13; 95% CI = 1.28-3.53; p = 0.003) but not with the "Low-stable" trajectory (p = 0.888). Participants with "High-peaked" trajectory exhibited faster declines in cognition (MMSE, memory, executive function) (p < 0.050) and a steeper reduction in CSF Aβ1-42 levels (p = 0.038) than those with non-sleep disturbance. However, there were no significant differences between groups in the rates of hippocampal, entorhinal, or middle temporal atrophy, global Aβ-PET burden, or FDG-PET changes (p > 0.050).

CONCLUSIONS: "High-peaked" and "Moderate-increasing" sleep trajectories predict higher AD risk, faster cognitive decline, and faster Aβ1-42 reduction. Long-term monitoring of sleep behaviors is essential for identifying and stratifying individuals at high risk for AD.},
}

@article {pmid42542170,
year = {2026},
author = {Xu, X and Li, H and Zhu, Y and Fu, X and Hu, Q and Dong, X},
title = {The critical role of ceramide in mental health and psychiatric diseases.},
journal = {Pharmacology & therapeutics},
volume = {},
number = {},
pages = {109093},
doi = {10.1016/j.pharmthera.2026.109093},
pmid = {42542170},
issn = {1879-016X},
abstract = {Ceramides (Cer) are lipid signaling molecules regulating cell proliferation, differentiation, senescence and apoptosis, whose metabolic disturbance disrupts organismal homeostasis. Accumulating evidence links ceramide imbalance to psychiatric and neurodegenerative diseases, yet few systematic reviews summarize subtype-specific ceramide functions. This review outlines ceramide anabolic and catabolic pathways, compares functional distinctions among ceramides with distinct acyl chain lengths, describes substrate preferences of ceramide metabolic enzymes, and introduces ceramide detection techniques. On this basis, we discuss regulatory roles and underlying molecular mechanisms of ceramides in schizophrenia, Alzheimer's disease, epilepsy, depression, bipolar disorder and anxiety disorders, identify disease-specific effects of distinct ceramide subtypes, and provide theoretical evidence for lipid-targeted pharmacological research on psychiatric disorders.},
}

@article {pmid42542289,
year = {2026},
author = {Rodrigues, ES and Gomes, J and Neto, AAC and Arena, RVP and Meus, SS and Evangelista, HC and Luzardo, BFS and Ávila, DS and Rosa, SG and Pinton, S},
title = {Differential effects of Lactobacillus casei in probiotic and paraprobiotic forms on behavioral performance, oxidative stress, neuroinflammation, and cholinergic dysfunction in a streptozotocin-induced model of sporadic Alzheimer's disease.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111865},
doi = {10.1016/j.pnpbp.2026.111865},
pmid = {42542289},
issn = {1878-4216},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, neuroinflammation, and cholinergic dysfunction. Increasing evidence suggests that gut microbiota disturbances contribute to AD progression, encouraging the investigation of microbiota-modulating approaches such as probiotics and paraprobiotics. This study evaluated the effects of Lactobacillus casei probiotic and its thermally inactivated paraprobiotic on cognitive, behavioral, oxidative, cholinergic, and inflammatory alterations in a sporadic AD model induced by intracerebroventricular streptozotocin (STZ-ICV; 3 mg/3 μL/site) in female rats. From day 4, animals received daily oral treatment with probiotic L. casei (1 × 10[9] CFU), paraprobiotic (100 mg/kg), or saline for 14 days. Behavioral assessments of memory and exploratory activity were performed alongside biochemical analyses of oxidative stress markers, antioxidant defenses, acetylcholinesterase (AChE) activity, and neuroinflammatory parameters in central and peripheral tissues. STZ-ICV administration induced impairments in working and long-term memory, increased oxidative stress and neuroinflammation, elevated AChE activity, and promoted intestinal and behavioral alterations. Both probiotic and paraprobiotic treatments attenuated memory deficits, reduced lipid peroxidation, inhibited AChE activity, and decreased inflammatory markers. However, their effects differed in magnitude and tissue specificity. The probiotic mainly improved peripheral antioxidant defenses, whereas the paraprobiotic exerted broader neuroprotective effects, reducing cerebral oxidative stress, restoring non-enzymatic antioxidant levels in the hippocampus and colon, improving jejunal catalase activity, and attenuating hippocampal astrogliosis. These findings demonstrate that modulation of the gut-brain axis through L. casei-based interventions mitigates key pathological features of sporadic AD, with paraprobiotics emerging as a promising and stable alternative with enhanced neuroprotective potential independent of bacterial viability.},
}

@article {pmid42542356,
year = {2026},
author = {Suciu, S and Jolly, P and Toumert, S},
title = {[Emergency care for patients with MA: the key role of IPA].},
journal = {Soins. Gerontologie},
volume = {31},
number = {180},
pages = {23-25},
doi = {10.1016/j.sger.2026.06.006},
pmid = {42542356},
issn = {1268-6034},
mesh = {Humans ; *Alzheimer Disease/nursing ; *Advanced Practice Nursing ; Aged ; *Nurse's Role ; Nurse-Patient Relations ; },
abstract = {The importance of advanced practice nurses (APNs) in improving emergency care for patients with Alzheimer's disease is a reality. APNs play a crucial role by providing advanced clinical skills and an approach centered on Naomi Feil's Validation®, a non-pharmacological therapy. This method involves empathetic acknowledgment and affirmation of patients' emotions and experiences, which helps build a relationship of trust and address their specific needs. By collaborating with other healthcare professionals, APNs ensure high-quality care tailored to the emergency situations faced by vulnerable patients.},
}

Humans
*Alzheimer Disease/nursing
*Advanced Practice Nursing
Aged
*Nurse's Role
Nurse-Patient Relations

@article {pmid42542440,
year = {2026},
author = {Wang, J and Huang, L and Li, B and Guo, Q and Xie, F},
title = {Advancing Alzheimer's disease research in China: insights, innovations, and future directions from the chinese preclinical Alzheimer's disease study (CPAS).},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42542440},
issn = {1476-5578},
abstract = {This review delves into the advancements in Alzheimer's Disease (AD) research in China, focusing on insights, innovations, and future directions derived from the Chinese Preclinical Alzheimer's Disease Study (CPAS). With an aging population, AD prevalence has risen, increasing societal and economic burdens. CPAS, initiated in 2019, aims to identify early Alzheimer's pathology using plasma biomarkers and PET imaging. The study includes participants across the cognitive spectrum, including cognitively unimpaired individuals, patients with mild cognitive impairment (MCI), and patients with dementia, undergoing comprehensive assessments. Key findings include the impact of Aβ-PET on diagnosis and management, risk factors for amyloid pathology, and the expansion of biomarkers to include synaptic and other PET imaging markers. Future directions involve exploring disease-modifying therapies and applying multi-omics approaches to enhance the understanding and treatment of AD. These efforts are crucial for advancing personalized medicine and improving therapeutic outcomes in China and globally.},
}

@article {pmid42542447,
year = {2026},
author = {Thierry, M and Leitner, D and Balcomb, K and Kavanagh, T and Tang, L and Kanshin, E and William, C and Oakley, D and Hyman, B and Ueberheide, B and Drummond, E and Wisniewski, T},
title = {Proteomic comparison of hippocampal neurofibrillary tangles in PART, intermediate Alzheimer's disease and advanced Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {152},
number = {1},
pages = {},
pmid = {42542447},
issn = {1432-0533},
support = {P30AG062421/NH/NIH HHS/United States ; P30AG066512 and U24NS141774/NH/NIH HHS/United States ; },
mesh = {Humans ; *Neurofibrillary Tangles/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; *Hippocampus/pathology/metabolism ; Proteomics/methods ; Aged, 80 and over ; Female ; tau Proteins/metabolism ; Male ; Aged ; Amyloid beta-Peptides/metabolism ; Laser Capture Microdissection ; },
abstract = {Alzheimer's disease (AD) is characterised by the intraneuronal aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles and by the extracellular deposition of β-amyloid (Aβ). Tau pathology restricted to the hippocampal formation is frequently observed in the elderly brain in the absence of any Aβ deposition and considered as "primary age-related tauopathy" (PART). Here, we applied an unbiased proteomic approach to determine how concomitant Aβ pathology modifies the neurofibrillary tangle proteome. Neurofibrillary tangles were isolated by dissecting Tau pSer202/pThr205 "AT8" immunopositive neuronal profiles, combining chromogenic immunohistochemistry with laser capture microdissection, from hippocampal sections of 17 post-mortem brains spanning three groups: PART (n = 5; A0, B1-2, C0 scores), intermediate AD (n = 6; A1-2, B2-3, C1-2 scores) and advanced AD (n = 6; A3, B3, C3 scores). A label-free quantitative liquid chromatography-mass spectrometry based proteomic analysis, using data independent acquisition (DIA) on a Bruker timsTOF, was performed. A conserved core of 63 proteins was identified as enriched in tangles across all groups, mostly associated with "RNA binding" and "regulation of mRNA metabolic process", based on the Gene Ontology database. Group-specific signatures were also observed: 33 proteins were significantly enriched only in tangles collected from PART cases and were predominantly linked to "structural molecule activity", whereas Aβ-positive cases showed specific enrichment of "RNA binding" and "cytoplasmic translation" pathways-with intermediate AD cases displaying a transitional profile. Our findings are consistent with PART having distinct tangle proteomic features; however, the majority of its proteomic signature is in common with tangles within the AD continuum. By addressing how Aβ accumulation alters the tangle proteome, this study provides mechanistic insights into the expansion of Tau pathology, paving the way towards the identification of biomarkers and therapeutic strategies that would allow for stabilisation of Tau pathology in the elderly.},
}

Humans
*Neurofibrillary Tangles/pathology/metabolism
*Alzheimer Disease/pathology/metabolism
*Hippocampus/pathology/metabolism
Proteomics/methods
Aged, 80 and over
Female
tau Proteins/metabolism
Male
Aged
Amyloid beta-Peptides/metabolism
Laser Capture Microdissection

@article {pmid42542553,
year = {2026},
author = {Linhares, MT and de Sousa, IV and de Castro Eloy, LR and de Oliveira Neto, JM and Quillas, LJA and Ubiali, DG and Carvalho, LRRA and Lucena, RB},
title = {Hepatic encephalopathy associated with extensive hepatic diaphragmatic herniation in an adult horse.},
journal = {BMC veterinary research},
volume = {22},
number = {1},
pages = {},
pmid = {42542553},
issn = {1746-6148},
mesh = {Animals ; Horses ; *Horse Diseases/pathology/diagnosis ; Male ; *Hepatic Encephalopathy/veterinary/pathology/etiology/complications ; *Hernia, Diaphragmatic/veterinary/complications/pathology ; Fatal Outcome ; },
abstract = {BACKGROUND: Diaphragmatic hernia in horses is a rare condition, most commonly presenting with signs of colic and, less frequently, respiratory compromise. Hepatic herniation through a diaphragmatic defect with secondary hepatic failure and encephalopathy has rarely been documented in horses.

CASE PRESENTATION: A 5-year-old Mangalarga Marchador stallion was evaluated for progressive neurological deterioration, including obtundation, head pressing, ataxia, and circling. Serum biochemistry revealed severe hepatobiliary dysfunction, characterised by increased gamma-glutamyl transferase and alkaline phosphatase activities, hyperbilirubinaemia and hypertriglyceridaemia. The horse died within 12 h of admission. Post-mortem examination revealed a chronic pleuroperitoneal diaphragmatic defect with herniation of the left lateral, left medial, and quadrate hepatic lobes into the thoracic cavity. The herniated portion showed severe atrophy, haemorrhagic necrosis, cholestasis, and ductular proliferation, while the non-herniated hepatic mass exhibited bridging fibrosis and nodular regenerative remodelling. Histopathological examination of the brain confirmed the presence of Alzheimer type II astrocytes in the cerebral cortical grey matter, consistent with hepatic encephalopathy.

CONCLUSIONS: This case documents an unusual manifestation of equine diaphragmatic hernia in which extensive chronic hepatic incarceration resulted in severe hepatobiliary dysfunction and hepatic encephalopathy. The findings suggest that diaphragmatic hernia with hepatic involvement should be considered in the differential diagnosis of horses presenting with severe hepatopathy and neurological signs compatible with hepatic encephalopathy, particularly when classical signs of colic are absent.},
}

Animals
Horses
*Horse Diseases/pathology/diagnosis
Male
*Hepatic Encephalopathy/veterinary/pathology/etiology/complications
*Hernia, Diaphragmatic/veterinary/complications/pathology
Fatal Outcome

@article {pmid42542663,
year = {2026},
author = {Choudhary, G and Rajput, H and Kulkarni, R and Siddiqui, H and Prakash, A and Medhi, B},
title = {Computational drug repurposing identifies flavoxate as a novel NLRP3 inflammasome inhibitor for Alzheimer's disease therapy.},
journal = {In silico pharmacology},
volume = {14},
number = {2},
pages = {200},
pmid = {42542663},
issn = {2193-9616},
abstract = {UNLABELLED: Alzheimer's disease (AD) remains a debilitating neurodegenerative disorder with limited therapeutic options, necessitating novel approaches to target its underlying mechanisms. The NLRP3 inflammasome has emerged as a critical player in AD pathogenesis, driving neuroinflammation and amyloid-beta aggregation, yet existing inhibitors face challenges such as hepatotoxicity and poor blood-brain barrier (BBB) penetration. We conducted a computational drug repurposing study to identify FDA-approved drugs with NLRP3 inhibitory potential and favourable BBB permeability. Using molecular docking we screened a library of 2600 FDA approved compounds against the NLRP3 structure (PDB ID:8WSM), followed by molecular dynamics (MD) simulations and binding free energy calculations to validate top hits. Our results identified Flavoxates as the most promising candidate, exhibiting a high docking score (- 10.241 kcal/mol) and stable binding affinity (- 52 kcal/mol via MMPGBSA). MD simulations confirmed its robust interaction with NLRP3, demonstrating low RMSD (0.168 +/- 0.019 nm) and RMSF (0.088 +/- 0.035 nm) values over 100 ns. Moreover, Flavoxate showed optimal pharmacokinetic properties, including BBB permeability and low toxicity, as predicted by SwissADME and ProTox 3.0 The study highlights the efficacy of in silico methods in accelerating drug repurposing, bypassing the need fo de novo drug development. By repurposing Flavoxate, we propose a clinically translatable strategy to mitigate NLRP3-mediated neuroinflammation in AD, offering a potential disease modifying therapy with an established safety profile. This work underscores the significance of computational approaches in bridging the gap between preclinical discovery and therapeutic application for neurodegenerative diseases.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00696-3.},
}

@article {pmid42542938,
year = {2026},
author = {Shea, YF and Wong, YL and Wong, TK and Chan, PL and Yam, KK and Wong, FCK and Chan, KPF and Cheung, YWE and Mak, HKF and Ip, SMM and Chiu, PKC and Lam, CW},
title = {Diagnosis and analysis of plasma phosphorylated tau 217 in a memory clinic cohort: limitations of Generative Pre-trained Transformer-5.},
journal = {Singapore medical journal},
volume = {},
number = {},
pages = {},
doi = {10.4103/singaporemedj.SMJ-2025-289},
pmid = {42542938},
issn = {2737-5935},
abstract = {INTRODUCTION: No published studies have evaluated the application of Generative Pre-trained Transformer-5 (GPT-5) in the analysis of memory clinic patient clinical notes or the interpretation of plasma phosphorylated tau (P-tau) 217 values. We compared Alzheimer's disease (AD) probability estimates generated by GPT-5 before and after incorporating plasma P-tau 217 with pre- and posttest probabilities.

METHODS: This was a retrospective study comprising 74 patients from a memory clinic in Queen Mary Hospital, Hong Kong. Final diagnoses were made by physicians, supported by medical history, physical examination, neuroimaging and amyloid positron emission tomography. Extracted clinical data included cognitive, functional and neuropsychiatric assessments. Pretest AD probabilities were derived from a published meta-analysis, while posttest probabilities were calculated using a Bayesian approach. These values were compared with those estimated by GPT-5. The diagnostic performance of GPT-5 and physicians was assessed using accuracy and Kappa coefficient, with final diagnosis as reference.

RESULTS: There were 40 amyloid-positive (A+) and 34 amyloid-negative (A-) patients. In A+ patients, Bayesian posttest probabilities were higher than GPT-5 estimates (median 97.0% vs. 80.0%, P = 0.003), while those of A- patients were lower than GPT-5 estimates (median 3.0% vs. 27.5%, P < 0.001). With application of plasma P-tau 217, physicians achieved higher diagnostic accuracy than GPT-5 (81.1% vs. 45.9%, P < 0.001), while GPT-5 suggested mixed aetiologies more frequently (23.0% vs. 8.1%, P = 0.04) and inappropriate anti-amyloid therapy in 31% (11/36) of scenarios.

CONCLUSION: Our findings show that GPT-5 has limitations in analysing clinical information of real-life memory clinic patients.},
}

@article {pmid42543113,
year = {2026},
author = {Calon, F and Otaegui, L and Bouali, ML and Hébert, SS},
title = {Are mouse models of Alzheimer's disease truly flawed, or are we misusing them?.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.07.069},
pmid = {42543113},
issn = {1873-7544},
abstract = {The first transgenic mouse models of Alzheimer's disease (AD) developed in the 1990 s were hailed as a major breakthrough. As newer generations of models have emerged over the decades after, they still face growing criticism for translating poorly into clinical outcomes, even if the effects of newer therapeutic compounds, including monoclonal antibodies, align well with those seen in mice. Like any disease model, AD mice have substantial limitations. The real issue is that they are often treated as miniature humans with AD, which they are not. Overreliance on specific pathogen-free (SPF) housing may also blunt immune-related endpoints and compromise translational relevance. The impact of biological sex and ambient temperature may also differ between animal models and humans. In this review, we argue that despite these limitations, they remain highly useful for specific scientific questions and preclinical development. They are far better suited for pharmacokinetic and biodistribution studies, and for testing target engagement in vivo on well-defined neuropathological processes. Thus, while criticisms of these models are justified, researchers have often used them with misaligned objectives. As discussed herein, these models should not be discarded, but used more thoughtfully, in ways that align with their true strengths.},
}

@article {pmid42543118,
year = {2026},
author = {Du, L and Yan, J},
title = {Lineage-calibrated peripheral monocyte-derived myeloid states in neurodegenerative disease: Recruitment, lesion decoding, and state persistence.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107556},
doi = {10.1016/j.nbd.2026.107556},
pmid = {42543118},
issn = {1095-953X},
abstract = {Peripheral monocytes and monocyte-derived macrophages are increasingly implicated in neurodegenerative disease, yet interpretation remains limited by phenotypic convergence with resident microglia, inconsistent lineage attribution, and strong dependence on experimental model and disease stage. We present a structured, lineage-calibrated framework that separates three linked processes: a recruitment gate controlling access to CNS borders and lesions; a lesion-decoding hub through which aggregate, lipid, cytokine, complement, antigenic, hypoxic, and danger-associated inputs are interpreted; and a state-persistence layer in which metabolic and epigenetic reinforcement stabilizes inflammatory, repair-supportive, or hybrid repair-restrictive programs. To make the framework operational, we first provide a cross-disease synthesis and then map representative models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis to their specific recruitment routes, lesion cues, lineage confidence, and functional outcomes. We also distinguish what single-cell or spatial data can infer from what only origin-resolving approaches can establish, and propose practical terminology for studies that cannot perform fate mapping or parabiosis. A worked therapeutic example illustrates why the same recruitment pathway may be harmful during lesion expansion but useful during debris clearance and recovery. The central question is therefore not whether monocytes are present, but which model, compartment, time point, evidentiary tier, and stabilized state justify a disease-modifying claim. This framework links mechanistic evidence to biomarkers, patient stratification, and stage-aware intervention while reducing over-attribution of peripheral origin.},
}

@article {pmid42543121,
year = {2026},
author = {Shenzhi, L and Nan, Z and Rongqiang, Z},
title = {Conditional neuroprotection: Blood selenium attenuates the cognitive toxicity of DEHP metabolites in older adults.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103537},
doi = {10.1016/j.neuro.2026.103537},
pmid = {42543121},
issn = {1872-9711},
abstract = {BACKGROUND: Phthalates, particularly di(2-ethylhexyl) phthalate (DEHP), are ubiquitous environmental contaminants with well-documented neurotoxic potential. Selenium, an essential antioxidant trace element, may mitigate oxidative stress-induced neuronal damage. However, whether selenium modifies the cognitive effects of phthalate exposure remains unclear in human populations.

METHODS: We analyzed cross-sectional data from adults aged ≥60 years in the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Urinary phthalate metabolites and blood metals (lead, cadmium, mercury, manganese) were quantified. Survey-weighted linear regression with interaction terms tested whether blood selenium modified the associations between these exposures and global cognitive Z-scores. Effect modification was further evaluated using restricted cubic splines, simple slope analysis, and joint Wald tests. Oxidative stress biomarkers (alkaline phosphatase, total bilirubin, serum iron) were assessed as potential mediators. To contextualize the main NHANES findings, we performed two supplementary analyses: (i) bidirectional two-sample Mendelian randomization (MR) to test whether selenium has an independent causal effect on Alzheimer's disease (AD), and (ii) an exploratory ecological analysis using Global Burden of Disease (GBD) 2021 data to illustrate the risk of ecological fallacy when environmental co-exposures are unaccounted for. These ancillary analyses do not constitute formal triangulation, as they address selenium's main effects rather than its interaction with phthalates.

RESULTS: Among 573 participants (mean age 69.5 years, 52.2% female), blood selenium significantly modified the associations of four DEHP metabolites with cognitive function, with the strongest interaction observed for MEHP (β = 0.00103, 95% CI: 0.00081-0.00124, P < 0.001). In individuals with low selenium, higher MEHP was associated with lower cognitive scores; this association was reversed in those with high selenium. In contrast, no significant interactions were found for any heavy metal (all P > 0.05). Joint Wald tests confirmed effect modification for phthalates (F = 13.34, P = 0.003) but not for metals (F = 1.03, P = 0.43). Oxidative stress biomarkers did not mediate the observed interactions. Bidirectional MR found no causal effect of selenium on AD (IVW β = -0.008, P = 0.87), ruling out reverse causation as an explanation. An exploratory ecological analysis using GBD data found a counterintuitive inverse association between dietary selenium inadequacy and dementia burden (β = -0.325, P = 0.037). This paradoxical pattern remained consistent in sensitivity analyses and likely reflects ecological confounding. It underscores that population-level nutrient-disease links can be strongly distorted by differences in diagnostic practices and unmeasured co-exposures, such as phthalates.

CONCLUSIONS: Selenium reduces the cognitive harm of DEHP metabolites in older adults, with clearer and more consistent evidence for phthalates than for heavy metals. Null MR results rule out an independent causal effect of selenium on Alzheimer's disease, reinforcing that selenium's role is conditional rather than universal. A paradoxical ecological pattern, presented as a cautionary example, highlights the risk of ecological fallacy when co-exposures are unaccounted for. Together, these findings suggest that selenium's neuroprotection is context-dependent-it appears to act mainly under specific toxicant exposure rather than offering universal benefits. These findings caution against indiscriminate selenium supplementation and suggest that further longitudinal studies are needed before targeted interventions can be recommended.},
}

@article {pmid42543123,
year = {2026},
author = {Suk, K},
title = {Brain aging clocks: From methodological advances to cellular mechanisms.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {113260},
doi = {10.1016/j.exger.2026.113260},
pmid = {42543123},
issn = {1873-6815},
abstract = {Brain aging represents a critical risk factor for neurodegenerative diseases and cognitive decline, yet the measurement of biological brain age remains challenging. Brain aging clocks, which quantify the discrepancy between predicted brain age and chronological age, have emerged as powerful tools for assessing brain health and predicting disease outcomes. Recent advances have transformed these clocks from simple global metrics to sophisticated, multi-modal approaches that capture regional heterogeneity, measure the pace of aging, and achieve cellular resolution. This review examines the methodological evolution of brain aging clocks, including the development of regional brain age gradients, pace-of-aging measurements, and multi-modal integration strategies. We then explore the cellular and molecular mechanisms underlying accelerated brain aging, with particular emphasis on cellular senescence, cell-type-specific aging patterns, vascular dysfunction and blood-brain barrier breakdown, mitochondrial decline, proteostasis failure, synaptic loss, and the accumulation of senescent cells in neurodegenerative conditions. Epigenetic clocks and emerging plasma biomarkers (neurofilament light, GFAP, phosphorylated tau), particularly DNA methylation-based approaches, are discussed in the context of their relationship with neuroimaging markers and cognitive outcomes. Clinical applications are reviewed, including the prediction of neurodegenerative disease, the impact of socioeconomic and geographic disparities on brain aging, and emerging senotherapeutic interventions. Finally, we address current challenges in biomarker standardization, the need for longitudinal validation, and future directions toward precision aging medicine. Together, these advances position brain aging clocks as essential tools for understanding neural aging mechanisms and developing targeted interventions to promote healthy brain aging. SIGNIFICANCE STATEMENT: As populations age globally, predicting who will develop dementia or cognitive decline before symptoms appear has become a critical medical challenge. Brain aging clocks - tools that measure whether a person's brain appears biologically older or younger than their chronological age - offer a promising solution. This review explains how these tools have advanced from simple brain scans to sophisticated methods that detect aging at the level of individual cell types, and how "zombie cells" called senescent cells drive accelerated brain aging. We also show that brain aging may be slowed through lifestyle changes and emerging drugs, though robust human efficacy trials are ongoing. These insights open new paths toward earlier diagnosis and personalized treatments for Alzheimer's disease and other brain disorders.},
}

@article {pmid42543199,
year = {2026},
author = {Sakurai, R and Montero-Odasso, M},
title = {Gait Impairment and Alzheimer's Disease Pathology: A Narrative Review on Mechanistic Links.},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {8},
pages = {e70675},
doi = {10.1111/ggi.70675},
pmid = {42543199},
issn = {1447-0594},
support = {MOP 211220//Canadian Institute of Health Research/ ; PJT 153100//Canadian Institute of Health Research/ ; BH210118//Weston Family Foundation/ ; FRN CNA 137794//Canadian Consortium on Neurodegeneration in Aging/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/physiopathology/complications ; *Gait Disorders, Neurologic/etiology/physiopathology ; Amyloid beta-Peptides/metabolism ; Aged ; Aging/physiology ; *Gait/physiology ; Brain/pathology ; },
abstract = {In older adults, gait has emerged as an important indicator of overall health and a strong predictor of adverse outcomes, including dementia. This association has been corroborated by findings from Alzheimer's disease (AD) research. In AD, amyloid-β brain accumulation is succeeded by tau pathology and neurodegeneration, commencing within the medial temporal lobe. Older adults exhibiting slower gait speed or reduced gait adaptability display greater amyloid and tau brain deposition, as well as more pronounced hippocampal atrophy, suggesting that gait impairment may serve as an early clinical marker of AD-related neurodegeneration. Despite accumulating evidence linking gait impairment to AD-related pathology, the underlying mechanisms remain inadequately understood. Traditional explanations have focused on shared neural substrates, including frontal-subcortical and motor control networks, which decline with aging and result in parallel deterioration of gait and executive function. Although this framework aligns with cognitive reserve theory, it fails to fully explain the potential pathways linking gait disturbances to AD-related and mixed brain pathology. In this review, we explore interacting mechanisms suggesting that gait impairment and AD-related changes may arise from common vulnerabilities and mutually reinforcing processes. By synthesizing the current evidence, we aim to advance the understanding of gait decline as a prodromal symptom of dementia, advocate for early screening of gait performance, and highlight the importance of maintaining gait function across the lifespan as part of healthy aging strategies that may help delay the onset of dementia. The conclusion underscores a life-course perspective on health, rather than one that focuses solely on functional decline in old age.},
}

Humans
*Alzheimer Disease/pathology/physiopathology/complications
*Gait Disorders, Neurologic/etiology/physiopathology
Amyloid beta-Peptides/metabolism
Aged
Aging/physiology
*Gait/physiology
Brain/pathology

@article {pmid42543274,
year = {2026},
author = {DU, YZ and Wang, Z and Ma, DC and Liu, T and Ma, LL and Zhou, YM and Li, XL and Dou, FY and Lyu, RL and Chai, MN and Zhang, YG and Li, YF},
title = {[Research progress on active ingredients of Astragali Radix and Acori Tatarinowii Rhizoma and mechanism of their herb pair against Alzheimer's disease].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {11},
pages = {3152-3159},
doi = {10.19540/j.cnki.cjcmm.20260209.501},
pmid = {42543274},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy/metabolism/genetics ; *Drugs, Chinese Herbal/chemistry/administration & dosage ; Humans ; Animals ; *Acorus/chemistry ; *Astragalus Plant/chemistry ; Rhizome/chemistry ; },
abstract = {Alzheimer's disease(AD) is a highly prevalent neurodegenerative disorder with complex pathogenesis. Currently available mainstream drugs offer limited efficacy and often cause significant side effects. The herb pair of Astragali Radix and Acori Tatarinowii Rhizoma, known for its Qi-tonifying and orifice-opening properties in TCM, has demonstrated advantages in multi-target and holistic regulation in anti-AD research. This review systematically summarizes the synergistic mechanisms of active ingredients such as astragaloside Ⅳ, calycosin, and β-asarone against AD through multiple pathways, including peroxisome proliferator-activated receptor γ(PPARγ)/brain-derived neurotrophic factor(BDNF) pathway, phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) pathway, and gut-brain axis. It also points out that current studies remain largely confined to in vitro and animal experiments, with insufficient evidence for clinical translation. Building on this, the review further proposes innovative research directions, such as constructing astragaloside Ⅳ-β-asarone co-delivery nanosystems, optimizing the compatibility ratio of the herb pair, and combining with fecal microbiota transplantation to validate causal mechanisms via microbiota-gut-brain axis. These proposals aim to provide a systematic theoretical framework and experimental pathway for the in-depth development and clinical translation of the herb pair of Astragali Radix and Acori Tatarinowii Rhizoma.},
}

*Alzheimer Disease/drug therapy/metabolism/genetics
*Drugs, Chinese Herbal/chemistry/administration & dosage
Humans
Animals
*Acorus/chemistry
*Astragalus Plant/chemistry
Rhizome/chemistry

@article {pmid42543712,
year = {2026},
author = {Karan, KR and Hackett, NR and Crystal, RG},
title = {Adeno-Associated Virus-Mediated Central Nervous System Gene Transfer to Suppress Alzheimer's Disease High-Risk APOE4 Variant and Replace with Protective APOE2.},
journal = {Human gene therapy},
volume = {},
number = {},
pages = {10430342261473427},
doi = {10.1177/10430342261473427},
pmid = {42543712},
issn = {1557-7422},
abstract = {Common genetic variants of APOE are major risk factors for sporadic late-onset Alzheimer's disease (AD). APOE has three common variants: APOE3, APOE4, and APOE2. Epidemiological, clinical, and experimental evidence demonstrate that APOE3 is associated with an average risk for AD, APOE4 is pathogenic and conveys a high risk, and APOE2 is protective and reduces risk. In prior mouse studies, we have demonstrated that (1) adeno-associated virus (AAV)-mediated central nervous system (CNS) gene transfer of APOE2 is highly protective against the toxic effects of APOE4 and (2) AAV-mediated CNS transfer of anti-APOE4 microRNA (miRNA) significantly suppresses the expression of APOE4. The ideal therapy for APOE4 homozygotes would both reduce CNS levels of APOE4 and substitute APOE4 with the addition of APOE2. We have developed a "silence-and-replace" therapy, where suppression of CNS APOE4 is achieved through AAV-mediated expression of miRNAs designed to silence the endogenous human APOE4 messenger RNA (mRNA), together with simultaneous replacement by an APOE2 coding sequence [APOE2(R)] resistant to those miRNAs. AAV vectors expressing APOE2(R) with and without the miRNAs were administered to the hippocampus of human APOE4 mice, and APOE levels at the mRNA and protein levels were the same for both vectors. Dideoxy Sanger sequencing and allele-specific real-time quantitative PCR were used to assess the CNS APOE2 to APOE4 ratio. As expected, both vectors with APOE2(R) increased the E2/E4 ratio relative to controls by 3.5 ± 0.6-fold for APOE2(R) and 6.3 ± 0.4-fold for APOE2(R) + miRNAs. We conclude that a single AAV vector can deliver a cassette with dual functionality: suppression of the toxic APOE4 variant and simultaneous delivery of the protective APOE2. This dual approach may provide a more potent gene therapy for APOE4-dependent AD than either strategy.},
}

@article {pmid42543724,
year = {2026},
author = {Rouanet, A and Philipps, V and Taddé, BO and Pérès, K and Proust-Lima, C},
title = {Modeling Temporal Relationships Between Multivariate Repeated Markers Along With Clinical Endpoints: Application to Alzheimer's Disease and Related Dementias.},
journal = {Biometrical journal. Biometrische Zeitschrift},
volume = {68},
number = {4},
pages = {e70157},
doi = {10.1002/bimj.70157},
pmid = {42543724},
issn = {1521-4036},
support = {ANR-18-CE36-0004-01//French National Research Agency/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/diagnosis ; Biomarkers/metabolism ; *Models, Statistical ; Multivariate Analysis ; *Biometry/methods ; *Dementia/metabolism/diagnosis ; Disease Progression ; Time Factors ; *Endpoint Determination ; },
abstract = {Diseases often involve multiple dimensions of interrelated impairments. Although significant advances have been made in joint models to simultaneously assess these processes in relation to clinical endpoints, they often fail to evaluate how these dimensions influence each other. We propose an original joint modeling framework to describe the temporal relationships between the processes involved in Alzheimer's disease and related dementias (ADRD) progression, and assess their association with ADRD diagnosis and death. The longitudinal submodel is a dynamic model that combines a structural multivariate mixed model based on differential equations to explain the instantaneous change over time of each latent dimension according to the others, and observation models that can accommodate ordinal, binary, and continuous (whether Gaussian or non-Gaussian) biomarkers. The association of the biomarkers with ADRD diagnosis and death are described via a shared random-effect joint modeling approach. The estimation procedure, carried out within the maximum likelihood framework is made available in the DynNet R package. The methodology is validated in a simulation study and is applied in a population-based French cohort study to disentangle the temporal relationships between three major drivers of ADRD natural history, depression, cognition, and functional dependency in link with the two major clinical events in ADRD progression: ADRD diagnosis and death. The methodology and application are designed to help understand the complex interplay between biomarkers over time.},
}

Humans
*Alzheimer Disease/metabolism/diagnosis
Biomarkers/metabolism
*Models, Statistical
Multivariate Analysis
*Biometry/methods
*Dementia/metabolism/diagnosis
Disease Progression
Time Factors
*Endpoint Determination

@article {pmid42544033,
year = {2026},
author = {Lou, Y and Monin, JK and Fowler, NR},
title = {How Does Receipt of Dementia Screening Impact Depressive Symptoms Among Patients and Their Family Members?.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70603},
pmid = {42544033},
issn = {1532-5415},
support = {1R24AG089064-01/AG/NIA NIH HHS/United States ; R01AG056325/AG/NIA NIH HHS/United States ; U54AG063546/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: The impact of dementia screening on the mental health of older adults and their family members remains insufficiently understood, particularly in light of the bidirectional dynamics within the older adult-family dyad. This study aims to examine how dementia screening affects older adults and their family members over time, and whether these effects occur independently or simultaneously within the dyad.

PARTICIPANTS AND SETTING: One thousand eight hundred five older adults (≥ 65 years old) and their family member dyads participated in the multi-site Caregiver Outcomes of Alzheimer's Disease Screening (COADS) trial were randomized into three study arms: screening only, screening plus referral for diagnostic assessment, and no-screening control.

METHODS: Depressive symptoms measured by Patient Health Questionnaire-9 (PHQ-9) were collected in both older adults and their family members at baseline, 6 months, and 12 months post-intervention. A cross-lagged panel model was used to examine longitudinal and dyadic associations in depressive symptoms between members of the dyad. Intervention status (0 = no-screening control, 1 = combined screening group who received negative results, 2 = combined screening group who received positive results) was included as a predictor of depressive symptoms at 6 months.

RESULTS: Compared with controls, dyads in the combined screening groups who received negative (β = -0.53, p = 0) and positive (β = -0.84, p = 0.058) results showed lower depressive symptoms among older adults at 6 months. Improvements in older adults' depressive symptoms subsequently influenced family members' mental health through a dyadic pathway, resulting in reduced depressive symptoms among family members at 12 months (β = 0.05, p = 0.016).

CONCLUSIONS: The findings suggest that screening for dementia in older adults has a spillover effect to family members. Dementia screening may have a double benefit in families. Further clinical trials should include measures of both dyad members to understand how to best target the mental health of families more efficiently.},
}

@article {pmid42544645,
year = {2026},
author = {Luth, EA and Brennan, C and Hurley, S and Sheldon, KG and Zhang, Y},
title = {Hospice Care in the Era of AI: Hospices' Views on Data-Driven Tools to Support Live Discharge Decisions.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70621},
pmid = {42544645},
issn = {1532-5415},
support = {R56 AG085541/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Live discharge occurs for 20% of hospice enrollees, resulting in loss of support and disruptive care transitions, with higher risk for patients with Alzheimer's disease and related dementias (ADRD). Little is understood about how data-driven clinical decision support tools (e.g., predictive algorithms) might support decision making regarding live discharge. As hospices adopt value-based care, identifying opportunities and challenges for data-driven tools to predict and support live discharge holds great potential to support hospice patients and their caregivers.

METHODS: Semi-structured interviews were conducted with 20 hospice leaders in clinical care, quality, and data science at seven non-profit United States hospices. Four-step rapid analysis and deductive approaches were used to summarize interview content in response to research questions and identify cross-organizational themes.

RESULTS: Participants identified multilevel-individual and family, organizational, community, and system-challenges and facilitators to support patients following live discharge. Families dealing with ADRD face a heavier care burden but also access ADRD-specific programs. Participants expressed strong interest in using predictive tools to identify patients at increased risk for live discharge and either support them to remain in hospice or facilitate robust discharge planning. Participants emphasized the importance of tool specification and clinical workflow integration to make predictive tools useful and impactful.

CONCLUSIONS: Hospices face barriers to support hospice patients and caregivers experiencing burden and suboptimal outcomes following live discharge. Predictive modeling could be a potentially powerful tool to facilitate support for patients discharged alive, provided they are accurately specified and thoughtfully integrated into clinical workflows.},
}

@article {pmid42544873,
year = {2026},
author = {Wang, DW and Liu, MM and Zhao, YC and Li, JY and Li, W and Yu, X},
title = {Targeting Hippocampal PTEN Suppresses Ferroptosis and Rescues Cognitive Decline in Alzheimer's Disease via Dual AKT/GSK3β/Nrf2 and AKT/STAT3 Axes.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76989},
doi = {10.1002/advs.76989},
pmid = {42544873},
issn = {2198-3844},
support = {81901116//National Natural Sciences Foundation of China/ ; 2024JH6/100800008//Department of Science and Technology of Liaoning Province/ ; LJKMZ20221207//Department of Education of Liaoning Province/ ; },
abstract = {Elevated phosphatase and tensin homolog (PTEN) expression is observed in Alzheimer's disease (AD) brain, yet the precise mechanism through which PTEN contributes to AD progression remains undefined. This study provides the direct evidence that PTEN promotes neurodegeneration by driving neuronal ferroptosis. Using APP/PS1 transgenic mice with hippocampal-specific PTEN knockdown mediated by adeno-associated virus (AAV), we demonstrated that downregulation of PTEN substantially ameliorates cognitive dysfunction and neuronal loss. Mechanistically, PTEN silencing upregulated glutathione peroxidase 4 (GPX4), inhibiting lipid peroxidation and ferroptosis. We identified a dual-signaling framework through which PTEN regulates GPX4 expression. PTEN reduction activates the PI3K/AKT axis, which drives GSK3β phosphorylation and facilitates nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Concurrently, PTEN knockdown induces phosphorylation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3). Both Nrf2 and STAT3 act as transcriptional activators of GPX4, establishing two convergent axes: PTEN/AKT/GSK3β/Nrf2/GPX4 and PTEN/AKT/STAT3/GPX4. These pathways cooperatively upregulate GPX4 expression, thereby attenuating lipid peroxidation and inhibiting ferroptosis. Importantly, PTEN knockdown restored redox homeostasis by bolstering cellular antioxidant defenses. Our findings reveal a novel PTEN-regulated ferroptotic pathway in AD pathogenesis and highlight PTEN as a promising therapeutic target for AD.},
}

@article {pmid42544975,
year = {2026},
author = {Branson, CO},
title = {Sleep and Neurodegeneration.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {32},
number = {4},
pages = {1142-1160},
doi = {10.1212/cont.0000000000001734},
pmid = {42544975},
issn = {1538-6899},
mesh = {Humans ; *Neurodegenerative Diseases/complications/diagnosis ; *Sleep Wake Disorders/complications ; *Sleep/physiology ; Female ; Male ; },
abstract = {OBJECTIVE: This article discusses the relationship between sleep and neurodegenerative disorders.

LATEST DEVELOPMENTS: Sleep disorders disrupt neurotransmitters, facilitating the progression of neurodegenerative changes. Sleep impairment promotes amyloid-β aggregation, propagating memory impairment in neurodegenerative disorders. The use of biomarkers for early diagnosis of neurodegenerative disorders may include sleep features. Sleep apnea is associated with an increased risk of Parkinson disease.

ESSENTIAL POINTS: Sleep disorders, such as obstructive sleep apnea, are five times more likely in people with Alzheimer disease. Notably, individuals with genetic factors, including carriers of APOE4, are found to have decreased overall regulation of regions within the brain that control sleep. External factors that increase the risk of dementia include long-term use of antihistamines. The risk of mild cognitive impairment is reduced with the intake of 200 mg/d of caffeine, which aligns the circadian activity of suprachiasmatic nucleus cells. People diagnosed with idiopathic rapid eye movement (REM) sleep behavior disorders have more than a 90% risk of developing an α-synucleinopathy at 14 years follow-up.},
}

Humans
*Neurodegenerative Diseases/complications/diagnosis
*Sleep Wake Disorders/complications
*Sleep/physiology
Female
Male

@article {pmid42545032,
year = {2026},
author = {Brik, SB},
title = {The systemic Ben Brik score, MAROC 22: A mechanism-anchored bedside instrument for the surveillance of reversible cognitive burden in octogenarians-A single-center pilot.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474889},
doi = {10.1177/13872877261474889},
pmid = {42545032},
issn = {1875-8908},
abstract = {BackgroundCognitive decline in octogenarians is routinely attributed to irreversible neurodegeneration, yet a substantial fraction is driven by partly reversible physiological mechanisms. Oxidative and mitochondrial damage are among the earliest events in Alzheimer's disease pathology, upstream of amyloid deposition, and this framework has not been operationalized into a bedside instrument for the oldest-old.ObjectiveTo present the SBG-MAROC 22-a 310-point, 22-parameter, seven-pillar bedside matrix whose item weights are anchored to published hazard ratios for incident dementia-and to report preliminary single-center data on its feasibility and capacity to flag reversible contributors and acute decompensation.MethodsSingle-center, single-author, retrospective pilot. Forty-seven consecutive patients aged ≥ 80 years [mean age 83.7 ± 2.9 years; 55.3% female; baseline Montreal Cognitive Assessment (MoCA) 16.2 ± 4.1] were assessed with the SBG-MAROC 22 alongside the MoCA. A subgroup (n = 11) received the PD-GOLD protocol with MoCA reassessment at ∼45 days. No power calculation or concurrent control group; reporting followed STROBE.ResultsThe score showed a preliminary association with concurrent MoCA (r≈0.78), within-pilot inter-rater agreement (κ≈0.85), and at least one reversible contributor in 89.4% of patients. The treated subgroup gained a mean +6.0 MoCA points at 45 days (95% CI +3.0 to +9.0; prediction interval -3.1 to +15.1, crossing zero). An exploratory FXTAS-versus-Alzheimer's area under the curve was 0.92. All values are internal, uncontrolled pilot estimates, not validation.ConclusionsThe SBG-MAROC 22 is a clinically feasible, MRI-independent bedside instrument whose hypothesis-generating profile warrants independent, blinded, prospective multicenter validation before any clinical use. Claims of validated discrimination or therapeutic efficacy are not made.},
}

@article {pmid42545253,
year = {2026},
author = {Li, L and Kenner, E and Wan, L and Yan, Z and Feng, J},
title = {Reduced expression of Brain Expressed X-linked genes in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471446},
doi = {10.1177/13872877261471446},
pmid = {42545253},
issn = {1875-8908},
abstract = {BackgroundAltered expression of Brain Expressed X-linked (BEX) genes has been implicated in Alzheimer's disease (AD) with inconsistencies and a lack of experimental confirmation.ObjectiveThis study aims to characterize BEX expression patterns, examine the association of their expression with AD pathology, and investigate cellular changes induced by altered BEX expression.MethodsWe integrated bulk and single-cell transcriptomics datasets to characterize cortical BEX expression changes in 5xFAD mice and AD patients, which were validated by RT-qPCR in postmortem AD cortical tissue. We manipulated the expression of BEX genes in SH-SY5Y cells and examined changes in oxidative stress.ResultsCortical expression of BEX genes was reduced in AD. With the dysregulation being more pronounced at a later stage of the disease, the reduction was closely related to the impairment of synaptic transmission and oxidative phosphorylation in excitatory neurons. Consistent with these, BEX3 knockdown increased oxidative stress.ConclusionsOur findings suggest that reduced BEX expression in neurons appears to be a contributing factor to AD pathogenesis and BEX depletion may increase oxidative stress.},
}

@article {pmid42545429,
year = {2026},
author = {Bjørklund, G and Gurgas, L and Hangan, T},
title = {Nicotine in Neurodegenerative and Neuropsychiatric Disorders: Mechanisms and Clinical Evidence.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42545429},
issn = {1573-6903},
mesh = {Humans ; *Nicotine/therapeutic use/pharmacology ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Mental Disorders/drug therapy/metabolism ; Receptors, Nicotinic/metabolism ; *Nicotinic Agonists/therapeutic use/pharmacology ; },
abstract = {Nicotine, a psychoactive compound primarily known for its role in tobacco addiction, has attracted increasing interest for its neuromodulatory and neuroprotective properties. Acting predominantly through nicotinic acetylcholine receptors, nicotine influences multiple neurotransmitter systems, modulates neuroinflammation, and supports synaptic plasticity. These mechanisms may be therapeutically relevant in disorders characterized by neurodegeneration or disrupted neurocircuitry, including Parkinson's disease, Alzheimer's disease, schizophrenia, attention-deficit/hyperactivity disorder, depression, and post-traumatic stress disorder. This review critically examines the current state of preclinical and clinical evidence, with particular attention to receptor subtype activity, cognitive and emotional modulation, and human trial data. Although nicotine's addictive potential and receptor desensitization remain concerns, advances in selective ligands offer new therapeutic avenues. By consolidating mechanistic insights and disease-specific data, this review highlights both the promise and challenges of developing nicotinic-based therapeutics for brain disorders.},
}

Humans
*Nicotine/therapeutic use/pharmacology
Animals
*Neurodegenerative Diseases/drug therapy/metabolism
*Mental Disorders/drug therapy/metabolism
Receptors, Nicotinic/metabolism
*Nicotinic Agonists/therapeutic use/pharmacology

@article {pmid42545504,
year = {2026},
author = {Hooshmandi, S and Rahimi Jaberi, K and Kamalov, F and Nami, M},
title = {Adaptive cascading artificial intelligence for Alzheimer's disease assessment: a clinically oriented narrative review and implementation framework.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42545504},
issn = {1590-3478},
support = {2024CANAD-KAM-060//Dubai Future Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Artificial Intelligence ; Biomarkers/blood ; },
abstract = {Artificial intelligence (AI) has achieved remarkable success in the diagnosis of Alzheimer's disease (AD) in the literature, where many of the models use multi-modal methods including neuroimaging, cerebrospinal fluid, genetics, and cognitive assessment. But clinical adoption of these systems is still limited since most systems are developed in an idealized setting, as cost-effective and specialized diagnostic studies are not universally accessible. We discuss the translation of benchmark performance of AI to real-world dementia care pathways. A practical framework that would be useful for scalable, equitable, and clinically deployable AI-assisted dementia care. In fact, recent advancements in blood-based biomarkers such as plasma phosphorylated tau, glial fibrillary acidic protein, and neurofilament light chain are providing new opportunities for a flexible and minimally invasive diagnosis method. Based on these advances, we propose a clinically grounded AI-assisted cascading model which mirrors real-world workflows via progressive screening, biomarker-guided assessment, selective imaging escalation, and longitudinal prognostic monitoring. We further discuss enabling methods such as sequential decision-making, reinforcement learning, cost-sensitive learning, missing-modality robustness, and explainable AI. Finally, we outline the challenges for data design, for future validation and integration into healthcare systems, and ethical use.},
}

Humans
*Alzheimer Disease/diagnosis
*Artificial Intelligence
Biomarkers/blood

@article {pmid42545654,
year = {2026},
author = {Wu, J and Wang, P and Wang, D and Yao, H and Zhou, B and Lu, J and Zhang, X and Han, Y and Zhao, Y and Zhang, Y and Zhao, K and Liu, Y},
title = {A Neuroimaging Biomarker for Hippocampal Network Dysfunction in Alzheimer's Disease.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42545654},
issn = {1995-8218},
}

@article {pmid42545731,
year = {2026},
author = {Maiese, K},
title = {Oxidative stress, aging, metabolism, SIRT1, and the gut microbiota: the neurocardiac basis of cognitive loss.},
journal = {Medical gas research},
volume = {},
number = {},
pages = {},
pmid = {42545731},
issn = {2045-9912},
abstract = {FactsCardiovascular disease, Alzheimer's disease, and multiple sclerosis share a neurocardiac basis linked by cellular metabolism and diabetes, indicating the presence of common pathological pathways.Current care remains symptomatic and prevention focused, and interventions targeting shared pathways such as oxidative stress, senescence, and autophagy are lacking.Apolipoprotein E (APOE), glucagon-like peptide-1 (GLP-1) agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mitochondrial dynamics, and the gut microbiome are key modulators of the neurocardiac axis and are highly interdependent.Understanding the interactions among ferroptosis, pyroptosis, and apoptosis under comorbid conditions is essential for clinical translation.Open questionsIs oxidative stress a primary driver or a consequence of autophagy dysregulation that links cardiac dysfunction to cognitive decline?Are GLP-1 receptor agonists neuroprotective independent of glycemic control, and what is the optimal timing and disease stage?Which microbial metabolites influence mitochondrial dynamics and senescence, and can microbiome targeting improve both cardiac and cognitive outcomes?Is combined inhibition of ferroptosis and pyroptosis superior to single-pathway blockade, and how can strategies for different comorbidity profiles be chosen?How can APOE genotypes and individual metabolic states guide personalized therapies that simultaneously reduce cardiovascular risk and neurodegeneration? Cardiovascular disease and cognitive loss have a neurocardiac basis. Poor vascular perfusion can impair cognitive function in both Alzheimer's disease and multiple sclerosis. However, a treatment gap exists because current approaches do not adequately address the shared underlying cellular mechanisms responsible for cognitive dysfunction in these conditions. Current treatments for cognitive impairment in diseases such as cardiovascular disease, Alzheimer's disease, multiple sclerosis, and diabetes often fail to fully address the shared underlying cellular mechanisms. Consequently, the prevailing precision treatment strategy, which focuses on managing symptoms and preventing disease progression, is insufficient. This highlights the urgent need for innovative approaches capable of targeting these common cellular pathways across these diverse conditions. Novel investigations into oxidative stress, cellular senescence, programmed cell death with apoptosis, ferroptosis, pyroptosis, and autophagy, cellular metabolism with apolipoprotein E and glucagon-like peptide-1 receptor agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), mitochondrial dynamics, and the gut microbiome offer the potential to address the risk factors and clinical treatments for cardiovascular disease and cognitive loss. These pathways are exquisitely dependent upon one another and require in-depth knowledge of the modulatory cellular mechanisms for effective translation to clinical care.},
}

@article {pmid42545796,
year = {2026},
author = {St-Amant, A and St-Georges, MA and Marier, A and Montembeault, M},
title = {Associations between clinician-observed test anxiety and neuropsychological performance in older adults.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/23279095.2026.2704635},
pmid = {42545796},
issn = {2327-9109},
abstract = {OBJECTIVE: As dementia diagnoses rise with population aging, understanding factors that influence neuropsychological performance become increasingly important. While research has established links between test anxiety and poorer test results in younger populations, its effects in older adults remain unclear.

METHOD: A total of 342 cognitively unimpaired older adults from the National Alzheimer's Coordinating Center were included. Participants were categorized according to clinician-observed test anxiety using the Social Behavioral Observer Checklist into Anxious versus Non-anxious groups and Self-conscious versus Non-self-conscious groups. Measures of episodic memory, executive functions, language, and visuospatial abilities were administered. Analyses of covariance tested performance differences, adjusting for sex, education, and age.

RESULTS: Anxious and self-conscious participants performed significantly worse than their counterparts on episodic memory (delayed recall), although effect sizes were small (η[2] ≈ .02-.04). No significant group differences were observed on other cognitive measures. The association between being Self-conscious during testing and lower episodic memory remained significant when controlled for everyday anxiety and depression symptoms, whereas the association for being Anxious did not.

CONCLUSIONS: Findings suggest that clinician-observed test anxiety may have minimal impact on cognitive results in aging. Nonetheless, the specific association between test anxiety and episodic memory performance underscores the need to minimize anxiety during assessments to support accurate diagnosis.},
}

@article {pmid42545807,
year = {2026},
author = {Ghahremani, M and Smith, EE and Ismail, Z},
title = {Reply to Comments on "Persistent Functional Impairment as an Early Indicator of Alzheimer's Disease Pathology and Progression".},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70615},
pmid = {42545807},
issn = {1532-5415},
support = {//NIHR Exeter Biomedical Research Centre/ ; //Gordie Howe CARES/ ; BCA527734/CAPMC/CIHR/Canada ; },
}

@article {pmid42541419,
year = {2026},
author = {Clément, G and Hansmannel, F and Hopes, L and Bossenmeyer-Pourié, C and Renaud, M},
title = {Alzheimer's disease and nutrition: Focus on the impact of hyperhomocysteinemia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471813},
doi = {10.1177/13872877261471813},
pmid = {42541419},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease. Despite advances in the understanding of the genetics of AD, environmental risk factors are still under investigation, and the etiology is still not completely understood. The environmental component of AD, which we explore in the first part of this review, takes on greater importance with more advanced disease onset. Moreover, genetics does not explain all of AD. Environmental risk factors are divided into modifiable and nonmodifiable risk factors. Among the modifiable risk factors, nutrition seems to play a predominant role. One-carbon metabolism (OCM) is involved in this food-related component, notably through B vitamins. Homocysteine, a sulfur-containing amino acid, is at the crossroads of OCM. Abnormal increases in homocysteine levels (hyperhomocysteinemia) are associated with deleterious effects on cognition. Various mechanisms can lead to hyperhomocysteinemia, including genetic factors associated with different polymorphisms, dietary deficiencies targeting vitamins B9 and B12, and renal insufficiency. The second part of the review details OCM and the role of homocysteine. Finally, part 3 highlights the numerous studies in the literature describing the association between hyperhomocysteinemia and cognitive decline. However, the mechanistic links between hyperhomocysteinemia and cognitive decline in AD are poorly understood. Several hypotheses have been proposed in the literature. The toxic effects of homocysteine could be mediated by N-homocysteinylation, a nonenzymatic reaction leading to the irreversible accumulation of N-homocysteinylated proteins. Finally, we detail some therapeutic trials targeting one-carbon metabolism in AD, notably vitamin B9 and B12 supplementation.},
}

@article {pmid42541423,
year = {2026},
author = {Sanz Simon, S and Gal, M and Lee, S and Walker, MD and Schnaider Beeri, M and Bachmann, G and Lauriola, V and Sloan, R and Stern, Y and Gazes, Y},
title = {Can menopausal status moderate the effects of aerobic exercise on executive functions? evidence from a randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261471900},
doi = {10.1177/13872877261471900},
pmid = {42541423},
issn = {1875-8908},
abstract = {BackgroundPhysical exercise is widely recognized for its cognitive benefits; however, the effect of menopausal status in modulating the cognitive effects of exercise is not definitively established.ObjectiveTo examine the cognitive benefits of two 6-month physical exercise programs in cognitively healthy older women across adulthood, and whether menopause status moderates these benefits.MethodsIn a post hoc analysis of a randomized controlled trial, 93 cognitively healthy women (aged 20-67; 43% at post-menopause) were assigned to either aerobic exercise (AE) or stretching/toning (ST) 4 days a week for six months. Neuropsychological assessment, cardiorespiratory exercise test, and blood draw were performed at baseline, 3-months, and 6-months. Linear mixed-effects regression models assessed whether menopausal status moderated the impact of exercise on executive functions and processing speed.ResultsSeventy-six participants (81.7%) completed the intervention. A time-by-group-by-menopause interaction emerged after 3 months (β = -0.89; p = 0.001) and 6 months (β = -0.67, p = 0.016). Post-menopausal women in the AE group showed greater improvement in executive functions compared to the ST group and pre-menopausal women. Models controlled for age, education, and baseline cognitive performance.ConclusionsOur results provide novel evidence that AE improves cognition with pronounced executive functions benefits in post-menopausal women, a population at higher risk for dementia. Since women are at a higher risk of developing Alzheimer's disease compared to men, these findings support AE as a relevant strategy to promote women's brain health. Although this is a secondary analysis, it may inform future exercise trials targeting women.},
}

@article {pmid42541425,
year = {2026},
author = {Jodlowska-Siewert, E and Liu, L and Yang, K and Ostroushko, D and Lutsey, PL and Chekouo, T and Safo, SE and , },
title = {A score based on MRI imaging variables can predict time to moderate progression in mild cognitive impairment: Multimodal data integration study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469162},
doi = {10.1177/13872877261469162},
pmid = {42541425},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI) is an intermediate stage between normal aging and Alzheimer's disease (AD). Because there is no treatment for AD, it is vital to establish which patients are at a higher risk of disease progression, and might benefit from early intervention.ObjectiveThis study investigates whether a score based on clusters of MRI and lipidomic variables can predict the time to moderate progression in MCI.MethodsWe analyzed MRI and lipidomics data from 480 individuals with MCI (mean age 72.14 years, range 55-90 years). Moderate progression was defined as a ≥ 2.5-point increase in the Clinical Dementia Rating Scale Sum of Boxes (baseline mean CDR-SB of 1.2, range 0-10 points). Multi-source data integration and clustering methods were used to derive predictive scores.ResultsThe MRI-based score outperformed the lipidomics score (c-index: 0.754 versus 0.666). A 1-unit increase in the MRI score was linked to a 13% higher risk of moderate progression. Individuals in the top 25% of MRI scores had a 3-fold greater risk of decline.ConclusionsAn MRI-based score offers a simple, effective tool to predict moderate MCI progression and identify high-risk individuals for AD.},
}

@article {pmid42541427,
year = {2026},
author = {Luna-Viramontes, NI and Méndez-Llaca, RE and Morlett Paredes, A and Ordoñez-Lozano, I and Acra-Despradel, C and Guillen-Sarita, J and Pacheco-Herrero, M and Gonzalez-Chavez, VE and Perry, G and Jaramillo-Loranca, BE and Vargas-Hernández, G and Garcés-Ramírez, L and de la Cruz-López, F and Villanueva-Fierro, I and Hernandes-Alejandro, M and Montiel-Sosa, JF and Rojas-Pérez, FJ and Pérez-Pérez, EG and Ocampo-Barba, N and Cenobio-García, FJ and Luna-Muñoz, J},
title = {Experience, challenges, and regional integration of the National Dementia Biobank (Mexico) and the National Brain Bank-UNPHU (Dominican Republic).},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474026},
doi = {10.1177/13872877261474026},
pmid = {42541427},
issn = {1875-8908},
abstract = {Neurobiobanks focused on the study of major cognitive impairment constitute a strategic infrastructure for translational research and personalized medicine in the neurosciences. In Mexico and the Dominican Republic, the National Dementia Biobank (BND) at the Universidad Politécnica de Pachuca and the National Brain Bank at the Universidad Nacional Pedro Henríquez Ureña (BNC-UNPHU) have developed integrated mechanisms for the collection, processing, and preservation of human brain tissue, as well as other tissues such as kidney, liver, intestine, pancreas, and skin, intended exclusively for biomedical research. Both institutions share research lines centered on the molecular pathological study of the tau protein and the amyloid-β peptide, key markers of Alzheimer's disease and other dementias. Protocols for immunohistochemistry, silver staining, single and multiple immunofluorescences, as well as staining with fluorochromes such as thiazine red and thioflavin-S, have been standardized for the precise detection of neuropathological lesions. Transgenic animal models, including the triple transgenic mouse with mutations in presenilin-1, amyloid-β protein precursor, and tau, have served as complementary tools to dissect the temporal sequence of protein aggregation. In parallel, both institutions have implemented sustained scientific outreach programs, including a traveling museum of neurodegenerative diseases, Brain Awareness Week, Alzheimer's fairs, and media campaigns, aimed at reducing stigma, promoting altruistic tissue donation, and building public trust. Collectively, these neurobiobanks represent an emerging model of research contextualized within Latin American populations, with the potential to integrate into regional and international networks that contribute to reducing knowledge gaps in neurodegeneration.},
}

@article {pmid42541545,
year = {2026},
author = {Hirschmüller, KCE and Prieto, E and Guillén, EF and Echeveste, B and Mínguez, F and Romera, M and Pareja, F and Fahmi, R and Riverol, M and Arbizu, J},
title = {From image reconstruction to clinical prognosis: A comprehensive analysis of centiloid-based amyloid PET assessment.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42541545},
issn = {1619-7089},
abstract = {PURPOSE: To investigate the sources of variability in Centiloid (CL) calculations, particularly the influence of image reconstruction and reference region selection, and to examine the relationship between baseline CL scores, visual interpretation and subsequent disease progression.

METHODS: 162 aMCI patients who underwent amyloid PET at a single center were retrospectively analyzed. Visual assessment was performed by two nuclear medicine physicians and Centiloid scoring was determined using syngo.MI Neurology Cortical Analysis, using different reference regions (RR) and image reconstruction settings. The CL values were compared against visual interpretation, using a ROC analysis. The value of CL in predicting the onset of Alzheimer's dementia was assessed.

RESULTS: The use of the whole cerebellum as RR provided the most robust and consistent CL values across reconstruction methods. The RR was critical in the case of flutemetamol, as CL varied in more than 20 units between pons and whole cerebellum. Visual classifications and CL values showed strong concordance (area under the ROC curve: 0.9786) and the CL cut-off value that maximized agreement with visual reading was 28 CL. During follow-up, 49% of patients progressed to AD dementia and CL-based amyloid positivity was a significant predictor of progression.

CONCLUSION: Standardized CL quantification using the whole cerebellum as RR enhances the reliability of amyloid PET interpretation across tracers and reconstruction settings. CL values strongly correlate with visual assessment and are predictive of clinical progression. These findings suggest the potential utility of CL quantification in both clinical and research settings.},
}

@article {pmid42541586,
year = {2026},
author = {Du, X and Shen, Z and Xu, Y and Song, W and Guo, Y and Kou, J and Gong, S and Ren, Q},
title = {Research progress of traditional Chinese medicine interventions for aging-related nervous system diseases.},
journal = {Biogerontology},
volume = {27},
number = {4},
pages = {},
pmid = {42541586},
issn = {1573-6768},
support = {82574744//National Natural Science Foundation of China/ ; JSTJ-2025-490//The Youth Science and Technology Talent Support Program of Jiangsu Association for Science and Technology/ ; YJQN2025005//Research Project Funding from Affiliated Jiangning Hospital of Chinese Medicine, China Pharmaceutical University/ ; },
mesh = {Humans ; *Medicine, Chinese Traditional/methods ; *Aging/drug effects ; Animals ; *Nervous System Diseases/drug therapy ; *Drugs, Chinese Herbal/therapeutic use ; Oxidative Stress/drug effects ; },
abstract = {Aging-related neurological disorders, including stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, and various neuroinflammatory conditions, affect over three billion individuals worldwide and constitute leading causes of morbidity, disability, and socioeconomic burdens. Aging contributes not only to the increased incidence of these disorders but also to their progression through interconnected mechanisms, including endothelial dysfunction, oxidative stress, chronic inflammation, mitochondrial dysfunction, cellular senescence, metabolic imbalance, and gut microbiota dysbiosis. These processes collectively impair neuronal survival, synaptic plasticity, and cognitive and motor functions. Traditional Chinese medicine (TCM), with its characteristic multi-component and multi-target therapeutic strategies, has emerged as a promising approach to counteract age-associated neurological decline. Accumulating preclinical studies suggest that TCM interventions may exert neuroprotective, anti-inflammatory, and antioxidant effects, modulate autophagy, restore metabolic homeostasis, and potentially delay cellular senescence. However, high-quality clinical evidence on safety and efficacy remains limited. This review summarizes current insights into the molecular interplay between aging and neurological disorders and highlights the therapeutic potential of TCM in targeting hallmarks of aging, providing perspectives for integrative prevention and treatment strategies for neurodegenerative and neurovascular diseases.},
}

Humans
*Medicine, Chinese Traditional/methods
*Aging/drug effects
Animals
*Nervous System Diseases/drug therapy
*Drugs, Chinese Herbal/therapeutic use
Oxidative Stress/drug effects

@article {pmid42541636,
year = {2026},
author = {Yang, F and Gao, W and Wang, J and Li, H},
title = {The Glial Autophagy-Lysosomal-Inflammation Axis in Alzheimer's Disease: a Unifying Mechanistic Framework.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42541636},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *Autophagy/physiology ; *Neuroglia/pathology/metabolism ; Animals ; *Lysosomes/metabolism/pathology ; *Inflammation/pathology/metabolism ; Signal Transduction ; },
abstract = {Recent studies suggest that impairment of the glial autophagy-lysosomal pathway (ALP) critically contributes to the sustained neuroinflammatory response and neurodegenerative processes in Alzheimer's disease (AD). Glial cells, comprising microglia, astrocytes, oligodendrocytes, and ependymal cells, serve as key immune regulators in the central nervous system, where they are essential for maintaining ALP homeostasis, promoting proteostasis, and modulating neuroinflammatory responses. Here, we systematically review the regulatory roles of glial ALP in AD pathology, emphasizing its involvement in amyloid accumulation, tau hyperphosphorylation, synaptic impairment, white matter damage, and mitochondrial as well as other organelle dysfunction, and provide an in-depth analysis of key signaling pathways including TFEB, mTOR, and NLRP3. Furthermore, we outline therapeutic strategies aimed at restoring lysosomal function, regulating autophagic flux, and suppressing inflammation, along with a discussion of the multi-target regulatory potential of acupuncture and natural bioactive agents. We also highlight emerging ALP-associated biomarkers and their potential utility in early diagnosis and treatment response assessment. The objective of this review is to uncover the mechanistic interplay between glial ALP dysregulation and the pathological cascade of AD, offering a conceptual framework for the development of novel therapeutics that integrate neuroprotection with immune modulation.},
}

Humans
*Alzheimer Disease/pathology/metabolism
*Autophagy/physiology
*Neuroglia/pathology/metabolism
Animals
*Lysosomes/metabolism/pathology
*Inflammation/pathology/metabolism
Signal Transduction

@article {pmid42541645,
year = {2026},
author = {Chu, M and Tan, M and Gan, X and Cui, S and Shi, L},
title = {Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42541645},
issn = {1559-1182},
mesh = {*Microglia/metabolism/pathology/drug effects ; Humans ; *Neurodegenerative Diseases/metabolism/pathology/therapy/drug therapy ; *Mitochondria/metabolism/pathology/drug effects ; Animals ; },
abstract = {Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.},
}

*Microglia/metabolism/pathology/drug effects
Humans
*Neurodegenerative Diseases/metabolism/pathology/therapy/drug therapy
*Mitochondria/metabolism/pathology/drug effects
Animals

@article {pmid42535671,
year = {2026},
author = {Mortazavi, N and Vandewalle, G and Talwar, P},
title = {Response to "On the Directionality of Predictor-Outcome Assignment When Modeling Polygenic Risk for Alzheimer's Disease Alongside Sleep Arousal Phenotypes".},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zsag211},
pmid = {42535671},
issn = {1550-9109},
}

@article {pmid42535759,
year = {2026},
author = {Yang, D and Wu, X and Luo, X and Teng, Y and Duan, X and Kang, T and Wu, W},
title = {Stable Isotope-Resolved Metabolomics in Elucidating Mitochondrial Metabolic Reprogramming and Therapeutic Targets.},
journal = {Biomedical chromatography : BMC},
volume = {40},
number = {9},
pages = {e70560},
pmid = {42535759},
issn = {1099-0801},
support = {25ZC-36//the Natural Science Funding Program of Yibin Vocational and Technical College/ ; },
mesh = {Humans ; *Metabolomics/methods ; *Mitochondria/metabolism ; Metabolic Reprogramming ; Animals ; Isotope Labeling/methods ; Neoplasms/metabolism ; },
abstract = {Stable isotope-resolved metabolomics (SIRM) has emerged as a pivotal methodology for dissecting mitochondrial metabolic reprogramming and its connection to therapeutic targets. By combining isotopically labeled substrates with metabolic flux analysis (MFA), SIRM enables dynamic, quantitative tracking of carbon flux through mitochondrial pathways. This review focuses on three disease contexts where SIRM has provided transformative insights: cancer, neurodegenerative disorders (Alzheimer's and Parkinson's diseases), and metabolic syndrome (type 2 diabetes and non-alcoholic fatty liver disease). Recent applications have delineated reprogramming signatures, identified metabolic dependencies, and elucidated drug mechanisms. SIRM also facilitates therapeutic monitoring and resistance assessment, offering quantitative biomarkers for patient stratification. We summarize recent advances, technical challenges, AI-powered innovations, and future directions, providing a foundation for optimizing metabolism-targeted therapies.},
}

Humans
*Metabolomics/methods
*Mitochondria/metabolism
Metabolic Reprogramming
Animals
Isotope Labeling/methods
Neoplasms/metabolism

@article {pmid42535978,
year = {2026},
author = {Gholami, M and Ahmadi, AA and Niaki, MAA and Asouri, M and Saeedi, S and Amoli, MM and Larijani, B},
title = {New Genetic Associations Between Alzheimer's Disease and Its Key Risk Factors.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70198},
pmid = {42535978},
issn = {1479-8301},
support = {1403-2-221-73223//Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Risk Factors ; Mitochondrial Precursor Protein Import Complex Proteins ; *Apolipoproteins E/genetics ; *Genetic Predisposition to Disease/genetics ; Membrane Transport Proteins/genetics ; ATP Binding Cassette Transporter 1/genetics ; Genome-Wide Association Study ; Female ; Polymorphism, Single Nucleotide ; Metabolic Syndrome/genetics ; Linkage Disequilibrium ; Male ; Haplotypes ; Aged ; Waist-Hip Ratio ; Diabetes Mellitus/genetics ; },
abstract = {INTRODUCTION: This study aimed to explore shared genetic architectures underlying Alzheimer's disease (AD) and its known risk factors.

METHODS: Significant common variants between AD and its risk factors were identified using GWAS data. The 1000 Genomes Project genotyping data enabled the detection of linkage disequilibrium (LD) blocks and haplotype structures. Functional impact assessments, protein-protein interaction analyses, pathway mapping and enrichment studies were performed.

RESULTS: Sixteen significant variants across nine genes were associated with AD and at least one risk factor (p ≤ 5 × 10[-8]). Genes APOE, ABCA1 and TOMM40 showed strong associations with AD (adjusted p = 9.75 × 10[-9]). High-confidence interactions were identified among these genes, as well as APP and LRP1, within the AD pathway. Variant rs429358 (p ≤ 3 × 10[-15]) on the APOE gene was linked to AD, metabolic syndrome (MetS), diabetes, waist-to-hip ratio (WHR) and ageing. Variant rs2075650 (p ≤ 6 × 10[-9]) on TOMM40 correlated AD risk with MetS, WHR and body mass index (BMI). Variants rs483082 (p ≤ 2 × 10[-32]) and rs71352238 (p ≤ 1 × 10[-11]) on APOC1 and TOMM40 were associated with AD and MetS. Variants rs4420638 (p ≤ 2 × 10[-34]) and rs1800978 (p ≤ 2 × 10[-9]) on APOC1 and ABCA genes were associated with AD and WHR. The rs13237518 (p ≤ 5 × 10[-11]) was associated with AD risk in diabetic patients. Furthermore, the rs4277405 (p ≤ 9 × 10[-20]) associated AD with cardiovascular disease (CVD). Haplotypic structures were also identified for all these variants (D' and r[2] ≥ 0.8).

DISCUSSION: This study identifies genetic variants and LD blocks on APOE, ABCA1, TOMM40 and APOC1 genes shared between AD and its risk factors, revealing common genetic links and potential shared susceptibility pathways.},
}

Humans
*Alzheimer Disease/genetics
Risk Factors
Mitochondrial Precursor Protein Import Complex Proteins
*Apolipoproteins E/genetics
*Genetic Predisposition to Disease/genetics
Membrane Transport Proteins/genetics
ATP Binding Cassette Transporter 1/genetics
Genome-Wide Association Study
Female
Polymorphism, Single Nucleotide
Metabolic Syndrome/genetics
Linkage Disequilibrium
Male
Haplotypes
Aged
Waist-Hip Ratio
Diabetes Mellitus/genetics

@article {pmid42536015,
year = {2026},
author = {Li, S and Jin, J and Liu, Y and Yuan, J and Dong, Y and Wang, Z and Li, L and Zhang, Y},
title = {Microglial immunometabolic reprogramming in Alzheimer's disease: From mitochondrial dysfunction and redox imbalance to NLRP3 inflammasome-driven neuroinflammation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261469862},
doi = {10.1177/13872877261469862},
pmid = {42536015},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a disorder in which amyloid-β deposition and tau pathology interact with neuroinflammation and metabolic dysregulation. Although mitochondrial dysfunction, redox imbalance, and NLRP3 inflammasome activation have each been implicated in AD pathogenesis, their mechanistic continuity within microglial immunometabolic reprogramming remains insufficiently defined. This narrative review integrates mechanistic, preclinical, and human-relevant evidence to propose a stage-dependent mitochondrial dysfunction-redox imbalance-NLRP3 inflammasome axis. We discuss how AD-related stimuli shift microglia toward a pro-inflammatory metabolic phenotype; how impaired mitochondrial quality control promotes reactive oxygen species generation and oxidized mitochondrial DNA release; and how these signals facilitate NLRP3 inflammasome activation and sustained inflammatory amplification. We further summarize therapeutic strategies targeting upstream mitochondrial homeostasis, intermediate metabolic-redox coupling, and downstream NLRP3 signaling, while emphasizing the translational limitations and biomarker needs. We conclude that this proposed axis provides a testable stage-dependent framework for interpreting chronic, self-amplifying neuroinflammation in AD and may inform biomarker-guided, combinatorial therapeutic strategies.},
}

@article {pmid42536022,
year = {2026},
author = {Rehman, MU and Masip, D},
title = {Artificial intelligence in retinal imaging for early Alzheimer's disease detection: A review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261473304},
doi = {10.1177/13872877261473304},
pmid = {42536022},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder that necessitates early, accessible, and non-invasive diagnostic methods.ObjectiveThis review examines the potential of artificial intelligence (AI)-based retinal imaging as a transformative and scalable tool for early AD detection across the full diagnostic continuum, including the preclinical stage.MethodsFollowing PRISMA guidelines, 63 primary studies were selected from an initial pool of 240 articles retrieved from PubMed, IEEE Xplore, Scopus, Web of Science, and Google Scholar (2017-mid-2025). Advancements in optical coherence tomography (OCT), retinal fundus imaging, and OCT angiography are examined for their capacity to capture structural and vascular biomarkers, including retinal nerve fiber layer thinning and microvascular alterations. AI architectures, including convolutional neural networks, vision transformers, and hybrid models, are evaluated for their accuracy in retinal biomarker analysis. Benchmark datasets, including public and private ones, are assessed for their role in supporting AI-based AD research.ResultsKey challenges are identified, including data heterogeneity arising from variability in acquisition protocols and demographic representation, as well as computational complexity and limited model interpretability. Emerging approaches-notably multimodal data integration and federated learning-offer promising avenues for enhancing diagnostic accuracy while preserving patient privacy.ConclusionsThe socioeconomic implications of integrating AI-based retinal imaging into clinical workflows are discussed. By synthesizing recent advancements, unresolved challenges, and future directions, this review underscores the transformative potential of AI-driven oculomics in facilitating early AD diagnosis and improving patient outcomes.},
}

@article {pmid42536222,
year = {2026},
author = {Serna, MF and Mosquera, M and García-Perdomo, HA},
title = {Motor performance and its association with Alzheimer's-related biomarkers: a systematic review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {8},
pages = {},
pmid = {42536222},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/physiopathology/diagnosis ; Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; *Cognitive Dysfunction/physiopathology/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Peptide Fragments/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; },
abstract = {PURPOSE: To examine associations between neurodegenerative and inflammatory biomarkers and motor function in adults with Alzheimer's disease (AD), mild cognitive impairment (MCI), or at risk of AD.

METHODS: A systematic review was conducted using MEDLINE, Web of Science, Scopus, LILACS, and CENTRAL.

RESULTS: Seventeen studies (2018-2026) were included. CSF Aβ42 levels were associated with gait speed, balance, and mobility outcomes, while p-tau, p-tau181, p-tau217, and t-tau correlated with mobility impairments, dual-task performance, and reduced physical function. Higher neurofilament light chain (NfL) levels were linked to poorer Short Physical Performance Battery (SPPB) performance, slower gait speed, and lower grip strength. One study found serum IL-8 associated with mobility outcomes.

CONCLUSIONS: AD-related biomarkers, particularly Aβ42, p-tau, p-tau181, p-tau217, t-tau, and NfL, show consistent associations with gait disturbances, mobility decline, and reduced physical function. Motor changes may precede cognitive decline, supporting their potential as early indicators of neurodegeneration.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/physiopathology/diagnosis
Biomarkers/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
*Cognitive Dysfunction/physiopathology/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Peptide Fragments/cerebrospinal fluid
Neurofilament Proteins/cerebrospinal fluid

@article {pmid42536296,
year = {2026},
author = {Li, YQ and Chen, DX and Zhu, XT and Li, W and Wu, JL and Fang, LM and Li, MQ},
title = {Therapeutic Potential of Jiedu Yizhi Formula for Alzheimer's Disease: A Randomized Controlled Trial.},
journal = {Chinese journal of integrative medicine},
volume = {},
number = {},
pages = {},
pmid = {42536296},
issn = {1993-0402},
abstract = {OBJECTIVE: To observe the clinical effect and safety of Jiedu Yizhi Formula (JYF) in Alzheimer's disease (AD) patients.

METHODS: Eligible patients with mild to moderate AD and Chinese medicine (CM) syndrome of Pi (Spleen)-Shen (Kidney) deficiency with phlegm-turbidity obscuring orifices were collected from the Third Affiliated Hospital of Changchun University of Chinese Medicine between December 2022 and December 2023. Patients were randomly assigned to JYF and donepezil groups at a 1:1 ratio by using a random number table and received a total of 24 weeks of continuous treatment. Both groups were given AD cognitive behavior training and health education at the same time. The Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), AD Assessment Scale-Cognitive (ADAS-cog), Activity of Daily Living (ADL), and Hamilton Depression (HAMD) scale scores were measured before treatment, 12 and 24 weeks after treatment. The cognitive domain scores and the total effective rates were also compared between groups. During the study period, any adverse reactions were recorded and compared between groups.

RESULTS: Totally 62 participants completed the study, with 31 in each group. The MMSE, MoCA, ADAS-cog, ADL, and HAMD scores significantly improved after 12 and 24 weeks of treatment in both groups (P<0.05 or P<0.01). Moreover, significant improvements in the ADL and HAMD scores were observed in the JYF group at 12 or 24 weeks than in the donepezil group (P<0.05 or P<0.01). Meanwhile, the cognitive domain scores of orientational and abstraction abilities and the total effective rate (64.52% vs. 45.16%) in the JYF group were significantly higher (P<0.05). No significant difference was found in the incidence of adverse reactions between groups (9.68% vs. 6.45%, P>0.05).

CONCLUSION: JYF can improve the cognitive dysfunction of mild to moderate AD patients with CM syndrome of Pi-Shen deficiency with phlegm-turbidity obscuring orifices, and its safety is good. (Trial registration No. NCT06393413).},
}

@article {pmid42536368,
year = {2026},
author = {Chiotis, S and Giannopoulos, G and Zagalioti, SC and Konstantinidou, SE and Mountourli, MI and Zgouridou, A and Anastasiou, A and Bakogiannis, K and Evaggeliou, A and Sapouridis, G and Toumpourleka, M and Triantafyllou, C and Poptsi, E and Symeonidis, A and Tsolaki, M and Vassilikos, V},
title = {Global and Domain-Specific Cognitive Outcomes After Catheter Ablation for Atrial Fibrillation.},
journal = {JAMA network open},
volume = {9},
number = {7},
pages = {e2626642},
doi = {10.1001/jamanetworkopen.2026.26642},
pmid = {42536368},
issn = {2574-3805},
mesh = {Humans ; *Atrial Fibrillation/surgery/complications ; *Catheter Ablation/adverse effects/methods ; Female ; Prospective Studies ; Male ; Middle Aged ; *Cognition ; *Cognitive Dysfunction/etiology ; Greece ; Magnetic Resonance Imaging ; Aged ; Treatment Outcome ; },
abstract = {IMPORTANCE: Atrial fibrillation (AF) is associated with cognitive impairment, but the cognitive effects of catheter ablation (CA) using contemporary techniques remain uncertain.

OBJECTIVE: To evaluate changes in global and domain-specific cognitive function after CA for AF.

This prospective cohort study included consecutive patients undergoing CA for AF and a nonablation AF control group at a tertiary university hospital in Greece between January 2022 and June 2024. Cognitive assessments were performed at baseline and at 6-month follow-up.

EXPOSURES: CA using cryoballoon or pulsed field ablation (PFA).

MAIN OUTCOMES AND MEASURES: Changes from baseline to 6 months in Montreal Cognitive Assessment (MoCA) scores and the novel REMEDES for Alzheimer (R4Alz) total and subdomain scores. Brain magnetic resonance imaging was performed before and within 48 hours after ablation to detect new cerebral infarcts.

RESULTS: Among 75 patients (40 [53.3%] female) undergoing ablation (mean [SD] age, 61.9 [10.4] years; 54 cryoballoon, 21 PFA) and 40 in a nonablation control group (26 [65.0%] female; mean [SD] age,61.4 [9.2] years), baseline cognitive scores were similar between groups. No new cerebral infarcts were detected after ablation. At 6 months, MoCA scores in the ablation group did not change significantly (mean change, 0.27; 95% CI, -0.08 to 0.62), whereas R4Alz total scores increased (mean change, 2.81; 95% CI, 1.55 to 4.07), mainly associated with gains in short-term working memory and perceptual inhibition. No significant changes were observed in the control group. Compared with the control group, the ablation cohort demonstrated significantly greater improvements in both MoCA (mean difference in change, 0.74; 95% CI, 0.17 to 1.31; P = .01) and R4Alz total score (mean difference in change score, 3.18; 95% CI, 0.87 to 5.49; P = .007). In adjusted analyses accounting for baseline cognitive score and clinical covariates, ablation was independently associated with higher follow-up MoCA (β = 0.88; 95% CI, 0.31 to 1.44) and R4Alz scores (β = 3.80; 95% CI, 1.70 to 5.90).

CONCLUSIONS AND RELEVANCE: In this prospective observational cohort study of 75 patients undergoing CA for AF, ablation was not associated with cognitive decline and was instead associated with modest short-term improvements in selected cognitive domains. Domain-specific assessment detected changes not captured by global cognitive screening, suggesting that modern ablation techniques may be associated with early subtle cognitive gains.},
}

Humans
*Atrial Fibrillation/surgery/complications
*Catheter Ablation/adverse effects/methods
Female
Prospective Studies
Male
Middle Aged
*Cognition
*Cognitive Dysfunction/etiology
Greece
Magnetic Resonance Imaging
Aged
Treatment Outcome

@article {pmid42536379,
year = {2026},
author = {Rubin, R},
title = {Soccer Players' Brains, P-Tau217 Blood Tests, Lifestyle and Dementia Risk, and More From AAIC 2026.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.14334},
pmid = {42536379},
issn = {1538-3598},
}

@article {pmid42536688,
year = {2026},
author = {Xie, Y and Lim, CT and Lam, XJ and Cheah, PS and Ling, KH and Huang, T},
title = {Integrative network pharmacology, transcriptomics, and molecular docking identify candidate Centella asiatica constituents and targets in neurodegenerative diseases.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0354882},
pmid = {42536688},
issn = {1932-6203},
mesh = {*Molecular Docking Simulation ; *Neurodegenerative Diseases/drug therapy/genetics/metabolism ; *Centella/chemistry ; Humans ; *Network Pharmacology/methods ; *Triterpenes/chemistry/pharmacology ; *Transcriptome/drug effects ; Gene Expression Profiling ; },
abstract = {BACKGROUND: Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are progressive disorders with limited therapeutic options. Centella asiatica (C. asiatica), a medicinal and edible plant, has been reported to exert neuroprotective and anti-neuroinflammatory properties. Yet, the mechanisms underlying its effects against neurodegenerative diseases remain largely unclear.

METHODS: We employed an integrative strategy combining network pharmacology, transcriptomic analyses, machine learning and molecular docking to prioritize disease-associated molecular networks and candidate compound-target relationships in AD, PD and HD.

RESULTS: Sixteen candidate constituents of C. asiatica met the predefined drug-likeness, gastrointestinal absorption and blood-brain barrier permeability criteria, yielding 370 unique predicted targets. Disease-gene mining identified 983 AD-associated genes, 1,103 PD-associated genes, and 3,316 HD-associated genes. Integration of compound targets, disease-associated genes, and transcriptomic profiles prioritized five hub genes in PD (CCKAR, MAPK8, PSEN2, SLC6A3, and TH), four in AD (APP, PGK1, PIK3CA, and TTR), and four in HD (CHRND, HSP90AA1, PRKCQ, and TH). Enrichment analyses highlighted disease-relevant processes involving neurotransmitter signalling, cAMP and calcium pathways, MAPK-related responses and inflammatory regulation. ROC analyses provided additional support for the discriminatory performance of the prioritized genes in independent datasets, whereas molecular docking identified favourable predicted Vina docking scores and structurally plausible interactions between selected compounds and hub targets.

CONCLUSION: This integrative computational analysis prioritizes candidate C. asiatica constituents, putative disease-associated targets, and molecular pathways in AD, PD, and HD. The findings provide a foundation for subsequent biochemical, cellular, and in vivo validation.},
}

*Molecular Docking Simulation
*Neurodegenerative Diseases/drug therapy/genetics/metabolism
*Centella/chemistry
Humans
*Network Pharmacology/methods
*Triterpenes/chemistry/pharmacology
*Transcriptome/drug effects
Gene Expression Profiling

@article {pmid42536712,
year = {2026},
author = {},
title = {Retraction: Detection of Peri-Synaptic Amyloid-β Pyroglutamate Aggregates in Early Stages of Alzheimer's Disease and in AβPP Transgenic Mice Using a Novel Monoclonal Antibody.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474572},
doi = {10.1177/13872877261474572},
pmid = {42536712},
issn = {1875-8908},
}

@article {pmid42537247,
year = {2026},
author = {Du, X and Bao, M and Li, Y and Ding, J and Zhang, Z and Chen, H and Liu, Y},
title = {Neuroprotective mechanism of Ribisin A on Aβ25-35-induced PC12 cell damage model.},
journal = {Tissue & cell},
volume = {104},
number = {Pt 1},
pages = {103825},
doi = {10.1016/j.tice.2026.103825},
pmid = {42537247},
issn = {1532-3072},
abstract = {Amyloid-β (Aβ) is a neurotoxic substance, and studies have found that its excessive deposition in the brain, forming senile plaques, is a major pathological feature of Alzheimer's disease (AD). In previous studies, Ribisin A, a benzofuran compound, was purified from Phellinus ribis and found to have neuroprotective effects. This study aims to elucidate the neuroprotective mechanism of Ribisin A in an Aβ25-35-damaged PC12 cell model. This study established an in vitro AD model using PC12 cells damaged by Aβ25-35. We applied methyl tetrazolium (MTT), enzyme-linked immunosorbent assay (ELISA) kits, flow cytometry, and western blotting techniques to study the effects of Ribisin A on the Aβ25-35 injury model and the relationship with the ERK pathway from the aspects of cell injury degree, cytokine content, Calcium ion (Ca[2 +]) concentration, mitochondrial membrane potential (MMP), and the ERK pathway-related protein expression. Results indicate that Ribisin A reduced lactate dehydrogenase (LDH), reactive oxygen species (ROS), tumour necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels in the Aβ25-35-induced cellular injury model while increasing superoxide dismutase (SOD) levels. Furthermore, it inhibited Aβ25-35-induced increases in Ca[2+] concentration and decreases in MMP, leading to upregulation of ERK pathway-related proteins TrkB, p-ERK1/2, and p-CREB, with significant elevations in p-ERK/ERK and p-CREB/CREB ratios (P < 0.01). Ribisin A can reduce oxidative damage, inhibit inflammation, restore mitochondrial function, and reduce apoptosis. The neuroprotective mechanism of Ribisin A may involve regulation of the TrkB-mediated ERK/CREB signaling cascade. Our study provides evidence for the neuroprotective mechanism of Ribisin A in an Aβ25-35-induced cellular injury model.},
}

@article {pmid42537334,
year = {2026},
author = {Larico-Ramirez, LP and Paco-Chipana, M and Herrera, MI and Goyzueta-Mamani, D and Chavez-Fumagalli, M and Barazorda-Ccahuana, HL},
title = {Integrative computational discovery of a lichen-derived acetylcholinesterase inhibitor candidate for Alzheimer's disease.},
journal = {Computational biology and chemistry},
volume = {125},
number = {},
pages = {109275},
doi = {10.1016/j.compbiolchem.2026.109275},
pmid = {42537334},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD), the leading cause of dementia worldwide, is a progressive neurodegenerative disorder for which current pharmacological treatments provide only limited symptomatic relief. Human acetylcholinesterase (hAChE) remains one of the most extensively validated therapeutic targets because its inhibition enhances cholinergic neurotransmission and temporarily improves cognitive function. Motivated by the remarkable structural diversity of lichen secondary metabolites, we investigated their potential as novel hAChE inhibitors using an integrated multiscale computational strategy that combined structure-based virtual screening, ADME/Tox profiling, density functional theory (DFT) calculations, molecular dynamics (MD) simulations, and MM/GBSA binding free-energy analysis, with donepezil employed as the reference inhibitor. Among the screened compounds, calycin emerged as the most promising candidate. It displayed high predicted binding affinity together with favorable pharmacokinetic characteristics, including high gastrointestinal absorption and blood-brain barrier permeability. Electronic structure analysis revealed greater chemical reactivity and electronic adaptability than donepezil, indicating an enhanced ability to establish stabilizing interactions within the hAChE active site. Molecular electrostatic potential and local reactivity descriptors further identified chemically active regions responsible for favorable non-covalent interactions along the active-site gorge. Long-timescale MD simulations confirmed the structural stability of the hAChE-calycin complex, while MM/GBSA calculations demonstrated a thermodynamically favorable binding process predominantly driven by van der Waals and hydrophobic interactions with key aromatic residues. Collectively, these findings identify calycin as a promising lead scaffold for the development of next-generation hAChE inhibitors and demonstrate the potential of lichen-derived natural products as an underexplored source of chemically diverse candidates for Alzheimer's disease drug discovery.},
}

@article {pmid42537728,
year = {2026},
author = {Zhang, Y and Ge, P and Mao, J and Wang, T and Yuan, H},
title = {Role of auricular vagus nerve stimulation in alleviating neuronal apoptosis and cognitive dysfunction in male rats with vascular dementia.},
journal = {Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association},
volume = {},
number = {},
pages = {108716},
doi = {10.1016/j.jstrokecerebrovasdis.2026.108716},
pmid = {42537728},
issn = {1532-8511},
abstract = {BACKGROUND AND PURPOSE: Vascular dementia (VD) is characterized by cognitive impairment resulting from cerebrovascular damage. Prior studies have shown that vagus nerve stimulation improves learning and memory in patients with Alzheimer's disease. This study, therefore, investigated whether auricular vagus nerve stimulation (aVNS) ameliorates cognitive dysfunction in a rat model of VD through activation of the adenosine A2A receptor (A2AR) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathways.

METHODS: Fifty male rats were randomly assigned to five groups by a computer-generated sequence: control (A), sham-operated (B), VD model (C), aVNS-treated (D), and aVNS combined with the A2AR antagonist SCH 58261 (E). Rats in the aVNS group received stimulation (0.6 mA, 40 Hz, 0.5 ms square pulses) for 4 weeks. Spatial learning and memory were evaluated using the Morris water maze test. Rat brain microvascular endothelial cells were cultured and treated with an A2AR agonist and/or a protein kinase A (PKA) inhibitor to verify the involvement of the A2AR-Nrf2/HO-1 pathway. Expression levels of inflammatory cytokines (IL-1β and IL-6), key signaling proteins (A2AR, p-PKA, p-Nrf2, and HO-1), and phosphorylated tau (p-tau) were measured using western blot or enzyme-linked immunosorbent assays.

RESULTS: Compared with Groups C and E, Group D exhibited improved spatial learning and memory. aVNS markedly increased the p-PKA and p-Nrf2/HO-1 levels while reducing p-tau and proinflammatory cytokine levels. In vitro experiments showed that A2AR agonist treatment upregulated p-PKA and p-Nrf2/HO-1 expression; however, this effect was abolished by PKA inhibition.

CONCLUSION: aVNS ameliorates cognitive impairments in VD rats and attenuates neuronal apoptosis, p-tau accumulation, and neuroinflammation, and these effects are associated with activation of the A₂AR/PKA/Nrf2/HO-1 signaling pathway. These findings suggest that aVNS may represent a promising therapeutic strategy for cognitive impairment associated with VD.},
}

@article {pmid42537760,
year = {2026},
author = {Misrani, A and Wang, J and Xu, Y and Liu, F},
title = {IL-17A levels in Alzheimer's Disease brains are mediated by X chromosome dosage.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112065},
doi = {10.1016/j.brainresbull.2026.112065},
pmid = {42537760},
issn = {1873-2747},
abstract = {Among inflammatory mediators, interleukin-17A (IL-17A) has emerged as a potential contributor to AD pathogenesis, although its role remains incompletely defined. Notably, sex differences are evident in AD, with males exhibiting earlier mortality and greater cognitive deficits during aging and preclinical stages compared to females. While hormonal influences have been widely studied, the contribution of sex chromosome complement was suggested critical and remains poorly understood. Here, we investigated the impact of sex chromosome on cognitive function and neuroinflammation using amyloid and tau mouse models. Female Tg2576 and PS19 mice were crossed with XY* males to generate XX, XO, XY, and XXY genotypes, enabling separation of X from Y chromosomal effect. Behavioral assessments, including fear conditioning, novel object recognition, and Barnes maze, revealed that XY mice exhibited significantly greater cognitive impairment compared to XX and XXY counterparts. The same pattern was seen in IL-17A levels, indicating an effect of X chromosome instead of Y. Amyloid-β and phosphorylated tau pathology by immunohistochemistry and Elisa confirmed robust disease-associated accumulation in Tg2576 and PS19 mice, but showed no differences across sex chromosome complements. Collectively, our study identifies X chromosome dosage as a key modulator of cognitive resilience and IL-17A-linked neuroinflammation in AD models. Future studies focused on understanding how X-linked factors regulate IL17 mediated neuroinflammatory pathways could reveal novel therapeutic targets for AD.},
}

@article {pmid42537824,
year = {2026},
author = {Abouali, O and Mokabber, A and Naderpour, S and Vojoudi, E and Sefat, F and Saeinasab, M and Rahimzadegan, M and Nosrati, R},
title = {Chitosan-based hydrogel for intranasal drug delivery; current advances in the brain diseases treatment.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {127259},
doi = {10.1016/j.ijpharm.2026.127259},
pmid = {42537824},
issn = {1873-3476},
abstract = {Neurodegenerative diseases represent a growing health concern that is projected to become more prevalent and affect more people in the upcoming decades. One of the most complicated components of recent neurodegenerative disease therapies is the penetration and delivery of therapeutics to the central nervous system (CNS), which are hindered via the blood-brain barrier (BBB). In response, innovative treatment approaches leveraging noninvasive techniques including nanosized drug delivery systems and intranasal (IN) administration with higher treatment efficacy and patient satisfaction are developing as potential options. IN administration delivers medications directly to the brain through both the olfactory and trigeminal pathways, with the olfactory pathway representing the primary route for nose-to-brain transport. Among various IN platforms, chitosan (CS)-based hydrogels have attracted considerable attention because of their excellent biocompatibility, biodegradability, mucoadhesive properties, and ability to enhance drug permeation by prolonging nasal residence time and transiently modulating epithelial tight junctions. This review critically summarizes recent advances in CS-based hydrogels for IN drug delivery for the treatment of brain diseases including Alzheimer's disease (AD), Parkinson's disease (PD), depressive manifestations, ischemia,brain tumors,epilepsy, seizures, and schizophrenia. In addition, the review discusses the relationships between hydrogel design and therapeutic performance, highlights current translational challenges, and outlines future perspectives for the clinical development of CS-based IN hydrogel systems.},
}

@article {pmid42537957,
year = {2026},
author = {Chen, K and Xuan, ZY and Sun, BY and Zhong, GN and Sun, XL and Yan, J},
title = {The critical role of microglia in the stress response.},
journal = {Neuroscience and biobehavioral reviews},
volume = {189},
number = {},
pages = {106894},
doi = {10.1016/j.neubiorev.2026.106894},
pmid = {42537957},
issn = {1873-7528},
abstract = {Microglia are the principal resident innate immune cells of the central nervous system (CNS). Beyond maintaining brain homeostasis via cytokine secretion and phagocytic clearance, they fulfill essential roles in synaptic pruning, oligodendrocyte maturation, and higher-order functions including learning and memory. In response to stress exposure, microglia undergo robust activation, characterized by morphological remodeling, altered phagocytic activity, and dysregulated inflammatory signaling, positioning them as active mediators of the integrated systemic stress response. This review systematically synthesizes preclinical and clinical evidence regarding the multifaceted contributions of microglia to stress processing, their mechanistic involvement in the pathogenesis of major stress-related disorders-including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD)-and summarizes emerging microglia-targeted therapeutic strategies. We underscore the substantial mechanistic and translational value of microglial research for advancing our understanding of stress adaptation and associated brain pathologies.},
}

@article {pmid42538506,
year = {2026},
author = {Zhang, M and Ho, FK and Pell, JP and Celis-Morales, C and Bailey, MES and Strawbridge, RJ and Lyall, DM},
title = {Heterogeneity in the association between APOE ε4 carrier status and dementia risk by modifiable and non-modifiable risk factors.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42538506},
issn = {2509-2723},
abstract = {Dementia is a major public health challenge, and Apolipoprotein E (APOE) ε4 is strongly associated with all-cause dementia, particularly Alzheimer's disease (AD). We aim to quantify the overall contribution of modifiable lifestyle, adiposity, socioeconomic status (SES), and health conditions occurring before dementia, to the association between ε4 genotype and the development of all-cause dementia, with AD examined as a major subtype. A population cohort study of 181,006 white UK Biobank participants aged ≥ 55 years at baseline was conducted, to examine the associations between APOE ε4 and all-cause dementia, and specifically AD, including modification and mediation role of lifestyle factors, adiposity, SES, and health conditions occurring before dementia. All risk factors, except for high alcohol intake, low diet quality, and phenotypic obesity, were associated with higher risk of all-cause dementia. The interaction contributions of lifestyle, adiposity, SES, and health conditions occurring before dementia varied by sex and dementia type. Low educational attainment had the strongest interaction effects with the association of APOE ε4 carriers and AD/all-cause dementia (up to 32.1%). In women, high deprivation level, abnormal sleep duration, anxiety, and depression showed interaction effects with APOE genotype (5-11.6%) as well. Phenotypic adiposity was associated with an increased risk of dementia among APOE ε4 non-carriers, but with a reduced risk among APOE ε4 carriers. Educational attainment explained a meaningful proportion of the APOE ε4 association with dementia. The strength of the association between APOE ε4 and dementia differed by risk factors and sex.},
}

@article {pmid42538752,
year = {2026},
author = {Van Langenhove, T and Van Mossevelde, S and Miatton, M and De Lepeleire, J and Bruffaerts, R and Bier, JC and Segers, K and Verschraegen, J and Petrovic, M and Ventura, M and Jedidi, H and Beyer, I and Mormont, E and Vandenberghe, R and Delva, A and Gilles, C and Van Weehaeghe, D and Picard, G and De Deyn, P and Strauss, M and Thiery, E and Salmon, E and Cypers, G and Vlaemynck, J and Gillis, K and Versijpt, J and Bjerke, M and Sieben, A and Hanseeuw, B and Engelborghs, S and Deryck, O and , },
title = {Biomarker-Based Diagnosis and Care Pathways for Alzheimer's Disease in the Era of Disease-Modifying Treatments: A Consensus Statement by Belgian Experts.},
journal = {European journal of neurology},
volume = {33},
number = {8},
pages = {e70668},
doi = {10.1111/ene.70668},
pmid = {42538752},
issn = {1468-1331},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; *Biomarkers/cerebrospinal fluid/blood ; Belgium ; },
abstract = {BACKGROUND: The recent approval of disease-modifying therapies (DMTs) for early Alzheimer's disease (AD) marks a major shift in clinical practice. Biomarker confirmation of amyloid pathology is now required alongside clinical assessment, and blood-based tests are improving accessibility. This creates increased demand for timely and accurate diagnosis while avoiding overdiagnosis in low-probability cases. This Belgian consensus aims to guide biomarker-based diagnosis of AD in the era of DMTs and to highlight the system adaptations required for safe and equitable implementation. Belgium, with universal healthcare but regionally organised dementia care, provides a relevant case to illustrate both opportunities and challenges.

METHODS: This consensus was developed by 31 experts in cognitive neurology, geriatrics, neuropsychology, neuroimaging, neurochemistry, and primary care, coordinated by the Belgian Dementia Council (BeDeCo). Recommendations were based on multidisciplinary discussion, current evidence, and the organisation of dementia care in Belgium.

RESULTS: The consensus outlines a stepwise diagnostic approach that integrates clinical assessment with biomarker confirmation using cerebrospinal fluid, amyloid-PET, and emerging blood-based tests. We review the strengths and limitations of each modality and provide guidance for use across clinical scenarios. Using Belgium as a case example, we illustrate challenges that are shared across European healthcare systems, such as limited reimbursement, unequal access to expertise, and insufficient diagnostic capacity, and formulate pragmatic recommendations to address these issues.

CONCLUSIONS: This consensus offers practical guidance for embedding biomarker-based diagnostic strategies into clinical care. By outlining structured pathways and system-level priorities, it facilitates safe, feasible, and equitable implementation of DMTs for AD.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
*Biomarkers/cerebrospinal fluid/blood
Belgium

@article {pmid42538765,
year = {2026},
author = {Sun, H and Huang, D and Yang, F and Zhang, P and Yang, D and Zeng, C},
title = {Metabolomic Discoveries for Traditional Chinese Medicine Efficacy in Alzheimer's Disease.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {e2455800},
pmid = {42538765},
issn = {2314-6141},
support = {2023008//Scientific Research Projects of Medical and Health Institutions of Longhua District, Shenzhen/ ; 82270940//The National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Medicine, Chinese Traditional/methods ; *Metabolomics/methods ; *Drugs, Chinese Herbal/therapeutic use ; Animals ; Brain/metabolism ; Metabolic Networks and Pathways/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral alterations. However, the complex etiology and pathogenesis of AD have thus far precluded the development of satisfactory therapeutic agents. Traditional Chinese medicine (TCM) has garnered increasing recognition for its potential in AD management due to its multicomponent, multitarget therapeutic strategy. Metabolomics, an advanced analytical methodology for investigating metabolic alterations in biological systems, has yielded significant insights into both the therapeutic efficacy and mechanistic underpinnings of TCM interventions for AD. This review synthesizes recent metabolomic findings associated with TCM approaches to AD treatment, identifying key metabolic pathways across diverse biological specimens, including brain tissue, blood, urine, and feces. Through systematic elucidation of these metabolic networks, metabolomics offers substantial potential to facilitate the advancement of TCM-derived therapeutics for AD, potentially enhancing global patient outcomes.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
*Medicine, Chinese Traditional/methods
*Metabolomics/methods
*Drugs, Chinese Herbal/therapeutic use
Animals
Brain/metabolism
Metabolic Networks and Pathways/drug effects

@article {pmid42538866,
year = {2026},
author = {Jiang, Y and Yang, T},
title = {In APP/PS-1 Transgenic Mice and Aβ-Induced P12 Cell Models, ADCYAP1 Inhibits Neuronal Apoptosis and Autophagy, Thereby Alleviating The Pathology of Alzheimer's Disease.},
journal = {Cell journal},
volume = {28},
number = {1},
pages = {1-13},
doi = {10.22074/cellj.2026.2045830.1718},
pmid = {42538866},
issn = {2228-5814},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly. ADCYAP1 encodes pituitary adenylate cyclase activating polypeptide (PACAP), which can exert neuroprotective effects in neurodegenerative diseases. This study aims to probe the specific function of ADCYAP1 in AD.

MATERIALS AND METHODS: In this experimental study, brain tissue samples from AD patients and healthy controls were collected to assess ADCYAP1 expression. APP/PS-1 transgenic mice were utilised as an AD mouse model along with amyloid beta (Aβ)-induced PC12 cells as an AD cell model. ADCYAP1 expression in the AD mice was determined by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. An IF assay was employed to test Aβ deposition and microtubule-associated protein 2 (MAP2) expression (a neuron marker). Behavioural tests, including the Morris water maze (MWM) and footprint tests, were performed to evaluate cognitive impairment and motor ability. Cell apoptosis was determined using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labelling (TUNEL) assay. Western blot was utilised to test the expression of autophagy-related genes, including LC3 and beclin1. The expressions of transcription factors involved in neuronal differentiation was assessed by RTqPCR.

RESULTS: ADCYAP1 expression was significantly downregulated in the brain tissues of AD patients and mice. ADCYAP1 overexpression reduced Aβ deposition and enhanced MAP2 expression in the AD mice. ADCYAP1 overexpression effectively improved cognitive impairment and mobility decline in the AD mice. ADCYAP1 upregulation inhibited neuronal apoptosis and autophagy both in vivo and in vitro. ADCYAP1 upregulated the expression of neuronal differentiationrelated factors [transforming growth factor β (TGFβ), early growth response 1 (Egr1), brain-derived neurotrophic factor (BDNF), fibroblast growth factor 21 (FGF21), and insulin-like growth factor 1 (Igf1)] in the AD models.

CONCLUSION: ADCYAP1 inhibits neuronal apoptosis and autophagy to improve AD progression in APP/PS-1 mice and Aβ-induced P12 cells.},
}

@article {pmid42538916,
year = {2026},
author = {Villalba-Moreno, JL and El-Amri, Y and Kim, KY and Villalba-Moreno, ND and Shafiq, M and Ortiz-Cordero, C and Wang, S and Ossa, JA and Suarez-Uribe, I and Cardona-Madrigal, D and Villegas, A and Glatzel, M and Krasemann, S and Posada-Duque, R and Kiessling, LL and Lopera, F and Arboleda-Velasquez, J and Kalaria, R and Ellisman, M and Sepulveda-Falla, D},
title = {Astrocyte-driven small vessel disease is an early, amyloid-independent feature of PSEN1 E280A familial Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.17.739026},
pmid = {42538916},
issn = {2692-8205},
abstract = {Cerebral Small vessel disease (cSVD) is a prevalent feature of Alzheimer's disease (AD) pathology. Whether this pathology is a late consequence of amyloid and tau accumulation or an early, direct effect of PSEN1 dysfunction has remained unresolved. We found that it is more severe in familial AD (FAD) caused by E280A mutation in presenilin 1 (PSEN1). These cases present with a distinctive proteomic signature, associated with pathological features, more dysregulated in the occipital cortex (OC) compared to the frontal cortex (FC), and characterized by multiple dysregulated proteins involved in extracellular matrix (ECM) and RNA-associated processes. This proteomic fingerprint was associated with abnormal collagen build up, ECM disorganization, and signatures of aberrant angiogenesis. Six months old transgenic knock-in mice homozygous for Psen1 E280A mutation (PSEN1Ki) also showed a similar phenotype with microvascular tortuosity and proteomic changes. Critically, these mice develop neither Aβ plaques nor tau tangles, indicating that the shared microvascular and RNA-associated changes are direct consequences of PSEN1 dysfunction rather than downstream effects of amyloid pathology. Remarkably, dysregulated RNA-associated protein networks overlapped between FAD and PSEN1Ki mice. Cerebral microvessels microstructure in PSEN1Ki mice at two months and six months showed abnormal astrocytic end-feet with lamellar deposits implicating blood-brain barrier damage. Finally, single nuclei transcriptomic analysis of AD patients and controls showed similar abnormal astrocytes in both sporadic and familial variants, but FAD astrocytes expressed dysregulated genes identified in the proteomic analyses, such as GLUL, APOE, and CLU. Our findings suggest that cSVD is an early pathological event in PSEN1 FAD and that is driven by abnormal RNA-associated processes and astrocytic dysfunction.},
}

@article {pmid42538997,
year = {2026},
author = {Krunic, A and Umesh Ganesh, N and Coskun, U and Brennan, W and Patel, C and Joshi, O and Lee, J and Gu, TS and Caruso, J and O'Connell, A and Lisboa, C and Crossland, N and Kurkela, M and Julia, T and Fowler, A and Tay, TL and Fischer, A and Delalle, I and Blusztajn, JK and Mellott, TJ},
title = {MicroRNA-223 Enhances Microglia-Dependent Clearance of Amyloid Beta Plaques and Ameliorates Behavioral Deficits in a Mouse Model of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.20.738977},
pmid = {42538997},
issn = {2692-8205},
abstract = {The Alzheimer's disease (AD) brain is characterized by dysregulated expression of multiple microRNAs (miRNA), positioning them as promising diagnostic and therapeutic targets. The levels of glia-enriched miR-223 are abnormal in the brains and plasma of AD patients and miR-223 is neuroprotective in models of stroke. However, whether miR-223 can be beneficial in AD is not known. Here, we report that intracerebroventricular (ICV) injection of miR-223 oligonucleotide mimic alleviated cognitive impairment, reduced amyloid beta (Aβ) pathology, and ameliorated the defects in synaptic marker expression in App [NL-G-F] AD model mice. Mechanistically, miR-223 induced microglial clustering around Aβ plaques with a concomitant upregulation of microglial phagocytic receptors AXL, TREM2 and CD11c, while pharmacological microglial depletion abolished the plaque-clearance phenotype. Moreover, in human iPSC-derived microglia miR-223 directly targeted multiple genes in the endo-lysosomal pathway, including AD risk gene SPPL2A , indicating that it acts as a major regulator of microglial phenotype. Lastly, long-term AAV-mediated overexpression of miR-223 recapitulates its beneficial effects on cognition, pathology, and synaptic marker expression. Our study demonstrates a novel approach for the treatment of AD using miR-223 and highlights the potential of RNAi-based therapeutics in neurodegenerative disease.},
}

@article {pmid42539005,
year = {2026},
author = {DeLong, LN and Salimi, Y and Balabin, H and Galdi, P and Fleuriot, JD and Brennan, P and , },
title = {Encoding Discordance in the Alzheimer's Disease A/T/N Framework.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.19.26358425},
pmid = {42539005},
abstract = {INTRODUCTION: The biomarker-based amyloid/ tau/ neurodegeneration (A/T/N) framework has become a popular staging method for Alzheimer's disease (AD) research. Previous studies use the framework either as a rule-based or data-driven approach but typically sacrifice either adaptivity or interpretability.

METHODS: We present an interpretable, hybrid method, called Neurosymodal Data Fusion, for predicting incident AD in the ADNI dataset. Specifically, we encode the A/T/N framework as a logic program, where the input biomarker features are extracted by one or more neural networks.

RESULTS: Our pipeline predicted four-year incident AD with a sensitivity of up to 0.84. Additionally, our models learned scores for each A/T/N profile, denoting relative importances to model predictions. These scores also indicated that empirically-derived cut-off values for the A and T criteria might be uninformative for the ADNI data.

DISCUSSION: Our pipeline provides a novel way to use the A/T/N framework that could potentially improve early AD screening years before clinical manifestations.},
}

@article {pmid42539013,
year = {2026},
author = {Stark, D and Shin, H and Münster, N and Federmann, L and Ritter, K and , },
title = {What Do Persistent Misclassifications Tell Us About Alzheimer's Disease Detection using Structural MRI?.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.17.26358326},
pmid = {42539013},
abstract = {Deep learning classifiers applied to structural MRI (sMRI) have achieved high performance in detecting Alzheimer's Disease (AD), yet systematic investigation of their failure modes remains limited. In this study, we trained two deep learning architectures to classify AD from cognitively normal (CN) participants using sMRI data from the ADNI dataset, and examined whether misclassifications persist across models and training configurations. We identified a subgroup of subjects who were persistently misclassified across 100 model instances, and found that these subjects exhibited a markedly different atrophy subtype distribution compared to correctly classified AD cases, with substantial enrichment of hippocampal-sparing and minimal atrophy subtypes. To disentangle whether persistent false negatives (FN) reflect earlier disease stage or atypically presenting disease, we analyzed longitudinal follow-up scans and tested whether model predictions changed as neurodegeneration progressed. A change in prediction (from FN to true positive (TP)) was observed in only a subgroup of subjects and required intervals of up to five years, suggesting that persistent misclassification may not always be explained by disease staging alone. Although the sample size is small, these findings underscore the importance of accounting for disease heterogeneity in the development and evaluation of clinical AI models for AD detection.},
}

@article {pmid42539024,
year = {2026},
author = {Yang, C and Cook, N and Zeng, Y and Fu, T and Budde, J and Cruchaga, C and Belloy, ME},
title = {LocusBlend: Flexible multi-index regional visualization of genomic association signals.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42539024},
abstract = {SUMMARY: It has become standard practice to visualize regional signals from genome-wide association studies (GWAS) using LocusZoom plots. Similarly, GWAS signals are compared to regionally matched quantitative trait loci (QTLs), i.e. variant-to-gene regulation data, using LocusCompare plots to aid assessment of candidate trait-related genes. Despite broad usage, these tools annotate variants by linkage disequilibrium (LD) to a single lead or index variant. This single-index representation has limitations for visualizing complex loci that contain multiple independent signals. We present LocusBlend, an interactive web application for multi-index LD-blended visualization of genomic loci. LocusBlend supports one or two genomic association summary-statistic datasets and one to three index variants, multi-index LocusZoom color-blended plots, and matching LocusCompare visualizations. Applications to Alzheimer's disease GWAS and QTL signals illustrate LocusBlend enables visualization and separation of independent signals despite shared LD and high genomic complexity. Overall, LocusBlend is aimed at supporting researchers handle the continuously expanding complexity of human genomics findings.

LocusBlend is freely available at https://locusblend.wustl.edu . Publication ready plots are generated in <1min. Source code, documentation, example datasets, input templates, and reproducibility instructions are available at https://github.com/Belloy-Lab/LocusBlend . LocusBlend is implemented in Python using Streamlit, Plotly, and PLINK.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}

@article {pmid42539043,
year = {2026},
author = {Krogsaeter, EK and McKetney, J and Li, L and Liu, I and Richards, AL and Subramanyam, V and Yin, K and Gordon, M and Belio Mairal, P and Stevenson, EJ and Qian, H and Huang, Y and Goodarzi, H and Krogan, NJ and Swaney, DL},
title = {APOE4 disrupts the central dogma by arresting neuronal proteome dynamics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.15.738801},
pmid = {42539043},
issn = {2692-8205},
abstract = {Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease and promotes neuronal dysfunction through incompletely understood mechanisms. Here, we integrated transcriptomic, translatomic, and proteomic profiling of isogenic APOE3 and APOE4 human iPSC-derived neurons and found that APOE4 fundamentally impairs neuronal proteome renewal. Although transcriptional changes were modest, APOE4 disrupted ribosome occupancy, altered translational dynamics, and uncoupled protein abundance from transcript levels. Proteome-wide turnover measurements revealed a global extension of protein half-lives and widespread accumulation of long-lived proteins. Functional proteomic analyses demonstrated concurrent lysosomal and proteasomal impairments associated with reduced proteasome activity and increased association of APOE with neuronal proteasomes. Longitudinal proteomics further showed that protein accumulation emerges during neuronal maturation and precedes a senescence-like cellular stress state. Together, these findings identify impaired proteome renewal as a central mechanism underlying neuronal vulnerability to APOE4 and establish defective proteostasis as an early pathogenic event in Alzheimer's disease.},
}

@article {pmid42539046,
year = {2026},
author = {Wang, H and Matei, E and Dou, J and Morgan, RK and Colacino, J and Bakulski, KM},
title = {Cell composition, transcriptomic, and functional pathway changes in the hippocampus in Alzheimer's disease and overlap with lead (Pb) exposure signatures.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.21.26358590},
pmid = {42539046},
abstract = {BACKGROUND: Lead (Pb) is associated with Alzheimer's disease (AD); however, the relationships between Pb and AD hippocampal transcription remains unclear. We evaluated overlap between Pb-response signatures and cell-type-independent AD transcriptomic signatures.

METHOD: Three toxicology studies (two neuronal cell lines, one mouse hippocampus) provided Pb-response genes. Five human postmortem hippocampal AD case-control transcriptional datasets (n=90 AD, n=106 normal cognition) were cell type deconvoluted and tested with beta regression. Differential gene expression, adjusted for age, sex, and estimated cell-types, were meta-analyzed. Overlapping Pb and AD genes and biological pathways were identified (p adj <0.05).

RESULTS: Consistent Pb response was observed at 25 genes (INPP5F , KIF20B , KIFC1) and 47 pathways (ensheathment of neurons, glial cell differentiation, regulation of nervous system processes). Relative to controls, AD samples had fewer neurons (-2.46%), greater microglia (0.42%), astrocytes (0.31%), oligodendrocytes (0.46%), and endothelial cells (0.95%), and 1,455 differentially expressed genes, which were enriched for cellular energy production and metabolism pathways. Six genes (EHD3 , LAP3 , NRXN3 , PPP1R16B , RPL29 , THRA) and four pathways (synaptic vesicle maturation, vesicle docking) overlapped between Pb and AD.

CONCLUSION: We identified overlapping Pb and AD transcriptomic signatures and pathways, providing molecular context for epidemiologic associations.},
}

@article {pmid42539058,
year = {2026},
author = {Bos, L and van Nederpelt, DR and Cole, JH and Jasperse, B and Meije Wink, A and Tranfa, M and Strijbis, E and Killestein, J and Uitdehaag, BMJ and Barkhof, F and Vrenken, H and Schoonheim, MM and Pontillo, G},
title = {The value of brain age as a transdiagnostic biomarker of neurodegeneration.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.21.26358569},
pmid = {42539058},
abstract = {Progressive structural brain changes are a hallmark of neurodegenerative conditions like Alzheimer's disease (AD), frontotemporal dementia (FTD), multiple sclerosis (MS), and Parkinson's disease (PD). The brain-predicted age difference (brain-PAD) has emerged as a promising biomarker to quantify these alterations, yet its unique clinical contribution relative to conventional measures of global brain atrophy such as the brain parenchymal fraction (BPF) remains underexplored. In this transdiagnostic study across AD, FTD, MS, and PD, we systematically evaluated brain-PAD's capacity to distinguish patients from controls, its cross-sectional and longitudinal associations with cognition, and its voxel-wise structural correlates. We benchmarked brain-PAD against BPF to determine its added explanatory value. Brain-PAD successfully distinguished patients from controls, adding to BPF alone, in AD, FTD, and MS, but not PD. Across disorders, higher brain-PAD correlated with worse cognition, showing clear added value beyond BPF particularly in AD and MS. Baseline brain-PAD also independently predicted subsequent cognitive changes in AD, FTD, and MS, over and above BPF. Voxel-wise analyses revealed spatial features underlying brain-PAD including, beyond global tissue loss, specific regional atrophy matching each disease's characteristic pattern. Collectively, these findings demonstrate that brain-PAD is a clinically meaningful, transdiagnostic biomarker of neurodegeneration that complements conventional volumetric measures like the BPF.},
}

@article {pmid42539062,
year = {2026},
author = {Ambaw, Y and Nana, A and Li, Z and Singh, S and Monetti, M and Miller, B and Spina, S and Grinberg, L and Seeley, W and Walther, T and Farese, R},
title = {Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10305293/v1},
pmid = {42539062},
issn = {2693-5015},
abstract = {Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick's disease, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.},
}

@article {pmid42539070,
year = {2026},
author = {Doherty, LK and Dechiario, I and Sherif, H and Bowers, A and Martinez, D and Sanchez, DL and Febres, GJ and Carmichael, O and Shah, V and Nadkarni, NK and Goldberg, TE and Noble, J and Luchsinger, JA and Temprosa, M and , },
title = {Implementing the National Alzheimer's Coordinating Center Uniform Data Set (v3) within the Diabetes Prevention Program Outcomes Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.17.26357765},
pmid = {42539070},
abstract = {INTRODUCTION: The Diabetes Prevention Program (DPP) was a randomized clinical trial designed to prevent type 2 diabetes (T2D) in adults with prediabetes. The DPP Outcomes Study (DPPOS) is the 30-year follow-up of this cohort, focusing on T2D, prediabetes, and related complications. Cognitive assessments began in 2009 and expanded in 2022 to examine cognitive impairment, including Alzheimer's disease (AD) and AD related dementias (ADRD), in the surviving cohort. To support these aims, the National Alzheimer's Coordinating Center Uniform Data Set version 3 (NACC-UDSv3), the standardized framework used by Alzheimer's Disease Research Centers, was implemented in DPPOS in 2022 to enable data sharing with NACC. These forms were complemented by cognitive tests administered in DPPOS. We aimed to integrate the NACC-UDSv3 into the existing longitudinal DPPOS framework while maintaining fidelity to its structure and developing automated reports to streamline cognitive outcomes adjudication.

METHODS: Items from the 16 NACC-UDSv3 data forms were compared with those already collected within DPPOS to integrate overlapping similar items, add missing NACC-UDSv3 items, and create a dataset harmonized with NACC-UDSv3. Forms were adapted for electronic data capture (EDC) using the MIDAS (Multimodal Integrated Data Acquisition System, George Washington University). Automated reports integrated current and prior neuropsychological scores to support adjudications. In the first wave of the DPPOS-AD/ADRD study, 1561 cognitive adjudications were successfully completed using the harmonized DPPOS and NACC-UDSv3 data implemented into MIDAS.

DISCUSSION: The DPPOS-AD/ADRD project demonstrated that NACC-UDSv3 can be successfully integrated into a long-standing longitudinal cohort not originally designed for AD/ADRD research. The harmonization, electronic capture, and automated adjudication processes may provide a practical framework for other cohorts seeking to incorporate NACC-UDSv3 to align with national AD/ADRD research standards.},
}

@article {pmid42539099,
year = {2026},
author = {Rabin, J and Alexander, MW and Nyman, A and Casaletto, K and Saloner, R and Vandeloo, K and Splinter, T and Swardfager, W and Ottoy, J and Masellis, M and Galea, L and Black, S and Einstein, G and Denkinger, M and Ashton, N and Caldwell, J and Johnson, S and Arvanitakis, Z},
title = {Age at menopause, APOE-ε4, and Alzheimer's disease risk.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10121551/v1},
pmid = {42539099},
issn = {2693-5015},
abstract = {Importance: APOE-ε4 is an established risk factor for Alzheimer's disease (AD) and confers greater risk in women than in men. Earlier age at menopause also increases AD risk in women. Yet whether menopause timing influences APOE-ε4 -related AD risk remains unclear. Objective: To examine whether age at menopause modifies the association of APOE-ε4 with AD risk. Design, setting and participants: Data were analyzed from postmenopausal women free from known dementia at study entry in two longitudinal datasets: (1) the harmonized data from the Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS), and (2) the Wisconsin Registry for Alzheimer's Prevention (WRAP). Data were collected between 1994-2025. Main outcomes and measures: In both datasets, neuropsychological tests assessed longitudinal memory performance, and MRI quantified cortical thickness and brain volume in AD vulnerable regions. In WRAP, which included in vivo AD biomarkers, AD pathology was assessed using longitudinal plasma p-tau217 and cross-sectional beta-amyloid (Aβ) PET. Menopause history was self-reported, and APOE status was classified as ε4 carrier vs. non-carrier. Linear mixed-effects or linear regression models were used, as appropriate, to test interactions between APOE-ε4 carrier status and age at menopause on memory decline, brain atrophy, p-tau217 accumulation, and Aβ-PET burden, adjusting for relevant covariates. Results: The study included 2,625 women in ROS/MAP/MARS (mean [ SD ] age=77.4 [7.77], mean [SD] age at menopause=47.9 [7.10]) and 512 women in WRAP (mean [SD] age=60.2 [5.57], mean [SD] age at menopause=50.1 [6.29]). In both datasets, earlier age at menopause strengthened associations of APOE-ε4 with memory decline (ROS/MAP/MARS: β=0.068, p =.02; WRAP: β=0.092, p =.03) and MRI measures of brain atrophy (ROS/MAP/MARS: β=0.071, p =.05; WRAP: β=0.256, p =.03). In WRAP, earlier menopause also amplified associations of APOE-ε4 with p-tau217 accumulation (β=-0.029, p =.05) and global Aβ-PET burden (β=-0.146, p =.01). Conclusions and relevance: Earlier menopause strengthened the associations between APOE -ε4 and key AD outcomes. These findings suggest that menopause timing may influence APOE -ε4-related susceptibility to AD, highlighting midlife endocrine processes as potential targets for prevention in women.},
}

@article {pmid42539115,
year = {2026},
author = {Tewolde, S and Rosellini, AJ and Michals, A and Skotko, BG and Fortea, J and Khor, B and Handelman, S and Rubenstein, E},
title = {Death in People with Down syndrome: Mortality statistics and novel predictors in US Medicaid and Medicare enrolled adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.17.26358090},
pmid = {42539115},
abstract = {People with Down syndrome have higher age-specific mortality rates compared to the general population as well as peers with other intellectual and developmental disabilities. While a large proportion of mortality is attributable to Alzheimer's disease, many die prior to Alzheimer's diagnosis and some live to old ages, dying without Alzheimer's. Our objectives were to use 11 years of Medicaid and Medicare data to describe characteristics and factors related to death in adults with Down syndrome and use machine learning to identify which conditions most strongly predict death in the full population and stratified by age. We identified death using Center for Medicare and Medicaid Systems reported date of death health conditions using ICD 9 and 10 codes. We used a case-control design with risk set sampling to have that controls to mimic the distribution of times of incident Alzheimer's disease. We trained gradient boosted trees to identify strongest predictors. Our cohort included 137,293 adults with Down syndrome. Among those, 30,894 (22.5%) died during the study period. Mean age at death among those who died was 55 years (SD=10). Mean age of death in those with Alzheimer's disease was 59 (SD=7) and those without was 52 (SD=12). The most influential predictors of mortality were any claim for dementia, any claim for pneumonia, re-occurring claim for cardiovascular disease three years before index death, and any claim for heart failure and epilepsy. Our results align with previous clinical work and highlight intervenable areas to reduce mortality in the Down syndrome population.},
}

@article {pmid42539145,
year = {2026},
author = {Brown, K and Storey, B and Williams, J and Simet, D and Umar, MB and Madsen, E and Shan, Z and Bi, L},
title = {Spatial MALDI-MSI Reveals a Coordinated Vicious Cycle of Oxidative Membrane Damage and Ceramide-Driven Sphingolipid Dysregulation in the Chronically Neuroinflamed Brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.14.738110},
pmid = {42539145},
issn = {2692-8205},
abstract = {BACKGROUND: Chronic neuroinflammation is a major driver of cognitive decline, vascular cognitive impairment, and Alzheimer's disease. However, the spatial lipidomic alterations underlying neuroinflammatory brain injury remain poorly defined. Oxidative stress and sphingolipid dysregulation have been implicated, but their regional distribution and interplay in the brain are not well characterized.

METHODS: We performed positive-ion mode matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) on coronal brain sections from middle-aged spontaneously hypertensive rats (SHR), a model of chronic neuroinflammation, and normotensive Wistar-Kyoto (WKY) controls. Spatial distributions and relative abundances of multiple lipid classes, including phosphatidylcholines (PCs), sphingomyelins (SMs), hexosylceramides (HexCers), ceramides, phosphatidylserines (PSs), phosphatidylinositols (PIs), phosphatidylethanolamines (PEs), phosphatidic acids (PAs), and sulfatides, were mapped and compared between genotypes. Region-of-interest analysis was used to quantify changes across cortex, hippocampus, and white-matter tracts.

RESULTS: SHR brains exhibited a coordinated lipidomic signature characterized by pronounced oxidative stress and membrane remodeling. Oxidized and short-chain PCs were markedly upregulated (up to 11.6-fold), while major structural diacyl PCs were broadly downregulated. Concurrently, sphingolipids were significantly altered, with robust upregulation of SM(d36:1) (7.5-fold) and multiple HexCer species (1.5-1.9-fold), accompanied by accumulation of ceramides. These changes were accompanied by heterogeneous redistribution of PS, PI, and PE species, particularly within the hippocampus. Sulfatide patterns in white-matter tracts were also altered, suggesting myelin remodeling. Region-of-interest analysis confirmed that the most pronounced lipid alterations were concentrated in the hippocampus and white-matter regions.

CONCLUSIONS: Chronic neuroinflammation induces a spatially organized, multi-class lipid remodeling response in the brain, driven by advanced oxidative membrane damage and a shift toward a pro-apoptotic sphingolipid profile. The convergence of these pathways creates a vicious cycle of membrane injury, mitochondrial dysfunction, and sustained neuroinflammation that is especially prominent in the hippocampus and white matter. These spatially resolved findings provide direct evidence that oxidative stress and sphingolipid dysregulation are central, interrelated mechanisms contributing to neurovascular injury and increased risk of cognitive impairment. The study highlights the power of MALDI-MSI to uncover region-specific lipid pathology and identifies potential lipid-based targets for therapeutic intervention in neuroinflammatory brain disease.},
}

@article {pmid42539244,
year = {2026},
author = {Wagle, MM and Wang, Y and Samanta, S and Liu, Z and Patrick, E and Yang, P and Kellis, M},
title = {Deep interpretable learning of sample representations for characterizing disease states in single-cell transcriptomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.21.738207},
pmid = {42539244},
issn = {2692-8205},
abstract = {Single-cell transcriptomics technology offers unprecedented insights into molecular heterogeneity. However, capturing sample-level representations that reflect both systemic and cellular states remains challenging, especially when disease annotations are mostly available as coarse sample-level labels. Here, we introduce Phenoverse, an interpretable deep learning framework that learns sample-level disease state representations through cell type-aware residual encoding, prototype learning, and Perceiver-based aggregation. Applied to independent single-cell transcriptomic cohorts of COVID-19, Alzheimer's disease, and systemic lupus erythematosus, totaling over 5 million cells, we demonstrate that learned sample representations enable disease state prediction and encode a continuous spectrum of disease severity on unseen data that correlate with multiple clinical and pathological measures, despite being trained solely on binary phenotype labels. Further, we demonstrate that trajectory-derived genes reveal cross-cohort molecular programs and show consistently higher reproducibility than traditional case-control comparisons. Finally, prototype learning provides intrinsic model interpretability and enables the characterization of cell type-specific disease states. Taken together, Phenoverse offers an interpretable disease-phenotyping approach to dissecting sample heterogeneity, and our results highlight its utility in translating complex single-cell transcriptomic data into patient-level biological insights.},
}

@article {pmid42539274,
year = {2026},
author = {Javid, S and Nir, TM and Zhu, AH and Bhatt, RR and Aksman, LM and Jahanshad, N and , },
title = {FastEBM: Fast, Scalable, and Uncertainty-Aware Event-Based Disease Progression Modeling.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.18.739221},
pmid = {42539274},
issn = {2692-8205},
abstract = {Event-based models (EBMs) are used to infer ordering of biomarker alteration patterns with respect to disease progression. However, EBM approaches rely on computationally expensive permutation-based inference, assumptions of feature independence, and likelihood optimization that can limit scalability and stability in high-dimensional settings. Here, we introduce Fast Event-Based Model (FastEBM), a scalable, uncertainty aware, Markov- chain-based framework that reformulates disease progression inference as a subject-ordering problem on a data-driven diffusion manifold. The progression uncertainty, used to derive positional variance diagrams, is quantified using first-passage-time variability derived directly from the inferred Markov process. Using synthetic experiments varying feature dimensionality, cohort size, noise level, and feature-correlation structure, we compared FastEBM with established methods, including Gaussian mixture model EBM (GMM-EBM), kernel density estimation EBM (KDE-EBM), and discriminative EBM (DEBM). FastEBM achieved the best accuracy and runtime. In low-subject/high-dimensional stress tests, FastEBM retained event-order recovery. FastEBM remained robust in simulations containing correlated and redundant features after decorrelation and feature-group handling. We applied FastEBM to real-world data to characterize biomarker progression in Alzheimer's disease. First, we evaluated a low-dimensional multi- modal dataset from The Alzheimer's Disease Prediction Of Longitudinal Evolution (TAD- POLE) challenge. Second, to demonstrate high-dimensional disease progression mapping, we applied FastEBM to regional cortical tau-PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In both cases, FastEBM recovered progression patterns broadly consistent with the literature, also revealing lateralized progression trends. These results show that diffusion-based Markov geometry provides a scalable and robust alternative to conventional event-based modeling. FastEBM is available at: https://github.com/sjusc07/FastEBM .},
}

@article {pmid42539283,
year = {2026},
author = {Chattopadhyay, T and Shelar, K and Thomopoulos, S and Thompson, PM},
title = {When does more data help? Spectral Geometry and Scaling Laws in MRI Transformers.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.14.738571},
pmid = {42539283},
issn = {2692-8205},
abstract = {Scaling laws describe how model performance improves as the amount of training data increases, and recent theories such as the zeta law suggest that scaling behavior is influenced by the eigenspectrum of the model's latent representation. Here, we evaluated whether the distribution of discriminative signals across spectral modes predicts the future scaling behavior, for MRI transformers trained for disease classification. We trained three supervised 3D vision transformers (ViT3D, MINiT, and NIT) for Alzheimer's disease classification using 2,822 training scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI); we compared their encoder spectra with that of a frozen self-supervised DINO ViT-B/16 encoder adapted to 3D MRI. The supervised models learned highly concentrated representations, with 90-96% of CLS-token variance captured by a single principal component, whereas DINO distributed signal across many latent directions. Via spectral expansion of the Mahalanobis signal, we found that supervised training concentrated disease information into a single dominant mode, while self-supervised training produced a richer spectral geometry with higher effective rank and discoverability. This led to different scaling behavior: supervised models exhibited flatter AUC(N) curves, yet DINO continued to improve as sample size increased, gaining 11.0 percentage points from N=50 to N=2,822. Overall, the spectral distribution of the discriminative signal, for these different encoder types, influenced how much performance remained discoverable as sample size increased. Distributed representations may retain signal across many latent modes and continue to improve with additional data, whereas concentrated representations tend to exhaust most of the discoverable signal at much lower sample sizes.},
}

@article {pmid42539361,
year = {2026},
author = {Srikanth, M and Jiang, S and Wellman, SM and Sarkar, S and Lorman, DE and Lantin, T and Runyan, AM and Kumar, M and Sydney, E and Figueroa, HY and Yang, M and Wang, Q and Myeku, N},
title = {Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.14.738427},
pmid = {42539361},
issn = {2692-8205},
abstract = {Immunoproteasome induction is prominent in Alzheimer's disease (AD), but whether it protects proteostasis or amplifies neuroinflammation remains unresolved. Here, we generated immunoproteasome-deficient PS19 tauopathy and APP/human tau double-knock-in mice by crossing each disease model with L7M1 mice lacking two immunoproteasome catalytic subunits. Immunoproteasome deficiency increased phospho-tau burden, exacerbated amyloid-β pathology and heightened microglial reactivity without suppressing constitutive 26S proteasome activity. In primary microglia and longitudinal two-photon imaging, immunoproteasome-deficient microglia engaged and engulfed tau aggregate-bearing material but failed to resolve internalized cargo, revealing a post-engulfment degradative checkpoint. Single-nucleus transcriptomics identified a remodeled P2ry12 [low] /Trem2 [high] microglial state with impaired phagolysosomal and mitochondrial programs. Reanalysis of human single-nucleus transcriptomic datasets showed that reduced microglial immunoproteasome expression was associated with cargo-processing gene-program changes similar to those observed in immunoproteasome-deficient mouse microglia. Together, these findings identify immunoproteasome biogenesis as a protective glial stress response that supports microglial aggregate clearance in AD.},
}

@article {pmid42539398,
year = {2026},
author = {Liu, L and Chen, X and Zeng, Q and Zhou, S and Zhang, X},
title = {An edge-aware salient context fusion and refinement network for hippocampal segmentation in MR images and its diagnostic value for mild cognitive impairment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1899123},
doi = {10.3389/fneur.2026.1899123},
pmid = {42539398},
issn = {1664-2295},
abstract = {BACKGROUND: Accurate assessment of hippocampal volume is of significant clinical value for the early diagnosis and disease monitoring of Alzheimer's disease (AD). However, automatic segmentation of the hippocampus in MR images remains challenging due to its elongated and irregular morphology, blurred boundaries, low contrast with surrounding tissues, and substantial inter-individual anatomical variability.

METHODS: We propose an Edge-aware Salient Context Fusion Refinement Network (ESCFR-Net). Built upon a classic U-shaped encoder-decoder architecture, the proposed network employs a Salient Feature Enhancer to suppress background interference and enhance weak feature responses of the hippocampus. A Global Channel Context Attention (GCCA) module is introduced to model long-range spatial dependencies, while a Multi-scale Context Fusion Refinement Module (MCFRM) improves the utilization of multi-scale features. Furthermore, an Edge-Guided Refinement Attention (EGRA) module synergistically enhances edge and semantic features to precisely delineate weak boundaries.

RESULTS: Experimental results on a self-constructed dataset comprising 225 3D-T1 MRI scans demonstrate that ESCFR-Net achieves a Dice coefficient of 0.9004, outperforming state-of-the-art methods such as SwinUNETR and PMFS-Net. Clinical association analysis, conducted on 91 healthy controls (HCs) and 91 patients with mild cognitive impairment (MCI), reveals that bilateral hippocampal volumes in MCI group are significantly smaller than those in HCs (p < 0.001). Additionally, the total hippocampal volume achieves an area under the curve (AUC) of 0.927 in distinguishing HCs from patients with MCI, with sensitivity and specificity reaching 90.11 and 83.52%, respectively.

CONCLUSION: This study provides a highly accurate and robust automated hippocampal segmentation tool for early diagnosis, disease monitoring, and clinical decision-making in Alzheimer's disease.},
}

@article {pmid42539584,
year = {2026},
author = {Lo, H and Li, S and Chen, J and Zhou, Q and Qiu, Y and Ma, S and Yu, B and Gu, T and Nie, L},
title = {Multispectral photoacoustic microscopy and NIR-II fluorescence imaging of TREM2-positive microglia in Aβ-driven Alzheimer's pathogenesis.},
journal = {Fundamental research},
volume = {6},
number = {4},
pages = {2235-2249},
doi = {10.1016/j.fmre.2026.04.016},
pmid = {42539584},
issn = {2667-3258},
abstract = {Monitoring microglial activation mediators remains challenging in neurodegeneration. Few imaging studies track amyloid-β (Aβ)-linked microglial dynamics across a wide field of view with high spatiotemporal resolution. Leveraging the triggering receptor expressed on myeloid cells 2 (TREM2), a pivotal Alzheimer's disease (AD) biomarker that enhances Aβ clearance while suppressing neuroinflammation, we developed a dual-modal probe, TREM2-ICG, by conjugating a TREM2-specific antibody with indocyanine green (ICG), an FDA-approved dye, for robust in vivo photoacoustic and near-infrared-II (NIR-II) fluorescence imaging. Multi-wavelength photoacoustic microscopy imaged AD pathology at 532 nm (hemoglobin, vasculature), 559 nm (Aβ probe AOI987), and 780 nm (TREM2-ICG for peri‑plaque microglia). Time-resolved NIR-II imaging (30 frames/sec) tracked Aβ-oligomer-induced microglial displacement at ∼50 µm resolution, showing a rapid chemotaxis phenomenon. Immunofluorescence-verified TREM2-microglia plaque engagement demonstrates AD pathogenesis. Overall, our multiscale photoacoustic-fluorescence imaging resolved cortex-wide Aβ-microglial interactions, combining wide-field, high-speed, and deep-penetration to overcome confocal depth and two-photon field of view limits. This enabled in vivo tracking of microglial responses to Aβ, revealing potential for investigating AD-specific mechanisms.},
}

@article {pmid42539597,
year = {2026},
author = {Varrasi, S and Pulvirenti, A and Catania, V and Palesi, M and Spampinato, C and Patti, D and Tomarchio, O and Micale, G and Simone, A and Passarello, L and Proietto Salanitri, F and Patanè, G and Ravidà, S and Chisari, CG and Zappalà, G and D'Amico, E and Avolio, C and Felicetti, F and Gasperini, C and Rossi, S and Manganotti, P and Busan, P and Rodolico, C and Laudani, R and Marino, R and Villari, M and Patti, F and , and , },
title = {AI-based predictive biomarkers for chronic neurological diseases: the rAIdD prospective, multicenter, observational study protocol.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1885919},
doi = {10.3389/fneur.2026.1885919},
pmid = {42539597},
issn = {1664-2295},
abstract = {BACKGROUND: Chronic neurological disorders such as Multiple Sclerosis (MS), Parkinson's disease (PD), and Alzheimer's Disease (AD) represent a major global health burden characterized by progressive neurodegeneration, functional disability, and cognitive decline. Despite differences in etiology and clinical presentation, these conditions share multifactorial pathophysiological mechanisms influenced by genetic, environmental, and lifestyle-related factors. Advances in artificial intelligence (AI), wearable technologies, and multimodal clinical data integration offer new opportunities for identifying predictive digital biomarkers and improving personalized disease management. The rAIdD project ("eHealth Network: AI and new ICT technology equipment for digital diagnosis") aims to develop an interoperable digital infrastructure to support early diagnosis, monitoring, and risk stratification in chronic neurological diseases. This study protocol describes the neurological component of the rAIdD network focusing on MS, PD, and AD.

METHODS AND ANALYSIS: This prospective, multicenter, observational study involves six Italian academic and clinical centers and will enroll 780 participants: 300 MS, 150 PD, 150 AD, and 180 healthy controls. Participants will be followed for 18 months within a 48-month study period. Standardized clinical, neuropsychological, neuroimaging, and digital assessments will be performed at baseline and at 6-, 12-, and 18-month follow-ups. Clinical evaluation includes disease-specific disability and functional scales, mood and quality-of-life assessments, and lifestyle and environmental risk factor profiling. Continuous digital monitoring will be conducted using wearable sensors to collect biometric and behavioral data, including physical activity, sleep patterns, and cardiovascular parameters. Structural neuroimaging will be acquired longitudinally and integrated with clinical and digital data through a centralized web-based electronic data capture platform. Machine learning approaches will be applied to identify multimodal predictive biomarkers and model disease progression patterns across disorders.

ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of the coordinating center and by local ethics committees of all participating institutions. Written informed consent is obtained from all participants in accordance with the Declaration of Helsinki and the General Data Protection Regulation (GDPR 2016/679). Results will be disseminated through peer-reviewed publications, scientific conferences, and digital communication platforms to support knowledge translation and implementation of precision neurology approaches.},
}

@article {pmid42539626,
year = {2026},
author = {Han, J and Zhao, W and Deng, R and Wang, Y and Gong, W and Wang, Z and Sun, G and Liu, H and Geng, M and Zhang, Y},
title = {Sodium oligomannate reduces cerebral infarction and improves neurological function through microbiota remodeling in MCAO/R rats.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1880590},
doi = {10.3389/fphar.2026.1880590},
pmid = {42539626},
issn = {1663-9812},
abstract = {BACKGROUND: Ischemic stroke is the second leading cause of death worldwide, characterized by high mortality and a narrow therapeutic window for thrombolysis. Gut microbiota dysbiosis and gliosis following ischemic stroke are key drivers of post-stroke neurological impairment. Sodium oligomannate (GV-971) is a low-molecular-weight acidic oligosaccharide that targets the gut-brain axis. It alleviates gliosis and improves cognitive dysfunction by remodeling gut microbiota in Alzheimer's disease. However, it is still unknown whether GV-971 has pharmacological activity against ischemic stroke.

METHODS: Here, we explore the efficacy of GV-971 on infarct volume, gliosis, blood-brain barrier integrity, gut microbiota composition, and post-stroke cognitive impairment (PSCI) using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in male Sprague-Dawley rats.

RESULTS: Administer medication before surgery for 4 consecutive days and once after surgery, after stroke 24-hour triphenyltetrazolium chloride (TTC) staining revealed that 0.3 mg/kg GV-971 significantly reduced infarct volume in ischemic brain tissue from 37.81±2.391% to 13.30±4.801% and neurological impairment score of GV-971 treatment significantly decreased from 11.50±0.54 to 7.29±1.47. After stroke 24-hour immunofluorescence analysis of glial activation confirmed that GV-971 significantly reduced central inflammatory responses. Western blot combined with Evans blue staining collectively demonstrated that after stroke 24-hour, GV-971 exerts a significant protective effect on the blood-brain barrier. In the gut, GV-971 reversed microbial dysbiosis, as revealed by shotgun metagenomics, enhanced intestinal barrier integrity, and suppressed colonic inflammation. Antibiotic depletion abolished GV-971's neuroprotective effect, while fecal microbiota transplantation from GV-971-treated donors restored protection, supporting a microbiota-dependent contribution. Furthermore, GV-971-treated rats subjected to MCAO/R exhibited significant improvements in motor and cognitive function. For example, on day 35, Y-maze test results indicated that GV-971 administered either before MCAO/R (pre-treatment) or during the perioperative period (co-treatment) increased spontaneous alternation rate from 60.95±4.91% to 85.60±6.32% and 85.64±5.027%. On day 32, novel object recognition assay results indicated that GV-971 treatment increased new-object exploration from 0.2039±0.03752 to 0.3991±0.1122 (pre-treatment) and 0.5066±0.06982 (co-treatment). On day 42, Barnes maze test results indicated that GV-971 treatment reduced the time required to locate the target hole from 76.45±17.41s to 31.03±20.75 s and 33.37±19.30 s for pre- and co-treatment, respectively.

CONCLUSION: Taken together, GV-971 demonstrated neuroprotective potential in experimental ischemic stroke.},
}

@article {pmid42539875,
year = {2026},
author = {Luo, Y and Yu, H and Ye, K},
title = {Distinct factors drive the progression of tau pathology in Alzheimer's disease.},
journal = {Fundamental research},
volume = {6},
number = {4},
pages = {2289-2298},
doi = {10.1016/j.fmre.2025.04.001},
pmid = {42539875},
issn = {2667-3258},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia worldwide. The primary histopathological markers for AD diagnosis are extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs), featured by aggregation of hyperphosphorylated and truncated tau proteins. Emerging evidence shows that tau pathology, rather than amyloid-β deposition, exhibits a stronger correlation with brain atrophy and cognitive decline in AD, emphasizing its pivotal role in disease progression. However, the molecular mechanisms of tau propagation in the brain are incompletely understood, and there is no effective therapy to halt tau pathology propagation in AD. In this review, we summarize current knowledge on the multifactorial triggers of tau pathology in AD in the aspects of (1) physiological or pathological driving factors, (2) different types of brain cells and (3) key regulatory proteins that steer tau aggregation and spread. Based on these findings, we also critically evaluate the current and potential therapeutic strategies against tau pathology in AD. Together, this review provides a comprehensive understanding of tau pathology regulation and highlights promising strategies for therapeutic intervention.},
}

@article {pmid42539876,
year = {2026},
author = {Singh, R and Asthana, S and Arya, A and Kaushik, M and Khan, M},
title = {The Oral-Brain Axis: Mechanistic Insights Linking Periodontitis With Alzheimer's and Parkinson's Diseases.},
journal = {Cureus},
volume = {18},
number = {6},
pages = {e111856},
doi = {10.7759/cureus.111856},
pmid = {42539876},
issn = {2168-8184},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are major causes of disability and mortality worldwide. Emerging evidence suggests that chronic peripheral inflammation and microbial dysbiosis may contribute to neurodegenerative processes. The oral-brain axis has recently gained attention as a biological framework linking oral microbial communities, systemic inflammatory responses, immune regulation, and central nervous system function. Within this context, periodontitis, a prevalent chronic inflammatory disease driven by oral dysbiosis, has been proposed as a potential modifiable risk factor for neurodegeneration. This narrative review examines current evidence supporting the oral-brain axis and its role in the relationship between periodontitis and neurodegenerative disorders. Key mechanisms include systemic dissemination of periodontal pathogens and their virulence factors, persistent inflammatory signaling, blood-brain barrier dysfunction, neuroimmune activation, oxidative stress, and protein aggregation. Particular attention is given to the contribution of Porphyromonas gingivalis and associated virulence factors to neuroinflammation, amyloidogenesis, and neuronal injury. Epidemiological, clinical, and experimental studies linking periodontal disease with cognitive decline, Alzheimer's disease, and Parkinson's disease are also discussed. Current evidence supports a biologically plausible association between periodontal disease and neurodegeneration through interconnected microbial, inflammatory, and vascular pathways. Although causality remains to be established, the oral-brain axis provides valuable insight into potential mechanisms underlying this relationship. Improved understanding of these interactions may facilitate the development of preventive and therapeutic strategies that integrate oral healthcare with approaches aimed at preserving neurological health and reducing the burden of neurodegenerative diseases.},
}

@article {pmid42540036,
year = {2026},
author = {Chan, AM and Ng, R and Inderjeeth, C and Nossent, J},
title = {Temporal incidence and impact of dementia in rheumatoid arthritis: a cohort study.},
journal = {EULAR rheumatology open},
volume = {2},
number = {2},
pages = {100159},
doi = {10.1016/j.ero.2026.03.007},
pmid = {42540036},
issn = {3050-7081},
abstract = {OBJECTIVES: The objective of this study is to address conflicting evidence that chronic inflammation may increase the risk of dementia in patients with rheumatoid arthritis (RA).

METHODS: Retrospective population-based study using longitudinally linked administrative health data over a 30-year period for ever hospitalised patients with RA (n = 14,041, age 64 years, 67.2% female) and controls (n = 33,785, age 65 years, 65.6% female). Dementia was defined by the International Classification of Diseases codes for Alzheimer's disease (AD), vascular dementia, and nonspecific dementia subtypes. Dementia incidence rate (IR) and mortality rate (MR) per 1000 person-years and comorbidities are reported.

RESULTS: During 9.6 years of follow-up, 1463 (10.4%) of patients with RA and 3701 (11%) of controls were diagnosed with dementia at respective age of 83 vs 84 years (P = .01). The IR was 12.07 (95% CI: 11.15-12.71) in patients with RA and 11.59 (95% CI: 11.22-11.97) in controls corresponding to an IR ratio of 1.04 (95% CI: 0.98-1.11, P = .21), which did not change significantly over 3 decades. Traditional risk factors for dementia were equal in both groups, but patients with RA with dementia were less likely to be classified as AD (odds ratio = 0.59, 95% CI: 0.48-0.73, P < .001). Hospitalisation rates after dementia diagnosis were higher for patients with RA, and the crude MR (overall 91.8 vs 90.4, P = .64) remained similar before or after 2000 for both groups.

CONCLUSIONS: There was no difference in temporal incidence and MRs for dementia between patients with RA and matched controls. These data suggest that there is minimal impact of RA on the frequency and outcome of dementia.},
}

@article {pmid42540093,
year = {2026},
author = {Floden, AM and Manocha, GD and Frolov, NI and Lerick, AE and Combs, CK},
title = {Comparison of amyloid and tau pathology in the small and large intestines of individuals with Alzheimer's disease, Parkinson's disease, and Dementia with Lewy bodies.},
journal = {microPublication biology},
volume = {2026},
number = {},
pages = {},
doi = {10.17912/micropub.biology.002056},
pmid = {42540093},
issn = {2578-9430},
abstract = {Alzheimer's disease (AD) brains are characterized by accumulations of neurofibrillary tangles and amyloid β (Aβ) plaques. Since enteric neurons express tau and the amyloid precursor protein (APP), we asked whether neurofibrillary tangles and Aβ aggregates were present in AD intestines compared to healthy controls and individuals with Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Neuron-like APP and Aβ immunoreactivities were observed in all groups with no observable plaques. No tangle-like structures were observed in any group although p-Ser 396/404 tau immunoreactivity was seen. The enteric nervous system appears to be protected from developing tangle and plaque pathology in AD.},
}

@article {pmid42540265,
year = {2026},
author = {Taşci, H and Avcı, A and Özenver, N and Sağlık Özkan, BN and Tozkoparan, B and Kelekçi, NG},
title = {Benzoxazolinone-Based Propionyl Thiosemicarbazides as Multi-Target-Directed Ligands for Alzheimer's Disease: Cholinesterase and MAO Inhibition, Docking, and Molecular Dynamics.},
journal = {ACS omega},
volume = {11},
number = {29},
pages = {43129-43156},
doi = {10.1021/acsomega.5c12925},
pmid = {42540265},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) benefits from multitarget-directed ligands (MTDLs) that can enhance cholinergic transmission while attenuating monoamine-oxidase-linked oxidative stress. Here, we report a benzoxazolinone-based propionyl thiosemicarbazide series, synthesized and fully characterized by infrared (IR) spectroscopy, [1]H nuclear magnetic resonance (NMR), and high-resolution mass spectra (HRMS). The compounds showed consistent submicromolar inhibitory activity across AChE, BChE, MAO-A, and MAO-B in vitro. Several AChE potencies approached the reference donepezil, and selected BChE activities were within an order of magnitude of tacrine. Notably, 4bk' (5-Me/benzyl) inhibited three targets (IC50: 0.029 ± 0.001 μM for AChE, IC50: 0.071 ± 0.003 μM for BChE, IC50: 0.048 ± 0.002 μM for MAO-B), and 4af' (5-Cl/phenyl) showed a balanced profile (IC50: 0.025 ± 0.001 μM for AChE, IC50: 0.056 ± 0.002 μM for BChE, IC50: 0.095 ± 0.003 μM for MAO-A), 4ac' (5-Cl/propyl) combined potent AChE and MAO-B inhibition (IC50: 0.035 ± 0.001 μM for AChE, IC50: 0.045 ± 0.002 μM for MAO-B), whereas 4ag' (5-Cl/4'-Cl-phenyl) was strongly MAO-B-selective (IC50: 0.041 ± 0.001 μM for MAO-B). Antioxidant capacity was pronounced for para-substituted analogues. The efficient compounds 4bk', 4af', 4ac', and 4ag' presented quite low toxicity on healthy cells (cell survival % was above %70 for 4bk', 4af', and 4ac', while it was around 64% for 4ag') even when they were applied at 100 times higher concentrations than their IC50 values, which indicates that they are safe at effective doses. Moreover, assessment of the compounds at a concentration of 10 μM demonstrated no cytotoxic effects on either healthy BV-2 microglial cells or H9c2 rat myoblastoma cells. Docking and 100 ns molecular dynamics (MD) simulations (AChE: 4EY7; MAO-B: 2V5Z) supported stable binding for dual-active representatives (RMSD ∼1.5-2.8 Å). In silico ADME (QikProp) indicated compliance with Lipinski's Rule of Five and Jorgensen's Rule of Three. Collectively, this scaffold is tunable from MAO-B-selective to balanced MTDL profiles suitable for further AD-relevant optimization.},
}

@article {pmid42540280,
year = {2026},
author = {Chu, AL and Chu, BSL and Qiang, W},
title = {Molecular Dynamics Simulations of Aβ42 Dimers with Solid-State NMR Restraints Capture the Key Structural Motifs in Aβ42 Fibrillation Pathways.},
journal = {ACS omega},
volume = {11},
number = {29},
pages = {44425-44433},
doi = {10.1021/acsomega.6c05189},
pmid = {42540280},
issn = {2470-1343},
abstract = {Formation of the β-amyloid (Aβ) plaques is a pathological hallmark of Alzheimer's disease (AD) and is believed to be a primary cause of dementia in elderly individuals. In the present work, we performed molecular dynamics (MD) simulations on the conformational evolution of Aβ42 dimers in solution and in a membrane-like environment to explore the folding of Aβ42 during fibrillation. Particularly, the MD simulation was steered by experimental internuclear distance restraints obtained using solid-state nuclear magnetic resonance (ssNMR) spectroscopy. Our results revealed that several hydrophobic and polar motifs within the Aβ42 sequence played key roles in the early-stage nucleation process of fibrillation, and these motifs are also the stabilizing agents in the mature fibrils, as judged by the energy contribution. Our results also indicated that the membrane-binding of small Aβ oligomers could modulate their structural evolution pathways toward fibrillation. These findings contributed to a better understanding of the molecular-level structural polymorphisms inherent to Aβ42 fibrils. Further, the current work demonstrated that the combination of MD simulations with ssNMR-based experimental restraints provided a reliable method for studying structural changes of Aβ.},
}

@article {pmid42540298,
year = {2026},
author = {McFall-Boegeman, H and Talbot, C and Montalbano, M and Puangmalai, N and Wang, KW and Kannan, M and Shi, J and Linning-Duffy, K and Nick, S and Yan, L and Kuo, MH and Kayed, R and Huang, X},
title = {A Virus-Like-Particle-Based Conjugate Vaccine Targeting the Microtubule Binding Region of Tau Protein.},
journal = {ACS omega},
volume = {11},
number = {29},
pages = {43242-43254},
doi = {10.1021/acsomega.6c00852},
pmid = {42540298},
issn = {2470-1343},
abstract = {There is a pressing need to develop novel strategies to ameliorate symptoms and slow the progression of Alzheimer's disease. One of the hallmarks of Alzheimer's disease is the high levels of tau protein, which can form toxic oligomers and characteristic neurofibrillary tangles in the brain. Antitau antibodies can potentially bind tau protein and reduce tau pathology. In order to elicit a powerful antitau antibody response, virus-like-particle bacteriophage Qβ-based conjugate vaccines were developed targeting the microtubule binding region of tau protein. The Qβ-tau vaccines were able to produce a strong antitau antibody response in not only wild-type mice but also in human tau transgenic mice and a llama. The levels of antibody induced were superior to those generated by a corresponding keyhole limpet hemocyanin-based tau conjugate mimicking the one vaccine that successfully completed phase 1/2 human clinical trials. The Qβ-tau vaccine significantly improved the cognitive functions of the immunized mice and reduced the levels of inflammatory cytokines and tau in the brains, suggesting its translational potential.},
}

@article {pmid42540333,
year = {2026},
author = {Gabb, VG and Neary, C and Mair, D and Kendrick, A and Russell, G and Clayton, J and Begum, S and Huckstepp, RTR and Turner, N and Coulthard, E},
title = {Sleep Apnoea and Memory (SAM): protocol for a prospective study of prevalence and symptoms of sleep apnoea in memory clinics.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1862599},
doi = {10.3389/fnagi.2026.1862599},
pmid = {42540333},
issn = {1663-4365},
abstract = {INTRODUCTION: Sleep apnoea is common in older adults and a risk factor for cognitive decline and dementia but is rarely assessed in memory clinics. The Sleep Apnoea and Memory (SAM) study will assess the prevalence of sleep apnoea and identify optimal screening for sleep apnoea in memory clinics.

METHODS: SAM is a prospective observational multi-site study recruiting adults attending NHS memory clinics. Participants will undergo a single night of polygraphy using a home sleep apnoea test (WatchPAT[®] 300) and complete questionnaires based on NICE guidance for sleep apnoea assessment. The primary outcome will be the prevalence of sleep apnoea. Secondary outcomes include determining sleep apnoea prevalence across different cognitive diagnoses, identifying which symptoms and risk factors which best predict sleep apnoea, and assessing feasibility of remote sleep apnoea screening.

DISCUSSION: The SAM study will improve understanding of the extent of sleep apnoea in people attending memory clinics and inform design of an interventional trial for treating sleep apnoea in patients with cognitive impairment. Treating sleep apnoea in memory clinics may help to improve symptoms and/or prognosis for people experiencing memory problems.},
}

@article {pmid42540517,
year = {2026},
author = {Otenaike, TA and Farodoye, OM and Olaniyan, H and Teibo, JO and Faleke, HO and Akinola, IA and Molik, ZA and Aschner, M and Abolaji, AO},
title = {Neurotoxicity of heavy metals across the lifespan: The beneficial role of nutrition from fetus to the elderly.},
journal = {Advances in neurotoxicology},
volume = {16},
number = {1},
pages = {307-349},
doi = {10.1016/bs.ant.2026.03.003},
pmid = {42540517},
issn = {2468-7480},
abstract = {Heavy metals pose a profound threat to neurological health across all stages of human life, from prenatal development to old age. Heavy metals such as lead, mercury, cadmium, and arsenic are pervasive environmental pollutants that disrupt neural function through mechanisms including oxidative stress, inflammation, mitochondrial dysfunction, and neurotransmitter system imbalances. During critical developmental windows such as fetal growth and early childhood, exposure can impair neurogenesis, synaptic plasticity, and myelination, leading to lifelong cognitive deficits, behavioral disorders, and increased vulnerability to neurodegenerative diseases in later life. Even in adulthood and aging, chronic exposure exacerbates neurodegeneration, accelerating conditions like Alzheimer's and Parkinson's diseases through persistent oxidative damage and inflammatory cascades. This chapter underscores the dual role of nutrition as both a shield and a therapeutic tool against heavy metal neurotoxicity. Key nutrients, such as polyphenols, vitamins, and essential minerals, counteract heavy metal-induced damage by scavenging free radicals, enhancing antioxidant defenses, modulating inflammation, and promoting neuronal repair. By integrating evidence from epidemiological, preclinical, and clinical studies, this chapter emphasizes actionable strategies, such as fortified infant formulas, plant-based proteins, and micronutrient supplementation to reduce heavy metal bioavailability and bolster neurological resilience. Public health initiatives targeting vulnerable populations, alongside policies regulating environmental pollutants, are critical to curbing this silent epidemic. This chapter advocates for a proactive, nutrition-centered approach to safeguarding brain health, demonstrating that dietary interventions are not merely complementary but foundational in combating the pervasive threat of heavy metal neurotoxicity across generations.},
}

@article {pmid42540519,
year = {2026},
author = {Rajabpour-Sanati, A and Nasiri, H and Khosravi, F and Ghahrieh, F and Asemanrafat, A and Bahaqiqat, AK and Saberian, P and Bakhshi, R and Rastegari, F and Ahangar-Sirous, R and Shahidzadehasadi, A and Seif, H and Ghahremani, M and Gandomi-Nasrabadi, F and Azizan, Z and Mayeli, M and , },
title = {Diagnostic Performance of the AlzoSure Predict Assay and Its Association With Alzheimer's Disease Biomarkers and Imaging Findings.},
journal = {Health science reports},
volume = {9},
number = {8},
pages = {e72914},
doi = {10.1002/hsr2.72914},
pmid = {42540519},
issn = {2398-8835},
abstract = {BACKGROUND: Early diagnosis of Alzheimer's disease (AD) is critical for improving patient outcomes. The laboratory-developed blood test of AlzoSure measures the unfolded conformational variant of p53 (U-p53AZ) in plasma and has shown promise as a screening tool for AD risk. We aimed to evaluate the association between U-p53AZ with established cerebrospinal fluid (CSF) and neuroimaging measures, and to determine its diagnostic performance in distinguishing cognitively normal (CN) individuals from those with mild cognitive impairment (MCI).

METHODS: Participants included CN and MCI individuals aged 55-90 years with complete baseline and 24-month follow-up assessments. Associations between U-p53AZ, CSF biomarkers, standardized uptake value ratio (SUVR) of glucose measured by fluorodeoxyglucose positron emission tomography (FDG-PET), and cognition were examined with multivariable regression models adjusted for age, sex, and APOE ε4 status. Diagnostic performance was assessed with receiver operating characteristic (ROC) analysis.

RESULTS: At baseline, no significant group differences were observed in plasma U-p53AZ, FDG SUVR, or CSF biomarkers between CN and MCI. Longitudinally, FDG SUVR significantly declined in MCI (p = 0.040), while CSF t-tau and p-tau181 increased in both groups (all p < 0.05). Higher U-p53AZ levels were independently associated with elevated CSF t-tau (β = 0.38; p = 0.033) and p-tau181 (β = 0.37; p = 0.033) at baseline, and these associations persisted at follow-up (β range 0.43-0.48; all p < 0.02). No significant associations were found with FDG SUVR or cognitive scores. The discriminative ability of U-p53AZ to distinguish CN from MCI was modest (AUC = 0.617, 95% CI 0.518-0.716).

CONCLUSION: AlzoSure measurements are significantly associated with CSF tau values but demonstrate limited utility in differentiating CN from MCI. Although promising as a marker of tau-related neurodegeneration, AlzoSure has a modest diagnostic performance as a stand-alone assessment.},
}

@article {pmid42540536,
year = {2026},
author = {Wang, S and Lin, Y and Che, Y and Zhao, J and Xu, L and He, W and Zhang, W},
title = {Genetically inferred effects of brain structure and gene expression on neurodegenerative diseases: a Mendelian randomization study.},
journal = {Archives of medical science : AMS},
volume = {22},
number = {3},
pages = {1663-1677},
doi = {10.5114/aoms/219499},
pmid = {42540536},
issn = {1734-1922},
abstract = {INTRODUCTION: Against the backdrop of accelerating population aging, the risk of neurodegenerative diseases (NDDs) has risen significantly. While brain structure plays a critical role in NDDs, the interplay between them remains unclear. This study employed Mendelian randomization (MR) to investigate potential causal relationships between brain structure, region-specific gene expression, and four NDDs - Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) - providing new directions and genetically informed hypotheses for disease research.

MATERIAL AND METHODS: MR analyses were conducted using inverse-variance weighted (IVW), MR-Egger, weighted median, weighted mode, and Wald ratio methods. Summary-data-based MR (SMR) was applied to identify brain genes influencing NDDs. We calculated F-statistics, 95% confidence intervals (CIs), odds ratios, and p-values. Sensitivity analyses included the heterogeneity I[2] statistic, Cochran's Q test, Egger intercept test, MR-PRESSO, and leave-one-out validation.

RESULTS: Data from 512 unsupervised deep-learning imaging phenotypes (UDIPs) were analyzed. Thirty-four UDIPs showed associations consistent with a potential causal role in AD, 56 in PD, 22 in ALS, and 92 in MS. After false discovery rate (FDR) correction, 4 remained significant for AD and PD, 3 for ALS, and 28 for MS (p < 0.05). Brain regions (excluding the cervical spinal cord C-1) exhibited shared causal genetic features across all four NDDs, primarily involving HLA-class genes.

CONCLUSIONS: This study provides genetic evidence suggestive of potential causal associations between UDIPs, brain gene expression, and NDDs. These findings offer genetically predicted evidence that may generate hypotheses and inform future mechanistic research into NDD pathogenesis.},
}

@article {pmid42540688,
year = {2026},
author = {Paonessa, F and Bizzini, BD and Campbell, T and Coode, E and Lam, J and Solanki, R and Butler, R and Smith, J and Davidson, CM and Larrieu, D and Brand, AH and Livesey, FJ},
title = {NAT10 inhibition corrects nuclear defects in tau mutant human neurons and extends lifespan in a Drosophila tauopathy model.},
journal = {iScience},
volume = {29},
number = {8},
pages = {116861},
doi = {10.1016/j.isci.2026.116861},
pmid = {42540688},
issn = {2589-0042},
abstract = {Mutations in the gene encoding the microtubule-associated protein tau (MAPT) that are causal for frontotemporal dementia result in nuclear envelope deformation and disrupted nucleocytoplasmic transport when expressed in human neurons. A small-molecule inhibitor of the acetyltransferase NAT10 has been shown to correct similar nuclear membrane defects in Hutchinson-Gilford progeria syndrome, primarily by modulating microtubule dynamics. We report here that NAT10 inhibition and loss of function correct nuclear membrane abnormalities in human MAPT-mutant neurons. Similarly, NAT10 inhibition and haploinsufficiency correct neuronal nuclear shape defects and extend lifespan in vivo in a Drosophila model of tauopathy. NAT10 inhibition changes microtubule dynamics and corrects aberrant nucleocytoplasmic transport, and NAT10 directly interacts with regulators of microtubule dynamics in human MAPT-mutant neurons. We conclude that NAT10 mediates neuronal pathologies in tauopathies and is a potential therapeutic target in these diseases.},
}

@article {pmid42540732,
year = {2026},
author = {Saloner, R and Paolillo, EW and VandeBunte, AM and Cadwallader, CJ and Chen, C and Steffen, BT and Bennett, DA and Boeve, BF and Rosen, HJ and Boxer, AL and Kramer, JH and Casaletto, KB},
title = {Plasma proteomics reveals molecular overlap between physical activity and dementia risk.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag287},
doi = {10.1093/braincomms/fcag287},
pmid = {42540732},
issn = {2632-1297},
abstract = {Physical activity (PA) is a modifiable lifestyle behaviour associated with lower dementia risk; however, molecular pathways bridging PA-related dementia prevention are poorly understood. We leveraged large-scale plasma proteomics to identify biological signatures of objectively monitored PA and cognitive ageing in functionally intact older adults, cross-validated these signatures in independent exercise cohorts and tested associations with both symptomatic and presymptomatic stages of neurodegeneration across multiple Alzheimer's disease and related dementias (ADRD) cohorts. We analysed large-scale plasma proteomics data (SomaScan 7k) across three cohorts including naturalistic, objective PA monitoring (University of California, San Francisco Brain Aging Network for Cognitive Health cohort, n = 65), self-reported PA (Atherosclerosis Risk In Communities study, n = 10 644) and PA intervention (Health Risk Factors, Exercise Training and Genetics study, n = 654). Differential regression models examined individual protein correlates of PA, adjusting for age and sex. Weighted gene co-expression network analysis assembled proteins into unbiased modules of protein co-expression, which were annotated for gene ontology and cell-type enrichment. To test clinical relevance to ADRD, we examined PA-related protein levels across-cohorts of symptomatic Alzheimer's disease and Parkinson's disease (Stanford Alzheimer's Disease Research Center), as well as frontotemporal dementia-spectrum disorders (ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium). PA-related plasma proteins were also tested as predictors of antemortem cognitive change and post-mortem brain tissue mass spectrometry proteomic signatures in brain donors from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort. Differential regression and network analyses identified PA plasma proteomic signatures linked to cell adhesion/extracellular matrix (ECM), immune response and lipid metabolism. Protein co-expression module M12 ECM/neurodevelopment harboured growth factor, cell adhesion and vascular remodelling proteins that (i) were positively associated with PA across exercise cohorts, (ii) positively associated with cognitive function and (iii) negatively associated with Alzheimer's disease, Parkinson's disease and frontotemporal dementia. Furthermore, M12 was enriched for proteins from Alzheimer's disease risk genes and antemortem plasma abundance of anthrax toxin receptor cell adhesion molecule 2 (ANTXR2), an M12 'hub' protein and top PA hit across-cohorts, forecasted longitudinal global cognitive decline and post-mortem brain tissue signatures of synaptic function and proteolysis in ROSMAP. Collectively, our integrated systems biology analysis of six independent plasma proteomic datasets facilitated discovery and validation of blood-detectable molecular signatures of PA and neurodegenerative disease, including PA-related proteins with clinical and biological relevance to early stages of disease. Circulating levels of PA-related proteins reflecting ECM biology (e.g. ANTXR2) may represent key molecular targets for dementia prevention.},
}

@article {pmid42541080,
year = {2026},
author = {Espinosa, PS and Li, S and Preisler, J and Hennekens, CH},
title = {Donanemab Infusion and Recurrent Seizures in a Patient With Alzheimer's Disease and Epilepsy in the Absence of Amyloid-Related Imaging Abnormalities (ARIA).},
journal = {Cureus},
volume = {18},
number = {7},
pages = {e111911},
doi = {10.7759/cureus.111911},
pmid = {42541080},
issn = {2168-8184},
abstract = {Donanemab is an immunoglobulin G1 (IgG1) monoclonal antibody that was recently approved by the United States Food and Drug Administration for the treatment of early symptomatic Alzheimer's disease (AD). The drug was approved with boxed warnings for amyloid-related imaging abnormalities (ARIA). While seizures are recognized adverse events, they are predominantly characterized in the context of ARIA and accompanied by edema (ARIA-E) or hemosiderin deposition (ARIA-H). The precise epileptogenic mechanisms of anti-amyloid immunotherapies independent of macroscopic ARIA remain poorly understood. We report the case of a 90-year-old man with mild cognitive impairment due to AD and a history of well-controlled focal epilepsy on levetiracetam, who experienced two generalized tonic-clonic seizures. Each paroxysmal event occurred within two hours of completing his fifth and sixth monthly donanemab (1,400 mg intravenous) infusions. Inter-ictal magnetic resonance imaging (MRI), including fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted imaging (SWI) sequences, demonstrated no evidence of ARIA-E or ARIA-H. Routine electroencephalography (EEG) revealed no interictal epileptiform discharges. Seizure recurrence necessitated an escalation of his levetiracetam dosage to 750 mg twice daily and the immediate discontinuation of donanemab therapy, after which he remained seizure-free. The temporal proximity of the seizures to the infusions, the positive rechallenge, and the absence of identifiable structural, metabolic, or infectious precipitants raise the possibility of an association with donanemab. However, causality cannot be established from a single case report. Several biologically plausible mechanisms may explain this temporal association, including rapid amyloid-beta (Aβ) clearance, microglial activation, neuroinflammatory responses, and transient blood-brain barrier dysfunction, which may lower the seizure threshold in a patient with pre-existing epileptogenic networks. However, these mechanisms remain hypothetical and were not directly demonstrated in this patient. Clinicians should maintain a high index of suspicion for acute post-infusion seizures in patients receiving donanemab, particularly those with a history of epilepsy, even in the absence of radiographically detectable ARIA. Clinicians should be aware of this potential safety signal in patients with pre-existing epilepsy. Additional studies are needed before specific monitoring or treatment recommendations can be established.},
}

@article {pmid42541117,
year = {2026},
author = {McNamara, E and Smith, C and Postlethwaite, N and Wozencraft, A},
title = {Privacy-Enhancing Technologies: Unlocking Responsible Cross-Border Data Research.},
journal = {International journal of population data science},
volume = {11},
number = {5},
pages = {3615},
doi = {10.23889/ijpds.v11i5.3615},
pmid = {42541117},
issn = {2399-4908},
mesh = {Humans ; *Information Dissemination/legislation & jurisprudence ; *Privacy/legislation & jurisprudence ; *Confidentiality/legislation & jurisprudence ; *International Cooperation ; *Computer Security/legislation & jurisprudence ; },
abstract = {International data transfer rules, designed to protect individuals, often create barriers to collaborative research by imposing constraints misaligned with modern data ecosystems. Frameworks like GDPR and UK GDPR can unintentionally hinder scientific progress by failing to recognise the safeguards provided by emerging technologies. More nuanced legal approaches are needed to preserve privacy while enabling responsible international research. We will examine how privacy-enhancing technologies (PETs) can help address these challenges. Informed by insights from pilot projects under the Alzheimer's Disease Data Initiative which seek to address critical dementia questions, while expanding dataset access. With dementia cases projected to rise globally from 57 million to 153 million by 2050, this work demonstrates the urgent need for cross-border data sharing in brain health research. Specifically, we will explore how PETs offer pathways through regulatory barriers, and how Trusted Research Environments (TREs), aligned with the Five Safes Framework, provide strong safeguards to prevent identifiable data disclosure. We will demonstrate how remote querying techniques enable international analysis without data transfers, as researchers receive only aggregate results. The presentation will address persistent challenges: under European Data Protection Board guidance, even viewing data across borders constitutes a transfer, meaning TRE access may trigger complex compliance requirements despite technical safeguards. We will explore the rapidly evolving landscape through new UK legislation, the European Health Data Space, and emerging case law. Finally, we will discuss whether PETs can bridge the gap between privacy protection and scientific progress, and what regulatory adaptations are required to recognise the protections they provide.},
}

Humans
*Information Dissemination/legislation & jurisprudence
*Privacy/legislation & jurisprudence
*Confidentiality/legislation & jurisprudence
*International Cooperation
*Computer Security/legislation & jurisprudence

@article {pmid42541418,
year = {2026},
author = {Zhang, J and Wang, C and Liang, C and Peng, T and Chang, K and Bu, J and Wang, Z and Wang, X and Hua, Q and Tan, Y},
title = {Neurolymphatic formula restores meningeal and peripheral lymphatic function via VEGFR3 activation: Mechanistic validation of coptisine as a key anti-Alzheimer's compound.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261470114},
doi = {10.1177/13872877261470114},
pmid = {42541418},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation with impaired lymphatic clearance, yet therapies targeting lymphatic dysfunction remain underexplored. The Neurolymphatic Formula (NLF), a traditional Chinese medicine, demonstrates lymphatic modulation potential, but its mechanistic role in AD remains unknown.ObjectiveThis study aimed to elucidate NLF's therapeutic efficacy in AD and investigate whether it enhances central and peripheral lymphangiogenesis via VEGF receptor 3 (VEGFR3) activation.MethodsWe evaluated NLF's pharmacological effects on behavior and AD pathology in APP/PS1 mice, including sunitinib-induced lymphatic impairment models. Underlying mechanisms were explored using network pharmacology, molecular docking, and in vitro assays on human lymphatic endothelial cells (HLECs).ResultsIn APP/PS1 mice, 4-week NLF treatment reduced Aβ plaque burden by 43% (p < 0.01) and improved spatial memory latency by 35% (p < 0.05). NLF restored meningeal and mesenteric lymphatic density in sunitinib-treated mice to 82% and 133% of baseline, respectively (p < 0.01), while upregulating serum VEGFR3 2.3-fold (p < 0.01). To validate NLF's molecular basis, coptisine was identified as a representative VEGFR3 ligand (-7.1 Kcal/mol). In vitro, coptisine (25 μM) enhanced HLEC viability by 60%, accelerated wound closure 2.5-fold, and increased tube junctions by 75% (all p < 0.01) alongside VEGFR3 upregulation.ConclusionsNLF alleviates AD pathology by promoting Aβ clearance through VEGFR3-mediated dual modulation of central and peripheral lymphatic systems. The in vitro efficacy of its constituent, coptisine, mechanistically validates this pro-lymphangiogenic pathway, highlighting NLF's therapeutic potential as a holistic lymphatic-targeted AD treatment.},
}

@article {pmid42531136,
year = {2026},
author = {Shen, D and Jin, H and Feng, H and Gao, R and Sun, R and Xiao, Y and Wan, W and Ma, C and Liu, Y},
title = {Neutral Borate Buffer Activates Diazo for Rapid Protein Labeling.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e1990347},
doi = {10.1002/anie.1990347},
pmid = {42531136},
issn = {1521-3773},
support = {22374148//National Natural Science Foundation of China/ ; 2024JH3/50100009//Liaoning Province Science Foundation for Distinguished Young Scholars/ ; 2022RJ04//Dalian Science Foundation for Distinguished Young Scholars/ ; 028GJHZ2023079FN//International Partnership Program of Chinese Academy of Sciences for Future Network/ ; 2023JJ12WZ037//Dalian Science and Technology Innovation Foundation/ ; 2024-MSBA-59//Natural Science Foundation of Liaoning Province/ ; DICP I202458//Innovation Program of Science and Research from the DICP, CAS/ ; DICP I202310//Innovation Program of Science and Research from the DICP, CAS/ ; DICP I202529//Innovation Program of Science and Research from the DICP, CAS/ ; },
abstract = {Diazo, a carbene precursor, offers an effective chemistry for bioorthogonal labeling upon activation by acids, metals, and/or photo-illumination. Here, we report neutral borate buffer can trigger diazo compounds into carbene for protein labeling without the need for acid, metal, or light. We show that such boron-diazo-mediated covalent modification rapidly occurs within seconds under physiological conditions and preferentially targets carboxylate-containing amino acid residues. Towards applications of such boron-diazo protein chemistry, we exemplify the design of an affinity-based covalent inhibitor for dihydrofolate reductase by installing diazo on the non-covalent trimethoprim drug. When extended to stressed cells, we also capture cellular aggresomes using a diazo-Thioflavin T probe that selectively labels aggregated proteins. Finally, in Alzheimer's disease brain tissue, we employ this boron-diazo chemistry to label, enrich, and profile amyloid plaques, identifying proteins related to pathological deposition. Together, the boron-diazo chemistry reported herein provides a rapid and facile protein modification strategy under mild conditions.},
}