@article {pmid40742455,
year = {2025},
author = {He, Q and Wan, Z and Yuan, S and Hidayat, K and Xu, JY and Qin, LQ},
title = {Association between serum lactoferrin concentrations and the prevalence of mild cognitive impairment among Chinese adults: a cross-sectional study.},
journal = {European journal of nutrition},
volume = {64},
number = {6},
pages = {250},
pmid = {40742455},
issn = {1436-6215},
support = {82173502//the National Natural Science Foundation of China/ ; 82073482//the National Natural Science Foundation of China/ ; PAPD//Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; },
abstract = {OBJECTIVE: Lactoferrin (Lf) expression is upregulated in the brain of patients with Alzheimer’s disease (AD), and mild cognitive impairment (MCI) is recognized as an early, pre-clinical stage of AD. However, the association between serum Lf and MCI remains unclear. METHOD: A cross-sectional study was performed to examine the association between serum Lf and the prevalence of MCI in Chinese adults aged ≥ 40 years. Lf concentrations in serum were measured using an enzyme-linked immunosorbent assay. MCI was diagnosed according to the Chinese version of the mini-mental state examination (MMSE). Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of MCI by quartiles of serum Lf concentrations were estimated using logistic regression. A dose-response relationship was analyzed using a restricted cubic spline. Subgroup analyses were performed by age, sex, weight status, and the presence of diabetes or hypertension, with interaction effects tested. RESULTS: Among 1,531 participants (mean age of 59.16 ± 6.35 years), 214 (13.98%) had MCI. The participants with MCI exhibited lower serum Lf concentrations than those without MCI (1.19 ± 0.67 µg/mL vs. 1.49 ± 0.75 µg/mL, P < 0.001). The MCI prevalence was decreased across ascending quartiles of serum Lf. Compared with the lowest quartile of serum Lf, the multivariable-adjusted OR (95% CI) for MCI prevalence were 0.83 (0.57–1.21), 0.45 (0.29–0.68), and 0.30 (0.19–0.49) with a significant trend (P for trend < 0.001). The restricted cubic spline regression analysis showed an inverted J-shape curve (p for overall < 0.001, p for nonlinear = 0.003). The inverse association persisted regardless of age, gender, and the presence of diabetes and hypertension (all P for trend ≤ 0.01). By weight status, the inverse association was observed in participants with normal weight and overweight (P for trend = 0.002 and < 0.001), but not in those with obesity (P for trend = 0.602). Test of interaction effects indicated that MCI risk decreased more significantly in participants with diabetes than those without diabetes (P for interaction < 0.001). CONCLUSIONS: Serum Lf was inversely associated with the prevalence of MCI. This association was not observed in participants with obesity, and was more pronounced in those with diabetes.},
}

@article {pmid41075142,
year = {2026},
author = {Zhu, C and Zhang, Q and Fan, H and Guo, B and Wang, H},
title = {EVA1A-Mediated Signaling Networks in Physiological and Pathological Contexts: Dual Roles in Autophagy and Apoptosis.},
journal = {Cell biochemistry and biophysics},
volume = {84},
number = {1},
pages = {361-372},
pmid = {41075142},
issn = {1559-0283},
support = {252102310124//he grants from the key scientific and technological projects in Henan Province, China/ ; },
abstract = {Eva-1 homolog A (EVA1A) is a transmembrane protein localized on the endoplasmic reticulum and lysosomes. As a key regulator of autophagy and apoptosis, EVA1A regulates neurogenesis, cardioprotection, tumor suppression, and metabolic homeostasis. In this review, we synthesize the multifaceted signaling networks through which EVA1A modulates physiological and pathological processes. These include the PI3K/AKT/mTOR axis (governing neural stem cell maintenance and hepatocellular carcinoma drug resistance), LKB1/AMPK/mTOR pathway (mediating mitochondrial quality control in cardiac injury), mTOR/RPS6KB1 signaling (suppressing glioblastoma proliferation via autophagy-apoptosis crosstalk), and the Hippo-YAP/TAZ cascade (influencing epithelial-mesenchymal transition in thyroid cancer). Crucially, EVA1A exhibits context-dependent dual roles: promoting autophagic flux for homeostasis or triggering apoptosis under stress. Most of these findings are derived from preclinical studies using cell lines and animal models, with limited validation in human tissues or clinical cohorts.We emphasize EVA1A paradoxical effects in cancers, where EVA1A acts as either a tumor suppressor or a modulator of therapy resistance, depending on the tissue-specific microenvironment. Furthermore, EVA1A’s involvement in neurodegenerative and metabolic diseases, such as Alzheimer’s, Parkinson’s, obesity, and diabetes, remains underexplored, despite its relevance to autophagy and inflammation. Understanding the spatiotemporal dynamics of EVA1A interactions with autophagy-related complexes (such as ATG16L1/ATG5/ATG12) and stress-responsive pathways is important to explore its therapeutic potential. However, EVA1A-targeted therapy is still in the early discovery phase, with no current clinical applications.Future studies should focus on the molecular crosstalk between EVA1A-mediated autophagy and metabolic/inflammatory pathways, aiming to facilitate EVA1A-targeted therapeutic development.},
}

@article {pmid41484730,
year = {2026},
author = {Das, S and Awasthi, A and Rawal, RK and Bhatia, R},
title = {Biomarkers in Disease Diagnosis and Monitoring: Insights into Clinical Applications and Mass Spectrometry-based Detection.},
journal = {Applied biochemistry and biotechnology},
volume = {198},
number = {3},
pages = {1453-1482},
pmid = {41484730},
issn = {1559-0291},
abstract = {Biomarkers have become crucial tools in the diagnosis, prognosis, and therapeutic monitoring of various diseases. This review focuses on the classification of biomarkers based on three core categories: (i) their characteristics, (ii) clinical applications, and (iii) relevance in genetic and molecular biology. The importance of biomarkers across diseases is emphasized, along with recent advancements in their detection. A comprehensive discussion on the biomarker development pipeline, particularly mass spectrometry (MS)-based biomarker discovery, validation, and verification, is presented. The article also delves into MS-based techniques used for the detection of disease biomarkers such as Alzheimer’s, hepatocellular carcinoma, ovarian cancer, kidney diseases, diabetes and tuberculosis, as well as highlighting recent research. Finally, the review explores future perspectives on biomarker discovery and detection, focusing on the evolving role of MS in advancing biomarker science and its application in clinical and research settings. In each disease area, we provide an important review of the limitations in individual studies. We also outline new solutions that use mass spectrometry to fill gaps in analysis and translation for biomarker development.},
}

@article {pmid41575646,
year = {2026},
author = {Ito, H and Yamakuni, R and Takano, H and Abe, M and Shima, A and Sawamoto, N and Hanakawa, T},
title = {Regional distribution of an amyloid radiotracer in healthy aged human brain measured by PET with [[18]F]flutemetamol: a relation with myelin distribution.},
journal = {Annals of nuclear medicine},
volume = {40},
number = {5},
pages = {575-583},
pmid = {41575646},
issn = {1864-6433},
support = {18dm0307003h0001//Japan Agency for Medical Research and Development/ ; 24wm0625001h//Japan Agency for Medical Research and Development/ ; },
abstract = {OBJECTIVES: To measure amyloid-β deposits by positron emission tomography (PET), several radiotracers have been employed in the examination of the pathophysiology of Alzheimer’s disease. Although the nature of amyloid radiotracer binding to white matter is not fully understood, they may bind to myelin, which is organized in a beta-sheet structure similar to that of amyloid-β deposits. In the present study, a normal database of myelin distribution measured by PET with the amyloid radiotracer [18F]flutemetamol was constructed in healthy subjects. METHODS: The data of [18F]flutemetamol PET and T1-weighted images (T1WI) of magnetic resonance imaging (MRI) for 45 healthy subjects were used. After anatomic standardization of all PET and MRI images, the standardized uptake value ratio (SUVR) images of PET, and white matter fraction (WM) images from MRI were obtained. RESULTS: A database of normal PET images with [18F]flutemetamol was constructed. The SUVR in the white matter were not uniform across the brain. However, the SUVR per WM were mostly uniform in the cerebral white matter, due to a correction of effects of the limited spatial resolution of the PET scanner. The regional distributions of SUVR and SUVR per WM were similar to those previously reported for myelin using the myelin water imaging technique with MRI. Significant increases in the SUVR or the SUVR per WM with age were observed in almost all white matter regions. The myelin content measured by MRI with the myelin water imaging technique has also been reported to increase with age. Increases in the SUVR or the SUVR per WM with age may reflect ongoing myelin formation continuing during normal aging. CONCLUSIONS: The present study supports the binding of [18F]flutemetamol to myelin. Thus, a database reflecting normal myelin distribution as measured by PET might be successfully constructed.},
}

@article {pmid41701421,
year = {2026},
author = {Mssillou, I and El Abdali, Y and Šovljanski, O and Bakour, M and Laaroussi, H and Aghoutane, Y and Calabrese, EJ and Khalid, A and Zarroug, SHO and Louafi, B and Bousta, D},
title = {Pharmacological properties, safety, pharmacokinetic and clinical trials of kukoamine A and B.},
journal = {Inflammopharmacology},
volume = {34},
number = {3},
pages = {1487-1508},
pmid = {41701421},
issn = {1568-5608},
support = {JU-202505361-DGSSR-ORA-2025//Jazan University/ ; },
abstract = {Kukoamine A (KuA) and kukoamine B (KuB) are spermine alkaloids characterized by polyamine backbones conjugated with phenolic moieties, primarily isolated from Lycium chinense root bark (Lycii Cortex). This review comprehensively analyses their pharmacological properties, mechanistic pathways, safety profiles, and clinical potential. KuA and KuB exhibit potent antioxidant activity by scavenging reactive oxygen species, enhancing superoxide dismutase and catalase activity, and chelating Fe2+. Their anti-inflammatory effects involve neutralizing pathogen-associated molecular patterns (e.g., LPS, CpG-DNA), suppressing TLR4/9-MyD88-NF-κB signaling, and reducing pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β). Both compounds demonstrate antimicrobial efficacy against sepsis triggers (e.g., E. coli) by inhibiting bacterial toxin-induced inflammation. Additionally, KuA and KuB significantly improve antidiabetic outcomes by activating the AKT/GSK-3β pathway, thereby enhancing insulin sensitivity, inhibiting DPP-4 and amyloid aggregation, and ameliorating metabolic disorders. Neuroprotective roles include mitigating oxidative stress, inhibiting neuronal apoptosis (via modulation of Bax/Bcl-2 and caspase-3), and attenuating the pathology of Parkinson’s and Alzheimer’s diseases by regulating α-synuclein and iron homeostasis. Additional benefits encompass anti-osteoporotic effects through osteoblast differentiation promotion and bone mineral density preservation. Moreover, pharmacokinetic studies indicate rapid plasma distribution and urinary excretion of KuB, with Phase I/II trials confirming tolerability in healthy and septic subjects (0.06–0.24 mg/kg doses). Safety assessments reveal mild adverse events (e.g., transient headaches). Despite promising preclinical data, clinical validation remains limited. Future research should prioritize mechanistic depth, large-scale trials, and therapeutic applications for neurodegenerative, metabolic, and inflammatory diseases.},
}

@article {pmid41863649,
year = {2026},
author = {Siddik, S and Patgiri, U and Sola, P},
title = {Molecular mirror: reflecting the complexity of Parkinson's disease.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {4},
pages = {},
pmid = {41863649},
issn = {1590-3478},
abstract = {Parkinson’s disease (PD) is a multifaceted neurodegenerative disorder driven by a complex interplay of genetic and environmental factors that disrupt normal cellular function. A hallmark of PD pathology is the abnormal accumulation of alpha-synuclein protein, leading to the formation of Lewy Bodies and the degeneration of dopaminergic neurons. Critical proteins like Akt1 and glycogen synthase kinase-3 beta (GSK-3β) are vital for cell survival and apoptosis regulation; their dysfunction adversely affects the health of dopaminergic neurons, accelerating neurodegeneration. Additionally, PARK2 (parkin) and PTEN-induced kinase 1 (PINK1) are crucial for mitochondrial function and energy homeostasis. In PD, mutations in these genes are reported and impair mitochondrial quality control, making neurons more vulnerable to stress and exacerbating disease progression. The enzyme glucocerebrosidase (GBA), crucial for lysosomal function, is also linked to PD, with mutations in the GBA gene associated with increased SNCA accumulation and faster disease progression. Interestingly, tau protein, typically associated with Alzheimer’s Disease, is also present in Parkinson’s disease pathology, suggesting a potential overlap in the mechanisms driving these neurodegenerative diseases. The vesicular monoamine transporter 2 (VMAT2) plays a crucial role in dopamine regulation, and its malfunction can render dopaminergic neurons more vulnerable to degeneration. In conclusion, PD represents a complex interplay of genetic, protein-related, and environmental factors leading to progressive neurodegeneration. Understanding these molecular mechanisms is crucial for developing biomarkers and advanced therapies. Ongoing research is essential for creating treatments that effectively manage symptoms, slow disease progression, and improve patient quality of life, ultimately transforming the lives of those affected.},
}

@article {pmid41874861,
year = {2026},
author = {Majrashi, TA and Alshahrani, MY and Asiri, MA and Zia-Ul-Sabah, and Abohassan, M and Kapoor, DU and Wahab, S},
title = {Computational Repurposing of Nilotinib and Radotinib as SIRT2 Inhibitors for Neurodegenerative Diseases.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {41874861},
issn = {1559-1166},
support = {RGP.1/167/46//Deanship of Scientific Research, King Khalid University/ ; },
abstract = {Neurodegenerative diseases (NDs) including Alzheimer’s and Parkinson’s disease involve progressive neuronal death, and current treatments are unsatisfactory. Sirtuin-2 (SIRT2), a NAD[+] dependent deacetylase with roles in microtubule dynamics and redox regulation, has been suggested as potential druggable target for neurodegeneration. As part of this work, we conducted a virtual screening using the FDA-approved drugs library against the SIRT2 protein to discover potential inhibitors more potent than SirReal2. The binding energy and its interaction study concluded that Nilotinib and Radotinib exhibited higher bindings (-13.2 kcal/mol and -12.8 kcal/mol) than SirReal2 (-11.8 kcal/mol) through the formation of crucial interactions with the catalytic residues located at binding and active sites. PASS analysis revealed anti neurodegenerative potential for both drugs. Long-time scale molecular dynamics (500 ns) simulations investigated structural stability of SIRT2-drug complexes with reduced RMSD and RMSF values compared to protein-ligand complexes from SirReal2 together with the maintained compactness within the protein. Principal component and free energy landscape analysis revealed that Nilotinib, Radotinib bound to SIRT2 in lower-energy conformation with limited movement than the higher dynamic fluctuations induced by SirReal2. Moreover, MMPBSA and DFT calculation also investigate the binding stability complexes. Taken together, our results demonstrate Nilotinib and Radotinib as potential lead drugs for repurposing toward the discovery of novel inhibitors of SIRT2 with therapeutic implications in neurodegenerative diseases. These crucial findings strongly recommended for further experimental validation through in vitro and in vivo analysis.},
}

@article {pmid41915110,
year = {2026},
author = {Asl, AD and Naeimzadeh, F and Yonjali, RM and Mohammadpour, A and Khankandi, PG and Afkhami, A and Mahmoodpoor, A and Sanaie, S and Naseri, A},
title = {Selenium and probiotics co-supplementation: A scoping review of clinical evidence.},
journal = {Inflammopharmacology},
volume = {34},
number = {5},
pages = {3625-3635},
pmid = {41915110},
issn = {1568-5608},
support = {74645//Student Research Committee, Tabriz University of Medical Sciences/ ; },
abstract = {BACKGROUND: Selenium and probiotics have been individually recognized for their antioxidant, anti-inflammatory, and immune-modulating properties. However, the potential synergistic effects of their co-supplementation in human health remain minimally investigated. This scoping review aimed to summarize the current evidence on the impact of co-supplementation with selenium and probiotics. METHODS: A comprehensive literature search was conducted across PubMed, Scopus, Embase, and Web of Science databases to identify clinical trials investigating the effects of selenium and probiotics co-supplementation. Eligible studies included randomized controlled trials (RCTs) and non-randomized clinical trials assessing clinical, metabolic, inflammatory, oxidative stress, and immune-related outcomes. RESULTS: Ten clinical studies met the inclusion criteria, including populations with polycystic ovary syndrome, Alzheimer’s disease, schizophrenia, leukemia, gestational diabetes, elderly nursing home residents, and ICU patients with stage I–II bedsores. Co-supplementation was associated with changes in glycemic indices (fasting plasma glucose, insulin, HOMA-IR, QUICKI), selected lipid parameters (triglycerides, total cholesterol, LDL cholesterol), oxidative stress markers (total antioxidant capacity, glutathione, malondialdehyde), and inflammatory markers, particularly high-sensitivity C-reactive protein. Studies also reported improvements in mental health scores, cognitive function (MMSE), and immune-related markers including adhesion molecules. Gene expression changes, including TNF-α and PPAR-γ, were reported in limited studies. Overall, co-supplementation was well tolerated, with no serious adverse events reported. CONCLUSIONS: Selenium and probiotics co-supplementation may provide beneficial effects on metabolic regulation, oxidative stress, and inflammation-related conditions. However, heterogeneity in study design, probiotics’ strains, selenium dosage, and treatment duration limits firm conclusions. Larger, well-designed randomized controlled trials with long-term follow-up are needed.},
}

@article {pmid41945008,
year = {2026},
author = {Vashisht, K and Kumar, H and Ankalgi, A and Ashawat, MS and Baldi, A and Kushawaha, SK},
title = {Auranofin reimagined: an emerging therapeutic candidate for neurodegenerative diseases through molecular mechanistic insights.},
journal = {Inflammopharmacology},
volume = {34},
number = {5},
pages = {3153-3164},
pmid = {41945008},
issn = {1568-5608},
abstract = {Drug repurposing presents a strategic shortcut in therapeutic discovery, especially in the complex landscape of neurological disorders where traditional drug development faces substantial challenges. A compelling candidate in this domain is auranofin (AF), an FDA-approved gold(I) compound initially indicated for rheumatoid arthritis, now gaining traction for its broad neuroprotective potential across multiple preclinical models, including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI), and epilepsy. AF exerts multifaceted neuroprotective effects primarily through the Keap1–Nrf2–ARE pathway, which upregulates the expression of antioxidant and anti-inflammatory genes while suppressing the production of pro-oxidant and pro-inflammatory mediators. In AD, AF reactivates the PI3K/AKT axis, downregulates GSK-3β, and mitigates tau pathology. In TBI, it disrupts the ASK1–MAPK cascade, enhances mitochondrial integrity, and upregulates the anti-apoptotic protein Bcl-2. In PD, it promotes neuronal survival through the AKT–FOXO/CREB pathway, while in epilepsy, it attenuates neuroinflammation and oxidative stress via inhibition of NF-κB signaling. By orchestrating a multi-targeted neuroprotective response converging on Nrf2 signaling, AF emerges as a potential repurposing candidate with multi-pathway neuroprotective activity. Peer-reviewed data from Scopus, PubMed, and Web of Science support all findings. To our knowledge, this is the first comprehensive review to highlight AF multi-pathway activity in neurodegenerative disorders, addressing critical gaps in current knowledge. These preclinical insights collectively underscore its translational potential and capacity to reshape the neurotherapeutic landscape.},
}

@article {pmid42047847,
year = {2026},
author = {Yao, W and Liu, L and Wang, J and Chen, S and Zhang, C and Liao, R and Wang, Y and Ou, K and Jiang, L and Yu, Y and Dong, W},
title = {Association Between Blood-Brain Barrier Disruption and Gut Microbiota Dysbiosis in Parkinson's Disease.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01738-2},
pmid = {42047847},
issn = {1573-6830},
abstract = {Parkinson’s disease (PD) is a chronic neurodegenerative disorder primarily characterized by motor dysfunction. It is the second most prevalent neurodegenerative disorder after Alzheimer’s disease. Its pathological manifestations include typical motor symptoms associated with Lewy bodies and loss of nigrostriatal dopaminergic neurons. Emerging evidence indicates that blood-brain barrier (BBB) dysfunction contributes to the onset and progression of PD. The BBB is essential for maintaining central nervous system (CNS) homeostasis by restricting the entry of circulating components and exogenous substances into the brain. In PD, disruption of BBB integrity facilitates the infiltration of circulating neurotoxins, macromolecules, and microorganisms, thereby triggering neuroinflammatory and immune responses. Furthermore, gut microbiota dysbiosis significantly impacts the integrity and function of the BBB via inflammatory mediators and metabolites, thus promoting PD progression. This study summarizes the associations between the BBB and gut microbiota with the onset and progression of PD and investigates the potential of enhancing BBB integrity and optimizing the gut microbiota as a theoretical foundation for developing novel therapeutic approaches for PD. Clinical trial number: not applicable.},
}

@article {pmid42053728,
year = {2026},
author = {Pirillo, A and Catapano, AL},
title = {CETP Renaissance with Obicetrapib.},
journal = {Current atherosclerosis reports},
volume = {28},
number = {1},
pages = {},
pmid = {42053728},
issn = {1534-6242},
abstract = {PURPOSE OF REVIEW: This review examines the emerging role of cholesteryl ester transfer protein (CETP) inhibition, with a focus on obicetrapib, in lipid management and its potential implications beyond atherosclerotic cardiovascular disease (ASCVD), including neurodegeneration, glycaemic control, age-related macular degeneration (AMD), sepsis, and kidney function. RECENT FINDINGS: Obicetrapib is a potent, selective CETP inhibitor that overcomes the limitations of earlier agents, demonstrating substantial reductions in LDL-C, apolipoprotein B, non-HDL-C, and lipoprotein(a), alongside marked increases in HDL-C. Phase 2 and 3 trials confirm robust lipid-modifying efficacy and favourable safety. Emerging data suggest broader biological effects. Genetic and mechanistic studies link reduced CETP activity to improved brain structure and lower dementia risk, with biomarker analyses showing attenuation of Alzheimer’s disease-related markers, particularly in APOE ε4 carriers. Evidence further indicates potential metabolic benefits, including reduced risk of type 2 diabetes and improved glycaemic control. While genetic studies raise concerns about increased AMD risk, clinical trial data have not confirmed this association. Preclinical and human data suggest a protective role in sepsis via HDL-mediated endotoxin clearance, and early analyses indicate possible renal benefits through slower decline in kidney function. Obicetrapib represents a promising advancement in CETP inhibition, combining potent lipid-lowering effects with a good safety profile. Beyond cardiovascular risk reduction, emerging evidence supports potential roles in neurodegenerative disease, metabolic regulation, infection outcomes, and renal function. Ongoing outcome trials will determine its clinical impact and broader therapeutic relevance.},
}

@article {pmid42060068,
year = {2026},
author = {Vilella, D and Urso, D and Valguarnera, A and Volpe, G and Accadia, M and Zecca, C and Vitulli, A and De Blasi, R and Bertolino, A and Logroscino, G},
title = {Behavioral and Personality Changes as the First Manifestation of Spinocerebellar Ataxia Type 2.},
journal = {Cerebellum (London, England)},
volume = {25},
number = {3},
pages = {},
pmid = {42060068},
issn = {1473-4230},
support = {B84I18000540002//Tecnopolo per la Medicina di Precisione/ ; },
abstract = {Background. Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the ATXN2 gene. Although classically characterized by progressive cerebellar ataxia and oculomotor abnormalities, increasing evidence indicates that SCA2 is a multisystem disorder with prominent cognitive, behavioral, and psychiatric manifestations. These non-motor symptoms may precede overt motor signs, leading to diagnostic challenges and misdiagnosis as primary psychiatric conditions. Case Presentation. We report the case of a 59-year-old man with a several-year history of progressive behavioral and emotional dysregulation, initially diagnosed as a personality disorder. Prominent features included irritability, impulsivity, disinhibition, hypersexuality, altered eating behavior, and recurrent self-endangering suicidal gestures, with relatively preserved functional autonomy. Neurological examination revealed subtle cerebellar signs. Neuropsychological assessment showed impaired verbal memory with preserved recognition and borderline attentional–executive deficits, consistent with cerebello–frontal dysfunction. Brain magnetic resonance imaging (MRI) demonstrated moderate-to-severe cerebellar and brainstem atrophy, while dopamine transporter SPECT revealed severe bilateral presynaptic dopaminergic denervation. Cerebrospinal fluid biomarkers excluded Alzheimer’s disease. Genetic testing confirmed SCA2 with 38 CAG repeats in ATXN2. Conclusions. This case illustrates an atypical presentation of SCA2 in which behavioral and psychiatric symptoms preceded motor manifestations by several years. Recognition of such presentations is crucial to avoid misdiagnosis, reduce diagnostic delay, and enable timely genetic counselling and multidisciplinary management, reinforcing the concept of SCA2 as a multisystem neurodegenerative disorder.},
}

@article {pmid42340875,
year = {2026},
author = {Meng, H and Cheng, G and Dong, H and Xie, X and Wang, J and Cai, C and Liu, X and Xu, Y and He, X and Tan, W and Zeng, Y},
title = {Sex-Specific Modifiable Factors for Incident Late-Onset Dementia in the Geographic Context: A Longitudinal Comparative Analysis of Multicohort Studies across 19 Countries.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-14},
doi = {10.1159/000551779},
pmid = {42340875},
issn = {1423-0208},
abstract = {BACKGROUND: Evidence regarding sex-specific risk factors across various regions contributing to late-onset dementia (LOD) incidence remains limited. We sought to explore the common influencing factors within the same sex across various regions.

METHODS: This cohort study used four independent samples across 19 countries between 2010 and 2020: the China Health and Retirement Longitudinal Study (CHARLS), the Survey of Health, Ageing and Retirement in Europe (SHARE), the Health and Retirement Study (HRS) in the United States, and the English Longitudinal Study of Ageing (ELSA). Feature selection was performed using LASSO and Boruta models. Hazard ratios (HRs) for selected variables and LOD or late-onset Alzheimer's disease (LOAD) were estimated using the Cox model.

RESULTS: We included 39,439 participants (56.3% female) aged 65 years and older without dementia at baseline. During the follow-up period, 3,548 patients (59.2% female) with LOD were recorded. Females had a 21% lower risk (pooled HR: 0.79 [0.69-0.89]) of developing LOD than males. While age was identified as a common risk factor across all female populations in four cohorts, no common risk factor was found among male populations. Current drinkers served as a consistent modifiable factor for females in 18 countries (from North America and Europe) other than China and for males in Europe (HR: 0.62 [0.47-0.82]). An additive interaction between current drinking and age was observed in females but not in males. The association between drinking alcohol frequency and LOD was inconsistent among females in the HRS and the ELSA. No significant associations between alcohol consumption and LOAD were found in the HRS and the ELSA.

CONCLUSION: These findings suggest that moderate alcohol intake may reduce the risk of LOD among younger-old females in North America and Europe, as well as males in Europe.},
}

@article {pmid42341216,
year = {2026},
author = {Liang, J and Wang, Q and Guo, S and Zhang, W and Xie, M and Song, Q},
title = {scDeepAPA: a deep learning framework for single-cell alternative polyadenylation identification.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {3},
pages = {},
pmid = {42341216},
issn = {1477-4054},
support = {R35GM151089//National Institute of General Medical Sciences of the National Institutes of Health/ ; R35GM128753//National Institute of General Medical Sciences of the National Institutes of Health/ ; CIS230237//Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support/ ; #2138259//National Science Foundation/ ; #2138286//National Science Foundation/ ; #2138307//National Science Foundation/ ; #2137603//National Science Foundation/ ; #2138296//National Science Foundation/ ; },
mesh = {*Polyadenylation ; *Deep Learning ; Humans ; Animals ; *Single-Cell Analysis/methods ; Mice ; RNA, Messenger/genetics/metabolism ; },
abstract = {Alternative polyadenylation (APA) is a widespread post-transcriptional regulatory mechanism that diversifies transcript isoforms and modulates mRNA stability, localization, and translation. Although single-cell RNA sequencing (scRNA-seq) provides an unprecedented opportunity to study cell-type-specific APA dynamics, existing computational tools are largely designed for bulk RNA-seq data or rely heavily on gene annotations, limiting their applicability to single-cell contexts. Here, we present scDeepAPA, a deep learning framework specifically optimized for scRNA-seq data to enable accurate polyadenylation site (PAS) detection, isoform quantification, and functional interpretation of APA events at single-cell resolution. Trained on high-confidence annotations from PolyASite v3.0, scDeepAPA integrates convolutional feature extraction with Mamba-based state-space modeling and bidirectional LSTM layers to capture both long-range and local sequence dependencies. Comprehensive benchmarking against five state-of-the-art PAS prediction models demonstrates that scDeepAPA consistently achieves superior performance across accuracy, F1 score, and area under the receiver operating characteristic metrics in both human and mouse datasets. Applying scDeepAPA to Alzheimer's disease mouse brain data revealed widespread, cell-type-specific APA remodeling across immune and glial populations, including shifts toward proximal PAS usage and 3' UTR shortening. In KRAS-mutant small cell lung cancer, scDeepAPA uncovered global proximal PAS activation and tumor-specific intronic polyadenylation events. Notably, several intronic APA events generated truncated transcripts encoding predicted neoantigenic peptides with strong major histocompatibility complex class I binding affinity, supported by structural modeling and tumor-specific expression patterns. By enabling accurate PAS identification and quantitative APA profiling, scDeepAPA facilitates in-depth downstream analyses of regulatory mechanisms and immunogenic consequences in single-cell transcriptomics, advancing the understanding of post-transcriptional regulation in neurodegeneration and cancer.},
}

*Polyadenylation
*Deep Learning
Humans
Animals
*Single-Cell Analysis/methods
Mice
RNA, Messenger/genetics/metabolism

@article {pmid42341223,
year = {2026},
author = {Fazio, S and Moczygemba, W and Stratton, L and Evans, K and Weidner, W and Banerjee, S and Zimmerman, S},
title = {Global Perspectives on Person-Centered Dementia Care: Results of an International Survey.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648251341098},
pmid = {42341223},
issn = {1552-4523},
abstract = {Person-centeredness is instrumental to quality dementia care but is inconsistently defined and descriptions often reflect higher-income and Eurocentric perspectives. This paper addressed these limitations by surveying 39 member associations of Alzheimer's Disease International regarding the global quality of dementia care, challenges and successes in providing person-centered dementia care, and definitions of person-centered dementia care in their countries. The economically and geographically diverse respondents described a common lack of both quality and person-centered dementia care and identified associated barriers. Results suggest that identifying shared perspectives is necessary to further the person-centeredness of dementia care, and should reflect five core tenets: individualize care, support and acknowledge caregivers, empower the individual, cultivate respectful relationships, and address dimensions of wellness.},
}

@article {pmid42341522,
year = {2026},
author = {Sun, M and Ye, D and Min, P and Guo, M and Zhao, X and Zhou, Y and Xu, L and Wu, Y and Meng, Z and Wang, G},
title = {Huang-Lian-Jie-Du Decoction alleviates cognitive deficits in Alzheimer's disease via aromatase-mediated regulation of Aβ metabolism.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {159},
number = {},
pages = {158467},
doi = {10.1016/j.phymed.2026.158467},
pmid = {42341522},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and pathological accumulation of amyloid-β (Aβ). Hippocampal aromatase (AROM), a key enzyme for local estrogen biosynthesis, has emerged as an important regulator of Aβ metabolism. Huang-Lian-Jie-Du Decoction (HLJD), a classical traditional Chinese medicine formula, has shown therapeutic potential in AD; however, its molecular mechanism remains largely unclear.

METHODS: The effects of HLJD on cognitive function and Aβ metabolism were evaluated in APP/PS1 transgenic mice and Aβ1-42-induced HT22 cells. Behavioral performance was assessed using the Morris water maze. Aβ burden and the expression of Aβ-related metabolic enzymes (BACE1, IDE, and NEP) were analyzed by western blotting, qRT-PCR, and immunofluorescence. Network pharmacology was applied to predict potential targets and pathways of HLJD. Gain and loss of function experiments targeting AROM were performed to determine its mechanistic involvement.

RESULTS: HLJD significantly improved learning and memory deficits and reduced hippocampal Aβ accumulation in APP/PS1 mice without altering APP expression. In both in vivo and in vitro models, HLJD significantly upregulated AROM expression. HLJD suppressed Aβ production by downregulating BACE1 while enhancing Aβ degradation through upregulation of IDE and NEP. Importantly, AROM knockdown largely abolished the regulatory effects of HLJD on Aβ metabolism, whereas AROM overexpression reproduced its protective actions.

CONCLUSION: These findings demonstrate that HLJD alleviates cognitive impairment in AD models by activating hippocampal aromatase and restoring Aβ homeostasis through coordinated regulation of Aβ production and degradation. This study identifies AROM as a critical mediator of HLJD's neuroprotective effects and highlights AROM-dependent modulation of local estrogen synthesis as a promising therapeutic strategy for Alzheimer's disease.},
}

@article {pmid42341593,
year = {2026},
author = {Wik, E and Dahlén, AD and Julku, U and Xiong, M and Michno, W and Syvänen, S and Sehlin, D},
title = {Brain interstitial fluid pharmacokinetics and therapeutic effect of a BBB penetrating amyloid beta antibody measured by microdialysis.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {4},
pages = {e00949},
doi = {10.1016/j.neurot.2026.e00949},
pmid = {42341593},
issn = {1878-7479},
abstract = {The disease-modifying antibody lecanemab for treating Alzheimer's disease (AD) was initially designed to target amyloid-beta (Aβ) protofibrils, i.e. soluble aggregates of Aβ, but it has also been successful in clearing insoluble amyloid plaques in clinical studies. Therefore, this study aimed to investigate how a brain penetrating, bispecific murine variant of lecanemab (RmAb158-scFv8D3) distributes in the brain and interacts with different pools of aggregated Aβ in APP transgenic mice. The alpha-synuclein targeting antibody RmAbSynO2-scFv8D3 was used as control. Further, by performing in vivo high cut-off microdialysis in freely moving animals, brain interstitial fluid (ISF) was continuously collected across 24 h to assess concentrations of free antibody in the brain. Post mortem distribution of the antibodies was analyzed by sequential extraction of brain tissue. RmAb158-scFv8D3 showed rapid ISF clearance as well as a redistribution from brain extracts containing small, soluble Aβ species toward brain extracts containing insoluble, plaque-associated Aβ with time. A treatment effect was detected already at 12 h post injection, whereby the RmAb158-scFv8D3-treated animals showed lower concentrations of the smallest, most soluble Aβ aggregates. Collectively, these findings suggest that within the first 24 h after a single injection of the bispecific RmAb158-scFv8D3 antibody we can capture the antibody's initial brain distribution and interactions with both soluble Aβ aggregates and insoluble, plaque-associated Aβ. These interactions mediate a swift reduction of soluble Aβ, while clearance of insoluble Aβ requires longer treatment time.},
}

@article {pmid42341704,
year = {2026},
author = {Khan, S and Godugu, C},
title = {Identifying multitarget directed phytoconstituent against Parkinson's disease: A network pharmacology approach.},
journal = {Computational biology and chemistry},
volume = {124},
number = {Pt 2},
pages = {109201},
doi = {10.1016/j.compbiolchem.2026.109201},
pmid = {42341704},
issn = {1476-928X},
abstract = {BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative condition after Alzheimer's disease, with no cure for either. The major hurdle in identifying a therapeutic agent for such progressive disorders is their complex pathology. The current understanding is still in the cradle stage due to multifactorial protein and pathway participation, with neuroinflammation playing a major role. In the quest to link neuroinflammatory processes with cell death, pyroptosis was found to play a key role in various pathologies, including PD.

METHODOLOGY: To identify the pathological mediators participating in pyroptosis and PD, we used network pharmacology tools. Inflammatory pathways like IL-17, TLR-, NLR-, besides cell death, were reported to be highly enriched in the Gene Ontology and KEGG analysis. Further, to screen the phytoconstituent that can potentially act through a multi-targeted approach in inhibiting the pyroptosis process, we used molecular docking and in vitro tools.

RESULT: We identified 11 hubb genes through network pharmacology and screened phytoconstituents against them, where 3 of them could bind with all the targets in the docking study. Rosmarinic acid and silibinin could be a promising multitarget ligand, corroborating the docking scores, MMGBSA energies, and MD simulation results. In the preliminary in vitro screening, we observed that cellular ROS, mitochondrial damage, and cell death, as predicted by macropore formation, were attenuated by both the phytoconstituent comparable to Brilliant blue G, supporting our hypothesis. This suggests the potential use of RA and SB against pyroptosis and neuroinflammation-mediated PD pathology.},
}

@article {pmid42341895,
year = {2026},
author = {Shirotani, K and Hatta, D and Watanabe, K and Saito, T and Saido, TC and Iwata, N},
title = {Trem2 R47H mutation shows mild, but functionally divergent alterations in microglial phenotypes compared to Trem2 deficiency in aged App[NL-F] knock-in mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115894},
doi = {10.1016/j.expneurol.2026.115894},
pmid = {42341895},
issn = {1090-2430},
abstract = {The TREM2 R47H variant increases the risk of Alzheimer's disease (AD), yet its functional impact in aged mouse models remains incompletely understood. We generated a humanized Trem2 R47H knock-in (KI) line on the App[NL-F] background and compared it with a Trem2 knockout (KO) line to assess the degree of TREM2 functional impairment. Accumulation of amyloid β 42 and formation of dystrophic neurites were increased in Trem2 KO mice but not in Trem2 R47H KI mice at 18 or 24 months. qPCR and transcriptomic analyses revealed Trem2 KO mice showed deficits in upregulation of microglial genes while Trem2 R47H KI mice showed a response similar to control mice. Differential gene expression analysis identified altered expressions of genes responsible for ER stress/unfolded protein response and intracellular signalling in Trem2 R47H KI mice. Among the differentially expressed genes, Pmel and Gpnmb were or tended to be downregulated in Trem2 R47H KI as well as in Trem2 KO mice indicating their involvement in AD pathogenesis. These results clearly indicate that the TREM2 R47H variant confers a mild, rather than null, effect on microglial alterations during AD development and that Trem2 R47H KI mice should be used to understand pathological mechanism elicited by TREM2. Further identification and characterization of genes differentially expressed in Trem2 R47H KI mice will provide important insights into how the TREM2 risk variant modulates Alzheimer's disease-related pathology.},
}

@article {pmid42342012,
year = {2026},
author = {He, Y and Lv, Z and Wang, T and Zhou, P},
title = {Differential Regulation of Neuroinflammation and Tau Pathology by Apolipoprotein E3 and E4 via the mTORC1 Pathway: Implications for Alzheimer's Disease Risk.},
journal = {Archives of biochemistry and biophysics},
volume = {},
number = {},
pages = {110914},
doi = {10.1016/j.abb.2026.110914},
pmid = {42342012},
issn = {1096-0384},
abstract = {OBJECTIVE: This study examined whether apolipoprotein E3 (apoE3) and apolipoprotein E4 (apoE4) are associated with differential neuroinflammatory and tau-related signaling in U87 MG cells, with particular focus on mTORC1-related markers relevant to Alzheimer's disease (AD).

METHODS: U87 MG cells were transiently transfected with apoE3- or apoE4-expressing plasmids, or transfected with apoE-targeting siRNA in the corresponding knockdown experiments. Phospho-NF-κB p65 (Ser536), phospho-mTOR (Ser2448), phospho-4E-BP1 (Ser65), and phospho-tau (Ser202/Thr205) were assessed by Western blotting, and TNFα and IL1β mRNA levels were measured by RT-qPCR.

RESULTS: Overexpression of both isoforms increased inflammatory and mTORC1-related signaling relative to vector control. Compared with apoE3, apoE4 overexpression was associated with higher TNFα and IL1β mRNA expression and higher phospho-tau levels, while differences in phospho-mTOR and phospho-4E-BP1 were not significant. Knockdown reduced these markers in both groups, with lower residual phospho-NF-κB p65, TNFα, IL1β, phospho-4E-BP1, and phospho-tau levels in the apoE3-knockdown condition than in the apoE4-knockdown condition. Because apoE4 protein expression was higher than apoE3 in the transient overexpression system, between-isoform differences in the gain-of-function arm should be interpreted cautiously.

CONCLUSION: These cell-based findings support an association between apoE isoforms and differential inflammatory and tau-related signaling linked to mTORC1. However, direct pharmacological or genetic validation of mTORC1 dependency was not performed, so the mechanistic relationship should be interpreted as suggestive rather than definitive.},
}

@article {pmid42342024,
year = {2026},
author = {Al-Kuraishy, HM and Fahad, EH and Jabir, MS and Rafeeq, MF and Sulaiman, GM and Amara, IB and Albuhadily, AK and Al-Gareeb, AI},
title = {Targeting of RhoA-ROCK pathway activators and linked molecular signaling in Alzheimer's disease: The paving dawn for future therapy.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.032},
pmid = {42342024},
issn = {1873-7544},
abstract = {Rho-associated protein kinase (ROCK) is a serine/threonine kinase that plays a central role in regulating cellular processes, including growth, proliferation, survival, and migration. ROCK exists as two isoforms, ROCK1 and ROCK2, which function as the principal downstream effectors of Rho GTPases. Activation of the RhoA-ROCK signaling pathway is induced by a variety of extracellular stimuli, including angiotensin II (Ang II), platelet-derived growth factor (PDGF), integrins, and vascular endothelial growth factor (VEGF). RhoA-ROCK pathway promotes the production of amyloid beta (Aβ) and increases the formation of neurofibrillary tangles (NFTs) the hallmarks of Alzheimer's disease (AD). It has been shown that Rho-kinase inhibitors are effective against AD neuropathology and other neurodegenerative diseases through modulation of synaptic activity and neuroinflammation. To date, no clinical trials have directly evaluated the efficacy and safety of ROCK inhibitors in patients with AD. This gap highlights the need to explore alternative therapeutic strategies within the RhoA-ROCK signaling axis. In particular, targeting upstream activators of this pathway such as angiotensin II (Ang II), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and integrin may represent a more conceivable approach to attenuate AD-related neuropathology. Modulation of these signaling inputs has the potential to suppress the aberrant RhoA-ROCK activation and its downstream pathological consequences. Accordingly, this review aims to elucidate the mechanistic role of the RhoA-ROCK pathway in AD, and to critically examine the therapeutic potential targeting its upstream activators as a therapeutic strategy for AD.},
}

@article {pmid42342156,
year = {2026},
author = {Wu, Y and Di, Y and Wang, H and Wang, L and Zhang, J and Zhang, Y and Lyu, D},
title = {Comparative efficacy and safety of pathway-targeted pharmacotherapies for Alzheimer's disease: a systematic review and network meta-analysis of phase III trials.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103216},
doi = {10.1016/j.arr.2026.103216},
pmid = {42342156},
issn = {1872-9649},
abstract = {OBJECTIVE: To compare the efficacy and safety of pharmacotherapies targeting different pathological pathways in Alzheimer's disease (AD).

METHODS: We systematically searched PubMed, Embase, the Cochrane Library, Web of Science, ClinicalTrials.gov, and AlzForum for randomized controlled trials (RCTs) from database inception to August 24, 2025. A random-effects network meta-analysis was then conducted.

RESULTS: A total of 75 RCTs involving 68,398 participants were included. For Alzheimer's Disease Assessment Scale-Cognitive subscale, interventions targeting inflammatory pathways (standardized mean difference [SMD] = -0.24, 95% confidence interval [CI]: -0.40 to -0.08) and neurotransmitters (SMD = -0.22, 95% CI: -0.29 to -0.15) were superior to placebo; sensitivity analysis additionally supported interventions targeting the gut-brain axis (SMD = -0.26, 95% CI: -0.51 to -0.01). No significant differences were observed for Clinical Dementia Rating-Sum of Boxes. For Mini-Mental State Examination, interventions targeting neurotransmitters significantly improved scores versus placebo (mean difference [MD] = 0.61, 95% CI: 0.37 to 0.86). Overall, interventions targeting neurotransmitters, mainly consisting of cholinesterase inhibitors, consistently ranked among the most effective treatments. Compared with placebo, interventions targeting neurotransmitters, amyloid-beta (Aβ), and synaptic plasticity/neuroprotection increased the risk of adverse events; interventions targeting Aβ and synaptic plasticity/neuroprotection also raised the risks of serious adverse events, while the risk of death did not differ significantly.

CONCLUSIONS: Pharmacotherapies targeting neurotransmitters, the gut-brain axis, and inflammatory pathways may offer comparatively favorable cognitive benefits in AD. However, variations in safety profiles across intervention classes highlight the need for careful benefit-risk assessment. Given the limited evidence base for certain strategies, further high-quality RCTs are warranted to confirm these findings.},
}

@article {pmid42342296,
year = {2026},
author = {Dave, S and Banerjee, J and Banerjee, S and Tiwari, AK},
title = {Neurodiagnostic: Advances in diagnostic tools.},
journal = {International review of cell and molecular biology},
volume = {405},
number = {},
pages = {111-147},
doi = {10.1016/bs.ircmb.2025.12.001},
pmid = {42342296},
issn = {1937-6448},
mesh = {Humans ; Biomarkers ; Animals ; *Neurodegenerative Diseases/diagnosis ; },
abstract = {Understanding the pathologies related to neurological issues, viz. Alzheimer's disease (AD), brain tumors, and multiple sclerosis (MS) are complex and still lack effective therapeutics. Management of the global health burden caused by the escalating cases of neurodegenerative diseases urgently requires early and precise diagnosis. While conventional diagnostic tools like X-ray, Computed Tomography (CT), and Electrophysiological Techniques still hold a crucial role in the field of neurodiagnosis, researchers and clinicians are searching for advancements and the development of cutting-edge tools to enhance diagnostic accuracy, early detection, and improved health outcomes. Some later developed tools like PET and fMRI have proven beneficial in diagnosing the structural and functional aspects of neurological pathologies. However, specific and differential diagnosis for different neurodegenerative diseases is critical. We discuss how Omics studies (including proteomics and genomics), Artificial Intelligence (AI), and Machine learning (ML) have further enhanced the advancements in the field of neurodiagnostics. Our chapter highlights the importance of identifying novel blood-based, cerebrospinal fluid (CSF) based biomarkers while giving emphasis to developing non-invasive biomarkers to uplift the field of neurodiagnosis. The chapter concludes that the importance of the development of advanced bioimaging, multi-omics studies, computational studies, and exploring futuristic technologies, including the development of biosensors, can pave the path for next-generation neurodiagnostic techniques.},
}

Humans
Biomarkers
Animals
*Neurodegenerative Diseases/diagnosis

@article {pmid42342369,
year = {2026},
author = {Escott-Price, V and Simmonds, E and Owen, MJ and O'Donovan, M},
title = {Genetic investigation of non-affective psychosis and depression as causal risk factors for dementia.},
journal = {BMJ mental health},
volume = {29},
number = {1},
pages = {},
pmid = {42342369},
issn = {2755-9734},
mesh = {Humans ; *Psychotic Disorders/genetics/complications ; Risk Factors ; Female ; Male ; *Dementia/genetics/etiology ; Genetic Predisposition to Disease ; Aged ; *Major Depressive Disorder/genetics/complications ; Genetic Risk Score ; *Alzheimer Disease/genetics ; *Depression/genetics/complications ; United Kingdom ; Schizophrenia/genetics ; },
abstract = {BACKGROUND: Major psychiatric disorders are associated with increased risk of dementia but establishing whether psychiatric disorders causally increase dementia risk is challenging because dementia pathology can precede clinical diagnosis by decades. Prodromal psychiatric symptoms may arise long before cognitive decline, leaving open the possibility of reverse causation.

OBJECTIVE: We aimed to determine whether non-affective psychosis or depression credibly causally influence dementia risk using a design robust to reverse causation. We tested whether people with psychiatric disorders who later develop dementia show reduced genetic liability to Alzheimer's disease (AD) compared with dementia cases without such history.

METHODS: We compared AD genetic liability, measured by polygenic risk scores (PRS) among dementia cases (N=7936) with and without prior non-affective psychosis (N=56) or depression (N=937) in the UK Biobank. We examined whether schizophrenia or major depressive disorder (MDD) PRS correlates with dementia liability to assess whether shared trait liability contributes to the association.

FINDINGS: Dementia cases with prior non-affective psychosis or depression had lower AD genetic liability than those without a psychiatric history (psychosis: B=-0.29, 95% CI (-0.54 to -0.05), p=0.036; depression: B=-0.12, 95% CI (-0.18 to -0.05), p=0.0004), which is inconsistent with the hypothesis that the association between psychiatric disorders in dementia is explained by prodromal dementia effects. After excluding people with psychiatric diagnoses, neither schizophrenia nor MDD liability showed the negative correlations with AD liability in people with dementia expected if trait liability to those disorders per se contributed to dementia risk. Our findings instead are consistent with exposure to the disorders themselves as being associated with dementia.

CONCLUSIONS: Our findings are consistent with the hypothesis that psychiatric disorders are associated with increased vulnerability to dementia.

CLINICAL IMPLICATIONS: Identification of potentially modifiable mechanisms for the association and optimal management of non-affective psychosis and depression may help reduce long-term dementia risk and inform prevention strategies.},
}

Humans
*Psychotic Disorders/genetics/complications
Risk Factors
Female
Male
*Dementia/genetics/etiology
Genetic Predisposition to Disease
Aged
*Major Depressive Disorder/genetics/complications
Genetic Risk Score
*Alzheimer Disease/genetics
*Depression/genetics/complications
United Kingdom
Schizophrenia/genetics

@article {pmid42342736,
year = {2026},
author = {Chang, HC and Su, YJ and Yang, SC and Chen, CC and Wu, MC and Gau, SY},
title = {Comparative dementia and Parkinson's disease risk associated with melatonin, benzodiazepine, or zolpidem use in patients with sleep disorders: a retrospective cohort study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-58529-4},
pmid = {42342736},
issn = {2045-2322},
abstract = {Melatonin is widely used for sleep disorders and has been hypothesized to exert neuroprotective effects. However, real-world evidence regarding its long-term association with neurodegenerative outcomes remains limited and may be confounded by prodromal sleep disturbances related to early neurodegenerative disease. We conducted a retrospective target trial emulation using the TriNetX Global Collaborative Network between 2015 and 2024. Adults aged ≥ 50 years with sleep disorders identified using ICD-10-CM diagnostic codes and newly prescribed melatonin, benzodiazepines, or zolpidem were eligible. Medication exposure was defined using prescription records documented in the electronic health record system. Two active-comparator cohorts were constructed: melatonin versus benzodiazepines and melatonin versus zolpidem. Outcomes included incident all-cause dementia (ICD-10-CM F01-F03), vascular dementia (F01), Parkinson's disease (G20), and Alzheimer's disease (G30). Analyses were performed in 1:1 propensity score-matched cohorts adjusted for demographic characteristics, healthcare utilization, body mass index, comorbidities, psychosocial risk factors, and selected comedications. Sensitivity analyses incorporated lag periods, varying follow-up durations, and alternative matching approaches. Among 91,216,302 eligible individuals in the TriNetX Global Collaborative Network, 189,858 matched pairs were included in the melatonin versus benzodiazepine analysis and 190,889 matched pairs in the melatonin versus zolpidem analysis. Median follow-up duration was 1.88 versus 2.88 years in the melatonin versus benzodiazepine cohorts and 2.37 versus 3.70 years in the melatonin versus zolpidem cohorts. Melatonin use was associated with higher observed risk of all-cause dementia compared with benzodiazepines (HR 2.09, 95% CI 2.01-2.16) and zolpidem (HR 1.74, 95% CI 1.67-1.82). Elevated risks were also observed for vascular dementia (HR 2.39, 95% CI 2.21-2.60; HR 1.99, 95% CI 1.81-2.19), Parkinson's disease (HR 1.63, 95% CI 1.51-1.76; HR 1.44, 95% CI 1.33-1.57), and Alzheimer's disease (HR 2.11, 95% CI 1.96-2.26; HR 1.54, 95% CI 1.41-1.67). Across sensitivity analyses, including lag-time analyses up to 4 years, the direction of associations remained consistent. Melatonin initiation was associated with higher observed risks of dementia and Parkinson's disease outcomes compared with benzodiazepine or zolpidem initiation among older adults with sleep disorders. These findings should not be interpreted as evidence of a causal pharmacologic effect of melatonin and may instead reflect residual confounding, confounding by indication, and prodromal neurodegenerative disease.},
}

@article {pmid42342913,
year = {2026},
author = {Ahmad, S and Wu, T and Arnold, M and Hankemeier, T and Ghanbari, M and Roshchupkin, G and Uitterlinden, AG and Borkowski, K and Neitzel, J and Kraaij, R and , and van Duijn, CM and Ikram, MA and Kaddurah-Daouk, R and Kastenmüller, G},
title = {The blood metabolome of brain health in midlife and influences of genes, microbiome and exposome.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42342913},
issn = {2662-8465},
support = {U19AG063744//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG058942//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG059093//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG061359//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG057452//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG063744//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG058942//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG063744//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG058942//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG059093//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG057452//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG046171//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG051550//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG061359//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 536691227//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; #733050814//ZonMw (Netherlands Organisation for Health Research and Development)/ ; },
abstract = {Metabolic alterations are increasingly implicated in neurological disorders, including Alzheimer's disease (AD), highlighting the relevance of the peripheral metabolome, shaped by genetic and environmental exposures, for brain health. We examined the relation of 991 blood metabolites with cognition and magnetic resonance imaging (MRI) measures cross-sectionally in 1,082 dementia-free middle-aged participants of the population-based Rotterdam Study and quantified contributions of genetic variation, lifestyle, comorbidities, medication and gut microbiota to metabolite variance. Cognition-associated metabolites were replicated in two independent cohorts of older adults and tested for associations with incident AD longitudinally in one cohort. Twenty-two metabolites were associated with MRI measures. Fourteen metabolites showed replicated associations with cognition, with ergothioneine exhibiting the largest effect. The metabolite signature of cognition mirrored that of incident AD. Lifestyle, clinical variables and medication were the strongest determinants of cognition-associated and MRI-associated metabolites, explaining up to 28.6% of their variance. Antacid use was associated with worse cognition and lower ergothioneine levels, which mediated 31.5% of the negative medication effect, suggesting implications for AD prevention.},
}

@article {pmid42343033,
year = {2026},
author = {Khurshid, A and Alkasir, A and Oliveira, E and Carton, TW and Chavez, D and Kendrick, D and Li, X and Pletcher, T and Porreca, D and Sarkar, IN and Seidman, G and Bynum, J},
title = {Establishing a health information exchange research network (HIERN) to support population health studies.},
journal = {NPJ digital medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41746-026-02908-8},
pmid = {42343033},
issn = {2398-6352},
abstract = {We propose the Health Information Exchange Research Network (HIERN) to advance population health research by leveraging state and regional HIEs and their representative real-world data. HIERN builds on existing governance and infrastructure to create centralized or distributed data repositories for longitudinal, multisource data integration. It helps study important clinical and epidemiological topics, such as Alzheimer's Disease and Related Dementias, one of the fastest-growing chronic conditions in the United States.},
}

@article {pmid42343038,
year = {2026},
author = {Tang, X and Li, M},
title = {Puerarin as a Modulator of Synaptic Plasticity: Molecular Mechanisms Underlying Learning and Memory Restoration in Neurodegenerative Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42343038},
issn = {1559-1182},
mesh = {*Isoflavones/pharmacology/therapeutic use ; *Neuronal Plasticity/drug effects ; Animals ; *Neurodegenerative Diseases/drug therapy/physiopathology ; Humans ; *Memory/drug effects ; *Learning/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; },
abstract = {Neurodegenerative disorders (NDDs) are likely to become a major challenge for healthcare and society in the coming years, largely because of shifting global demographics. These conditions mainly involve the progressive deterioration or loss of neurons, which is a key factor behind serious mental health issues. Usually, NDDs are linked to a slow decline in neurons and their connections, often happening as people grow older. Synaptic dysfunction represents a fundamental pathological characteristic of these diseases and serves as a significant contributor to deficits in learning and memory. Puerarin, an isoflavonoid derived from Pueraria lobata, has surfaced as a promising neuroprotective compound with diverse molecular and cellular mechanisms of action. This review consolidates contemporary evidence regarding the function of puerarin as a modulator of synaptic plasticity and its therapeutic prospects in the restoration of cognitive function across various neurodegenerative conditions. We examine the manner in which puerarin impacts critical molecular pathways implicated in synaptic transmission and structural remodeling, encompassing the modulation of BDNF/TrkB signaling, the regulation of NMDA and AMPA receptor activity, the activation of CREB-dependent transcription, the enhancement of mitochondrial bioenergetics, and the mitigation of oxidative stress and neuroinflammation. Furthermore, we underscore its influence on dendritic spine density, long-term potentiation, and synaptic vesicle cycling, correlating these mechanisms with the observed enhancements in learning and memory in experimental models of Alzheimer's disease and Parkinson's disease. The review further explores the pharmacokinetic obstacles, methodologies for delivery, and translational viewpoints necessary to connect preclinical discoveries with clinical relevance.},
}

*Isoflavones/pharmacology/therapeutic use
*Neuronal Plasticity/drug effects
Animals
*Neurodegenerative Diseases/drug therapy/physiopathology
Humans
*Memory/drug effects
*Learning/drug effects
Neuroprotective Agents/pharmacology/therapeutic use

@article {pmid42343047,
year = {2026},
author = {Jiang, Z and Zhang, J and Zhang, X and Xie, C and Chen, X and Ma, G and Lu, X and Ai, Y and Jia, T},
title = {Targeting NOX4 with Quercetagetin-PLGA nanomaterials: a novel therapeutic strategy for Alzheimer's disease.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42343047},
issn = {1432-1912},
abstract = {This study aims to address NOX4 (NADPH oxidase 4)-driven oxidative injury in Alzheimer's disease (AD) and the poor bioavailability of the natural flavonoid Quercetagetin, we developed an α7 nicotinic acetylcholine receptor (α7-nAChR)-targeted, Quercetagetin-loaded PLGA nanocarrier (PLGA@Quercetagetin@α7-nAChR) for receptor-mediated delivery, NOX4 suppression, and neuroprotection. Using the GSE97760 dataset, bioinformatic screening combined with LASSO regression was performed to identify candidate targets. Single-cell RNA sequencing (scRNA-seq) with pseudotime analysis was applied to delineate cell type-resolved and trajectory-associated expression patterns. Nanoparticles were fabricated by a double-emulsion method and characterized for physicochemical properties. In an Aβ-induced HT-22 neuronal injury model, genetic perturbation, western blotting, and flow cytometry were used to validate the pathogenic role of NOX4 and to evaluate the pharmacological efficacy of the nanoplatform. NOX4 emerged as the key gene, showing enriched expression in oligodendrocytes and endothelial cells and an increase along the inferred disease-associated trajectory. In vitro, Aβ stimulation upregulated NOX4, whereas NOX4 knockdown or Quercetagetin treatment alleviated Aβ-induced cytotoxicity and apoptosis. The nanoparticles exhibited an average diameter and sustained drug release over 72 h. α7-nAChR targeting enhanced neuronal uptake by ~ fivefold, markedly reduced NOX4 mRNA levels, and decreased the apoptotic rate from 18.3% to 5.0%. Notably, encapsulation also mitigated the hepatorenal toxicity observed with high-dose free Quercetagetin. These in vitro findings suggest NOX4 as a potential target in AD, and the PLGA@Quercetagetin@α7-nAChR nanoplatform shows improved cellular uptake and reduced short-term toxicity compared to free drug. However, claims regarding brain targeting and translational potential are limited by the absence of in vivo validation, non-targeted controls, drug exposure normalization, and key formulation parameters (e.g., encapsulation efficiency). Future in vivo studies are required to substantiate this targeted strategy for AD.},
}

@article {pmid42343405,
year = {2026},
author = {Chen, X and Han, S and Chen, Y and Yuan, S and He, J and Ye, Z and Song, Y and Dou, K},
title = {Impact of a comprehensive healthy lifestyle score on a broad spectrum of cardiometabolic and related diseases and its incremental value for risk prediction based on the UK biobank database.},
journal = {Journal of cardiothoracic surgery},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13019-026-04485-z},
pmid = {42343405},
issn = {1749-8090},
support = {JC202508//Science Foundation of Peking University Cancer Hospital/ ; 2022-GSP-QN-06, 2023-GSP-GG-02, 2023-GSP-QN-17, 2023-GSP-QN-34, 2023-GSP-RC-05//National High Level Hospital Clinical Research Funding/ ; 2025ZD0548200//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; },
abstract = {BACKGROUND: Cardiometabolic and related diseases (CMDs) represent a major global disease burden. While traditional risk factors are well-established, the role of lifestyle factors in primary prevention has not been sufficiently studied.

METHODS: This study analyzed data from 148,155 participants in the UK Biobank without baseline CMDs. Cox proportional hazards models were used to assess the impact of healthy lifestyle factors (non-current smoking, non-excessive drinking, regular physical activity, healthy diet, and healthy sleep) on 11 types of CMDs (coronary heart disease, type 2 diabetes, atrial fibrillation, hypertension, stroke, heart failure, Alzheimer's disease, non-alcoholic fatty liver disease, valvular heart disease, cardiomyopathy, and pulmonary hypertension). Participants were categorized into four groups based on weighted lifestyle scores. Improvements in predictive models after incorporating lifestyle factors were evaluated.

RESULTS: Most individual healthy lifestyle factors were associated with a lower risk of CMDs, while regular physical activity was not independently associated with composite CMD risk in the fully adjusted model; healthy sleep contributed the largest weight to the composite lifestyle score (β = 0.342). Adhering to a healthier lifestyle demonstrated a significant and dose-response association with a reduced risk of composite CMDs. In the fully adjusted model, compared to the "very unhealthy" group, the "very healthy" group exhibited a significantly lower risk of developing CMDs (HR: 0.70, 95% CI: 0.67-0.74). Similar inverse associations were observed across several individual CMDs, with the strongest association observed for pulmonary hypertension (HR: 0.34, 95% CI: 0.24-0.50). Incorporating the lifestyle score into traditional risk models was associated with modest improvement in predictive performance. The findings were generally consistent across subgroups and sensitivity analyses.

CONCLUSIONS: These findings suggest that adherence to a comprehensive healthy lifestyle, including adequate sleep, is associated with reduced risk of various CMDs and may improve risk stratification. The particularly strong association observed for pulmonary hypertension also supports further investigation of lifestyle patterns across a broader range of cardiometabolic and related conditions.

TRIAL REGISTRATION: Not applicable.},
}

@article {pmid42343423,
year = {2026},
author = {Baixu, H and Qing, W and Chunming, X},
title = {Perspective of retinal Chlamydia pneumoniae infection in Alzheimer's disease pathogenesis.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00964-y},
pmid = {42343423},
issn = {1750-1326},
support = {2022ZD0211600//Science and Technology Innovation 2030 Major Projects [2022ZD0211600, CMX]/ ; grant numbers 82271574, CMX; 82202137, CCH; 82502335, WQ//National Natural Science Foundation of China/ ; },
}

@article {pmid42343430,
year = {2026},
author = {Wang, H and Wen, R and Parker, E and Yang, L},
title = {A 'Tangled Web' in the CNS: unraveling neutrophil extracellular traps in neurological disorders.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00967-9},
pmid = {42343430},
issn = {1750-1326},
abstract = {Neutrophil Extracellular Traps (NETs) are web-like structures composed of DNA, histones, and antimicrobial proteins released by activated neutrophils, which play a critical role in modulating neutrophil-mediated immune responses. Initially recognized for their role in host defense, NETs function as "molecular traps" that rapidly ensnare pathogens. They then achieve efficient clearance by directly degrading virulence factors through the action of associated antimicrobial proteins. However, the functions of NETs extend beyond immune defense. Dysregulation of NETs in pathological conditions can lead to detrimental effects. Recent studies have highlighted the importance of aberrant NET formation and impaired clearance in the pathogenesis of central nervous system (CNS) diseases, making them a field hotspot. In view of this, we discuss NETs, the structural characteristics and diverse generation patterns of NETs, and clarify how neutrophils cross the blood-brain barrier (BBB) to enter the CNS. We also explore triggers of NETosis within the brain, such as oxidative stress and inflammatory mediators. Furthermore, we analyze the pathological contributions of NETs to a range of CNS disorders, including stroke, traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), Alzheimer's disease (AD), multiple sclerosis (MS), etc. Finally, we summarize emerging neuroprotective strategies that target NETs, highlighting advances in interventions designed to inhibit NET formation or promote their degradation. By synthesizing current evidence, this review aims to uncover the mysterious veil of NETs in neurological diseases and to offer new insights for understanding disease mechanisms and developing targeted therapeutic approaches.},
}

@article {pmid42343519,
year = {2026},
author = {Zhou, B and Zhu, C and Chen, X and Li, J and Gao, D and Wu, A and Tao, L and Yuan, X and Yang, G and Chen, X and Xie, M and Cheng, L and Wang, X},
title = {[Mechanism of moxibustion at the governor vessel for regulating autophagy against Alzheimer's disease via lncRNA-RP4-mediated Wnt/β-catenin pathway].},
journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion},
volume = {46},
number = {6},
pages = {929-947},
doi = {10.13703/j.0255-2930.20250309-k0001},
pmid = {42343519},
issn = {0255-2930},
mesh = {Animals ; *Alzheimer Disease/therapy/genetics/metabolism/physiopathology ; *RNA, Long Noncoding/genetics/metabolism ; *Moxibustion ; *Autophagy ; Mice ; Humans ; *Wnt Signaling Pathway ; Male ; Mice, Inbred C57BL ; *beta Catenin/metabolism/genetics ; Mice, Transgenic ; MicroRNAs/genetics/metabolism ; Acupuncture Points ; Membrane Proteins/genetics/metabolism ; },
abstract = {OBJECTIVE: To observe the effect of moxibustion at the governor vessel on lncRNA-RP4/miR-939-5p and Bnip3 in APP/PS1 double transgenic mice mediated by Wnt/β-catenin pathway, and to explore the mechanism of moxibustion in the treatment of Alzheimer's disease (AD).

METHODS: Sixty 6-month-old APP/PS1 mice were randomly divided into a model group, a rapamycin group, a moxibustion+ 3-methyladenine (3-MA) group and a moxibustion group, with 15 mice in each group. Fifteen C57BL/6J mice of the same age were used as the control group. The rapamycin group was given intraperitoneal injection of rapamycin (2 mg/kg). The moxibustion group was given moxibustion at "Baihui" (GV20),suspended moxibustion at "Fengfu" (GV16) and "Dazhui" (GV14) for 20 min. The moxibustion+3-MA group was injected with 1.5 mg/kg 3-MA on the basis of the moxibustion group. After 6 consecutive treatments, rest for 1 d, and lasted 2 weeks.HEK293T cells were cultured in vitro and transfected with miR-939-5p and its empty plasmid, and transfected with lncRNA-RP4 and Bnip3 wild-type and mutant. HT22 cells cultured in vitro were randomly divided into a control group and a model (Aβ 1-42) group. The lncRNA-RP4 overexpression group, the lncRNA-RP4 knockdown group, the miR-939-5p mimic group, the miR-939-5p inhibitor group, the Bnip3 overexpression group, the Bnip3 knockdown group and the corresponding empty plasmid group were set up, and transfection was performed on the basis of the model group. Morris water maze test was used to detect the learning and memory ability of mice. HE staining was used to observe the morphology of hippocampus in each group. The structure of nerve cells, the number and structure of autophagic vacuoles and autophagic lysosomes in hippocampal CA1 region of mice in each group were observed by transmission electron microscopy. The expression of Aβ 1-42 protein in hippocampus was detected by immunohistochemistry. The expression of mTOR, TFEB, P62, Wnt3 a, β-catenin, GSK-3β, lncRNA-RP4, miR-939-5 p and Bnip3 mRNA in hippocampus of mice in each group was detected by real-time fluorescence quantitative PCR. Western blot was used to detect the expression of mTOR, TFEB, P62, LC3 B-Ⅰ,LC3 B-Ⅱ, CTSB, Lamp1, V-ATPase, Wnt3a, β-catenin, GSK-3β and Bnip3 protein in hippocampus of mice in each group.Dual luciferase assay was used to verify the targeting relationships among lncRNA-RP4, miRNA-939-5p and Bnip3 in HEK293T cells. The concentration of Aβ 1-42 in HT22 cells of each group was detected by ELISA. The expression of lncRNA-RP4, miR-939-5p, Bnip3, Wnt3a, β-catenin and GSK-3β mRNA in HT22 cells of each group was detected by real-time fluorescence quantitative PCR. The expression of Bnip3, Wnt3a, β- catenin and GSK-3β protein in HT22 cells of each group was detected by Western blot.

RESULTS: Compared with the model group, the escape latency of the rapamycin group and the moxibustion group was shortened (P<0.05), and the number of crossing the platform was increased (P<0.05).The number of hippocampal neurons was large, and a small amount of cell necrosis was observed. The cells were arranged in an orderly manner with clear boundaries. Some neurons were deformed, atrophied and irregular, and autophagic vacuoles increased. The expression of A β 1-42 protein, mTOR, P62, GSK-3β mRNA and protein, and miR-939-5p mRNA in hippocampus was decreased (P<0.05), while the expression of TFEB, Wnt3a, β-catenin, Bnip3 mRNA and protein, LC3B-Ⅰ, LC3B-Ⅱ, CTSB, Lamp1, V-ATPase protein, and lncRNA-RP4 mRNA was increased (P<0.05). Compared with the rapamycin and moxibustion groups, the escape latency of the moxibustion+3-MA group was prolonged (P<0.05), and the number of crossing the platform was decreased (P<0.05). The number of hippocampal neurons decreased slightly, the cell necrosis was more, the cell arrangement was irregular, the boundary was blurred, and a small amount of autophagic vacuoles and more deformed neurons were occasionally seen. The expression of A β 1-42 protein, mTOR, P62, GSK-3β mRNA and protein, and miR-939-5p mRNA in hippocampus increased (P<0.05), while the expression of TFEB, Wnt3a, β-catenin,Bnip3 mRNA and protein, LC3B-Ⅰ, LC3B-Ⅱ, CTSB, Lamp1, V-ATPase protein, and lncRNA-RP4 mRNA decreased (P<0.05). Dual luciferase assay confirmed that there was a targeting relationship among lncRNA-RP4, miR-939-5p and Bnip3.After the intervention of lncRNA-RP4 in vitro, compared with the model group, the expression of Aβ 1-42 protein,miR-939-5p mRNA, GSK-3 β mRNA and protein in the lncRNA-RP4 overexpression group was decreased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a, β-catenin mRNA and protein was increased (P<0.05). The expression of Aβ 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in lncRNA-RP4 knockdown group was increased (P<0.05), while the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a and β-catenin mRNA and protein was decreased (P<0.05). Compared with the lncRNA-RP4 overexpression group, the expression of Aβ 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in the lncRNA-RP4 knockdown group was increased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a, β-catenin mRNA and protein was decreased (P<0.05). After intervention with miR-939-5p, compared with the model group, the expression of Aβ 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in the miR-939-5p mimic group was increased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a,β-catenin mRNA and protein was decreased (P<0.05). The expression of A β 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in miR-939-5p inhibitor group was decreased (P<0.05), while the expression of lncRNA-RP4 mRNA,Bnip3, Wnt3a and β-catenin mRNA and protein was increased (P<0.05). Compared with the miR-939-5p mimic group, the expression of Aβ 1-42 protein, miR-939-5p mRNA, GSK-3β mRNA and protein in the miR-939-5p inhibitor group was decreased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a, β-catenin mRNA and protein was increased (P<0.05). After Bnip3 intervention, compared with the model group, the expression of Aβ 1-42 protein,miR-939-5p mRNA, GSK-3 β mRNA and protein in the Bnip3 overexpression group was decreased (P<0.05), while the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a and β-catenin mRNA and protein was increased (P<0.05). The expression of A β 1-42 protein, miR-939-5p mRNA, GSK-3 β mRNA and protein in the Bnip3 knockdown group was increased (P<0.05), while the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a and β-catenin mRNA and protein was decreased (P<0.05). Compared with the Bnip3 overexpression group, the expression of Aβ 1-42 protein, miR-939-5p mRNA,GSK-3β mRNA and protein in Bnip3 knockdown group was increased (P<0.05), and the expression of lncRNA-RP4 mRNA, Bnip3, Wnt3a, β-catenin mRNA and protein was decreased (P<0.05).

CONCLUSION: Moxibustion at the governor vessel ameliorates AD cognitive deficits by activating the lncRNA-RP4/miR-939-5p/Bnip3 axis, enhancing Wnt/β-catenin pathway, restoring autophagosome-lysosome activity, promoting autophagy, accelerating A β 1-42 clearance, and improve cognitive dysfunction of AD. This study elucidates a novel epigenetic mechanism underlying moxibustion's therapeutic efficacy in AD.},
}

Animals
*Alzheimer Disease/therapy/genetics/metabolism/physiopathology
*RNA, Long Noncoding/genetics/metabolism
*Moxibustion
*Autophagy
Mice
Humans
*Wnt Signaling Pathway
Male
Mice, Inbred C57BL
*beta Catenin/metabolism/genetics
Mice, Transgenic
MicroRNAs/genetics/metabolism
Acupuncture Points
Membrane Proteins/genetics/metabolism

@article {pmid42343545,
year = {2026},
author = {Carpenter, JG and Oduro, EB and Hodgson, N and Zhu, S and Gurlu, M and Ersek, M and Hanson, LC},
title = {Outcomes of a Palliative Care Intervention for Older Adults With and Without Dementia in Skilled Nursing Facilities.},
journal = {Research in gerontological nursing},
volume = {},
number = {},
pages = {1-7},
doi = {10.3928/19404921-20260615-01},
pmid = {42343545},
issn = {1938-2464},
abstract = {PURPOSE: Older adults living with Alzheimer's disease and related dementias (ADRD) receiving skilled nursing facility (SNF) care have different clinical trajectories and care needs compared to those without ADRD. Little is known about whether palliative care affects these two populations differently.

METHOD: We conducted a secondary comparative cohort analysis of a feasibility pragmatic pilot trial (n = 52) to explore the effect of a primary palliative care intervention among older adults with and without ADRD. SNF nurse practitioners received training in the delivery of a primary palliative care intervention. The Palliative Outcomes Scale version 2 measured quality of life at baseline and 14 to 21 days follow up.

RESULTS: No statistically significant intervention effect was found; however, quality of life scores in the ADRD cohort trended toward improvement, whereas the non-ADRD cohort trended toward worsening with a similar effect size.

CONCLUSION: Further research is needed to optimize palliative care interventions for SNF residents with different illness trajectories.},
}

@article {pmid42343664,
year = {2026},
author = {Rivera, EA and Spigelmyer, PC and Zoucha, R and Jarrín, OF},
title = {Beliefs and Values of Puerto Rican Family Caregivers Regarding Dementia: An Integrative Review.},
journal = {Hispanic health care international : the official journal of the National Association of Hispanic Nurses},
volume = {},
number = {},
pages = {15404153261461743},
doi = {10.1177/15404153261461743},
pmid = {42343664},
issn = {1938-8993},
abstract = {IntroductionAlzheimer's disease and related dementias affect Latino older adults who are living longer with dementia. Puerto Ricans are the second-largest Hispanic group in the United States, and they differ in language, norms, and values from other cultures. As the number of dementia cases increases, the demand for caregivers will rise.MethodThe integrative review was guided by Whittemore and Knafl's framework and aimed to evaluate and synthesize the existing literature regarding the experience, beliefs, and values of Puerto Rican dementia family caregivers. A comprehensive search of PubMed, CINAHL, Embase, PsycInfo, and LILACS databases was performed to examine the literature from 2013 to 2025.ResultsFour key themes emerged: (1) spirituality is essential for caregiving, (2) home is a better place to be, (3) toll of caregiving, and (4) long-established gender roles.ConclusionThe findings demonstrate the scarcity of Puerto Rican caregiver representation in the literature. Further research is needed to determine Puerto Rican values and beliefs regarding caregiving.},
}

@article {pmid42343674,
year = {2026},
author = {Feng, ZP and Xiao, J and Yu, CC and Zhang, X and Yu, ZX and Pan, YK and Yang, S and Shen, F},
title = {[Mechanism of electroacupuncture at "Neiguan" (PC6) and "Jianshi" (PC5) in ameliorating blood-brain barrier damage in APP/PS1 mice based on the nucleus tractus solitarius-locus coeruleus neural circuit].},
journal = {Zhen ci yan jiu = Acupuncture research},
volume = {51},
number = {6},
pages = {677-687},
doi = {10.13702/j.1000-0607.20250903},
pmid = {42343674},
issn = {1000-0607},
mesh = {Animals ; *Electroacupuncture ; *Locus Coeruleus/metabolism ; *Blood-Brain Barrier/metabolism ; Male ; Mice ; *Solitary Nucleus/metabolism ; Mice, Inbred C57BL ; *Alzheimer Disease/therapy/metabolism/genetics/physiopathology ; *Acupuncture Points ; Humans ; Disease Models, Animal ; },
abstract = {OBJECTIVES: To observe the role of tyrosine hydroxylase (TH)-positive neurons in the nucleus tractus solitarius (NTS) and locus coeruleus (LC) in electroacupuncture (EA)-mediated improvement of blood-brain barrier (BBB) damage in APP/PS1 mice, so as to explore the mechanism of the NTS[TH]-LC neural circuit underlying the effect of EA on prevention and treatment of Alzheimer's disease (AD).

METHODS: (1) Eight 4-month-old male C57BL/6 mice served as the control group, and 16 age-matched male APP/PS1 mice were randomly divided into the model and EA groups (n=8). The EA group received EA stimulation at "Neiguan" (PC6) and "Jianshi" (PC5) once every other day for 4 weeks. After intervention, Morris water maze and novel object recognition tests were used to evaluate learning and memory abilities. Western blot was performed to detect the expression levels of hippocampal tight junction proteins, including Occludin, Claudin-5, and zonula occludens-1 (ZO-1). Immunofluorescence was used to assess the co-localization of TH/c-Fos in NTS and LC, as well as TH/norepinephrine (NE) co-localization in LC. (2) Five TH-cre mice received retrograde tracing virus injection into LC to observe whether TH-positive neurons in NTS project to LC. (3) Twenty-one 7-month-old APP/PS1 mice were injected with chemogenetic activation virus (AAV2/9-hSyn-DIO-hM3D-mCherry-WPRE-hGH-pA) or empty virus (AAV2/9-Ef1α - DIO-mCherry-WPRE-hGH-pA) into the NTS, and AAVretro-TH-CRE-WPRE-hGH-pA virus into the LC. After 21 d of virus expression, 6 mice injected with empty virus were taken as mCherry+CNO+EA group;3 mice from the activation virus group were randomly selected for brain slice patch-clamp to verify virus functionality. The remaining mice were randomly divided into 2 groups (n=6):hM3D+CNO+EA, and hM3D+saline+EA groups. EA was applied to PC6 and PC5 once daily for 15 d. After intervention, learning and memory abilities were evaluated by Morris water maze and novel object recognition tests. BBB permeability was detected by Evans blue (EB) staining. Immunofluorescence was used to measure TH/c-Fos and TH/NE co-localization in the LC.

RESULTS: (1) Compared with the control group, the model group showed significantly impaired learning and memory abilities (P<0.01), decreased expressions of hippocampal Occludin, Claudin-5, and ZO-1 (P<0.01), and increased TH/c-Fos co-localization (c-Fos expression in TH-positive neurons) in NTS and LC, as well as TH/NE co-localization in LC (P<0.01). Compared with the model group, the EA group exhibited improved learning and memory abilities (P<0.05, P<0.01), increased expressions of hippocampal tight junction proteins (P<0.01), and reduced TH/c-Fos and TH/NE co-localization (P<0.01, P<0.05). (2) Retrograde tracing confirmed that TH-positive neurons in NTS project to LC. (3) Compared with the mCherry+CNO+EA group and hM3D+saline+EA group, the hM3D+CNO+EA group showed significantly impaired learning and memory (P<0.01), increased EB content in brain tissue, and elevated TH/c-Fos and TH/NE co-localization in the LC (P<0.01).

CONCLUSIONS: EA at PC6 and PC5 can ameliorate BBB damage and learning/memory deficits in AD mice, and its mechanism may be related to inhibiting the activation of the NTS[TH]-LC neural circuit.},
}

Animals
*Electroacupuncture
*Locus Coeruleus/metabolism
*Blood-Brain Barrier/metabolism
Male
Mice
*Solitary Nucleus/metabolism
Mice, Inbred C57BL
*Alzheimer Disease/therapy/metabolism/genetics/physiopathology
*Acupuncture Points
Humans
Disease Models, Animal

@article {pmid42343870,
year = {2026},
author = {Marta-Ariza, M and Wisniewski, T},
title = {Multiomics and proteomic insights into Alzheimer's disease biology in down syndrome.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14737175.2026.2695187},
pmid = {42343870},
issn = {1744-8360},
abstract = {INTRODUCTION: Down syndrome (DS) confers a high risk of Alzheimer's disease (AD) and is widely recognized as a genetically determined form of AD. As such, DS provides a uniquely informative biological context in which to investigate AD initiation and progression. Defining the molecular mechanisms that link trisomy 21 to neurodegeneration has broad implications for AD biology and neurotherapeutic development.

AREAS COVERED: This review summarizes findings from brain, cerebrospinal fluid, and blood-based proteomic studies, integrated with transcriptomic and multiomics analyses, to characterize molecular pathways underlying AD in DS. The literature was identified through iterative PubMed/MEDLINE searches and manual review of reference lists, considering studies available through June 2026 with no limitation to publication dates. We discuss evidence for early disruption of proteostasis, mitochondrial and synaptic function, immune and vascular signaling, and the convergence of these alterations with sporadic and familial AD. Large cohort studies and lesion-specific proteomics are reviewed to highlight shared and subtype-specific molecular features, as well as current technical and data interpretation limitations.

EXPERT OPINION: Brain, lesion-specific, cerebrospinal fluid, and blood-based proteomics, interpreted alongside transcriptomic and complementary omics data, position DSAD as a network-level disorder in which amyloid and tau pathology interact with immune, vascular, metabolic, synaptic, and proteostasis pathways. This integrated proteomic framework helps define shared and subtype-specific mechanisms across DSAD, sporadic AD, and autosomal dominant AD, while supporting biological staging, patient stratification, and therapeutic target discovery.},
}

@article {pmid42343889,
year = {2026},
author = {Xie, MR and Chen, YJ and Yuan, H},
title = {Sphingolipids associated research in Alzheimer's disease: an explored trends analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1723883},
pmid = {42343889},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment. Numerous studies have indicated that dysregulation of sphingolipid metabolism is closely associated with the core pathology of AD and acts as a crucial driving factor. This study aims to employ bibliometric methods to comprehensively summarize the relevant research on sphingolipids in AD, identify research hotspots and emerging trends, and thereby provide objective data to guide future research directions.

METHODS: Publications were retrieved from the Web of Science and Scopus databases. Visual analyses were performed using CiteSpace, VOSviewer, and Bibliometrix.

RESULTS: A total of 623 publications related to sphingolipids and AD were included. The United States and China were the leading contributors in this field. Johns Hopkins University was the most prolific institution. Journal of Alzheimer's Disease was the most frequently published journal. Dr. Erhard Bieberich was the author with the highest number of publications. High-frequency keywords included AD, sphingolipids, sphingolipid metabolism, ceramide, sphingomyelin, and cholesterol. Keywords with the strongest bursts in recent years included lipidomics, metabolomics, microglia, and cognitive impairment.

CONCLUSION: Research on sphingolipids in AD exhibits an overall fluctuating upward trend. Extensive collaboration among researchers from various institutions has facilitated advancements in this field. Sphingolipid metabolism represents a key focus in AD research, with ceramides and sphingomyelins identified as critical molecules. Lipidomics, metabolomics, and microglia are likely to represent future research frontiers.},
}

@article {pmid42343890,
year = {2026},
author = {Rizzi, L and Ribeiro, IC and da Rocha Silva, MC and Aventurato, ÍK and Santos, LE and Dos Santos Silva, AM and Pinheiro, TL and Fernandes, GBP and De Felice, FG and Balthazar, MLF},
title = {Correction: Plasma Aβ42/p-Tau217 ratio and p-Tau217 independently predict CSF-defined Alzheimer's disease pathology in a Brazilian admixed cohort.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1875333},
doi = {10.3389/fnagi.2026.1875333},
pmid = {42343890},
issn = {1663-4365},
abstract = {[This corrects the article DOI: 10.3389/fnagi.2026.1773606.].},
}

@article {pmid42344186,
year = {2026},
author = {Asghar, A and Narayan, RK and Kumar, R and Sarangi, PK and Patra, A and Kumar, A and Zabihullah, M},
title = {Exploring Olfactory Bulb Volume and Its Shrinkage in Aging and Neurodegeneration: A Systematic Review and Meta-Analysis of Observational Studies.},
journal = {The Indian journal of radiology & imaging},
volume = {36},
number = {3},
pages = {374-393},
pmid = {42344186},
issn = {0971-3026},
abstract = {BACKGROUND: The olfactory bulb (OB) plays a crucial role in processing smells and has significant neuroplasticity throughout life. Age-related changes in OB volume (OBV) are associated with declining olfactory function, potentially impacting quality of life and serving as an early marker of neurodegenerative diseases. This study conducted a meta-analysis to assess OBV changes across diverse age groups in healthy individuals, explored its association with olfactory function, and further examined OB atrophy in Parkinson's disease (PD) and Alzheimer's disease (AD).

MATERIALS AND METHODS: A systematic review and meta-analysis were conducted following PRISMA guidelines. Studies evaluating OBV through MRI in healthy individuals and patients with PD or AD were included. Data were extracted on age, sex, olfactory function, and OBV. Meta-regression was performed to assess the correlation between OBV and age, while subgroup analyses examined the effects of sex and laterality.

RESULTS: Twenty-nine studies were analyzed, including 12 on healthy individuals, 7 on AD, and 11 on PD. The pooled mean OBV was 54.5 mm [3] (95% CI, 42.03-66.98) for the right OB and 55.56 mm [3] (95% CI, 42.96-68.15) for the left OB, with no significant sex or laterality differences. OBV showed a moderate negative correlation with age (r  = -0.53 to -0.59, p  < 0.05), suggesting progressive atrophy with aging. Olfactory function, assessed through the Threshold, Differentiation, and Identification (TDI) and the University of Pennsylvania Smell Identification Test (UPSIT) scores, was also moderately correlated with OBV (r  = 0.48, p  < 0.01). In neurodegenerative diseases, OBV reduction was greater, with shrinkage of 0.9 to 0.93 SD in PD and 1 to 1.05 SD in AD, primarily attributed to pathological degeneration.

CONCLUSION: Age-related OBV reduction is a normal physiological process with a moderate impact on olfactory function. While neurodegenerative diseases exacerbate OB atrophy, at least 40% of OB shrinkage observed in PD appears to be age-related. OBV could serve as a potential biomarker for aging and early neurodegeneration.},
}

@article {pmid42344202,
year = {2026},
author = {Guth, MAS},
title = {Alzheimer's disease in the Plasticene era: a clinicopathological update on the dual sequestration of amyloid and tau as hijacked innate immune responses.},
journal = {Free neuropathology},
volume = {7},
number = {},
pages = {14},
pmid = {42344202},
issn = {2699-4445},
abstract = {Background: The defining neuropathological hallmarks of Alzheimer's disease (AD)-amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFTs)-are now understood to exist along a continuum with brain aging, yet their fundamental trigger in sporadic disease remains enigmatic. The clinical failure of therapies targeting these proteins, despite their successful removal, underscores a critical dissociation between hallmark pathology and core pathogenesis. Objective: This clinicopathological update synthesizes emerging evidence on pervasive environmental nanoplastics (NPs) with the persistent paradoxes of AD to propose the dual sequestration hypothesis (DSH). Methods and Results: We suggest that Aβ plaques and tau NFTs could be reinterpreted as evolutionarily conserved, compartment-specific innate immune sequestration mechanisms-an extracellular "sarcophagus" and an intracellular "lockbox"-based on their roles in microbial defense and stress response. We posit that in the modern "Plasticene" era, indestructible NPs detected in human cerebrospinal fluid (CSF) and brain tissue act as permanent, inorganic nucleation seeds that hijack these responses, forming indigestible synthetic protein complexes. NPs directly nucleate Aβ fibrillation and tau hyperphosphorylation, initiating the sequestration response. Chronic microglial engagement with these complexes triggers a state of "immune frustration," leading to a maladaptive phase transition. This pivot could be explained by glutamate excitotoxicity, which drives microglial NLRP3 inflammasome activation and pyroptotic cell death. Lytic pyroptosis liberates intact synthetic seeds into the paravascular space, where they are distributed via glymphatic flow, physically obstructing clearance and providing a mechanistic model for the stereotypical progression of Braak stages. Conclusion: The DSH offers a unified explanation for the therapeutic failure of anti-Aβ/anti-tau antibodies (which remove the biological response but not the synthetic trigger) and amyloid-related imaging abnormalities (ARIA) as an inflammatory rebound. It necessitates a paradigm shift in neuropathological practice, calling for novel detection techniques to visualize the synthetic core within classical lesions, thereby unifying environmental etiology with canonical pathology. The presence of synthetic NPs at the physical center of Aβ plaques and tau tangles in human AD brain tissue is currently a prediction of the DSH awaiting empirical validation, not an established finding.},
}

@article {pmid42344495,
year = {2026},
author = {Yadav, C and Yadav, S and Panwar, A and Donelli, M and Jain, A},
title = {An intelligent gradient-guided hybrid inpainting framework for brain MRI reconstruction and Alzheimer's disease classification in connected healthcare systems.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1849122},
pmid = {42344495},
issn = {2296-858X},
abstract = {Brain magnetic resonance imaging (MRI) is essential for early Alzheimer's disease diagnosis, yet clinical scans are often degraded by motion artifacts, signal loss, or incomplete acquisitions. Image inpainting offers a promising preprocessing solution, but existing methods have limitations: deep learning models such as LaMa generate visually plausible reconstructions but may compromise structural fidelity, while classical diffusion-based approaches like OpenCV Telea preserve local continuity but tend to oversmooth complex anatomy. This study proposes a gradient-guided hybrid inpainting framework that integrates OpenCV Telea and LaMa to leverage their complementary strengths. A gradient magnitude-based weighting mechanism enables structure-aware reconstruction, assigning edge-rich regions to the classical method and smoother regions to the deep model, thereby preserving both fine anatomical details and global consistency. Experiments on a four-class ADNI-based MRI dataset, balanced using SMOTE-NM and split 70:15:15, with 10%-30% random masking, demonstrate improved reconstruction performance. The proposed method reduces mean squared error by 8% compared to LaMa and 30% compared to OpenCV, while achieving SSIM ≈0.93 and PSNR ≈25.7 dB. A VGG16 classifier trained on clean images achieves 94.35% accuracy on hybrid-inpainted data, showing only a 1.69 percentage point drop from the baseline and outperforming individual methods. These results highlight the effectiveness of the proposed framework for reliable, AI-driven neuroimaging pipelines in intelligent and connected healthcare systems.},
}

@article {pmid42344710,
year = {2026},
author = {Zhang, B and Chen, Z and Li, W and Xu, L and Yang, S and Wang, F and Yan, K and Wei, X and Li, T},
title = {Frequency-Specific Transcranial Photobiomodulation Elicits Complementary Glial Mechanisms for Neurovascular Protection and Amyloid Clearance in Alzheimer Disease.},
journal = {Cyborg and bionic systems (Washington, D.C.)},
volume = {7},
number = {},
pages = {0551},
pmid = {42344710},
issn = {2692-7632},
abstract = {Alzheimer disease (AD), a devastating neurodegenerative disorder, is pathologically defined by amyloid-β (Aβ) deposition and neurofibrillary tangles. Critically, concomitant cerebrovascular dysfunction compromises neuronal homeostasis and significantly accelerates AD progression by impairing the neurovascular unit. However, effective strategies to modulate this complex neurovascular pathology remain unclear. Here, we applied transcranial photobiomodulation (tPBM) with continuous-wave (CW) and 40-Hz pulsed light to target neurovascular pathology in 5xFAD mice. The results showed that both tPBM modalities comparably ameliorated cognitive dysfunction through distinct glial-mediated mechanisms. Specifically, CW light primarily enhanced astrocyte-vascular coupling, which ameliorated vascular dysfunction and protected synapses. In contrast, 40-Hz light predominantly drove spatial redistribution of microglia toward Aβ plaques, thereby enhancing localized amyloid clearance. These findings reveal complementary pathways for tPBM in AD intervention, highlighting that CW and 40-Hz light offer modality-specific therapeutic advantages: The former targets cerebrovascular dysfunction, while the latter addresses Aβ plaque deposition. Collectively, our study provides critical mechanistic insights for optimizing tPBM protocols, establishing a foundation for more precise and comprehensive AD interventions.},
}

@article {pmid42344833,
year = {2026},
author = {Wang, Y and Wang, L and Zhan, D},
title = {Differential Causal Associations of Gut Microbiota, Blood Metabolites, and Immune Cell Phenotypes With Early- and Late-Onset Alzheimer's Disease: A Bidirectional Mendelian Randomization Analysis.},
journal = {Cureus},
volume = {18},
number = {5},
pages = {e109543},
pmid = {42344833},
issn = {2168-8184},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a heterogeneous syndrome with distinct genetic and clinical profiles between early-onset AD (EOAD) and late-onset AD (LOAD) subtypes. However, specific causal etiologies linking the gut microbiota-immune-metabolic axis to these subtypes remain poorly understood.

METHODS: We employed a comprehensive bidirectional two-sample Mendelian randomization (MR) framework to systematically investigate the causal associations of gut microbiota, immune cell phenotypes, and blood metabolites with EOAD and LOAD. Large-scale genome-wide association study (GWAS) summary statistics were utilized from the MiBioGen consortium, Sardinian cohort, and Canadian Longitudinal Study on Aging, alongside AD outcome data from the FinnGen consortium. Causal estimates were generated using the inverse variance-weighted method, with rigorous sensitivity analyses including false discovery rate (FDR) correction and Steiger directionality tests to ensure robustness.

RESULTS: Our analysis revealed divergent multi-omics signatures for AD subtypes. While the genus Veillonella and myeloid dendritic cells emerged as shared protective factors, the risk profiles were distinct. EOAD susceptibility was primarily driven by adaptive immune dysregulation and lipid metabolism disturbances. In contrast, LOAD risk was predominantly associated with innate immune dysfunction and perturbations in amino acid and gut-derived metabolite turnover, such as hippurate.

CONCLUSIONS: This study provides genetic evidence that EOAD and LOAD are driven by fundamentally different peripheral mechanisms across the gut-immune-metabolic axis. These findings challenge the monolithic view of AD pathogenesis and underscore the critical necessity of stratifying patients by onset age to develop precision therapeutic interventions.},
}

@article {pmid42344858,
year = {2026},
author = {Jiménez-Balado, J and Prescot, A and Stark, C and Kaplan, J and Mack, WJ and Knowlton, B and Oeltzschner, G and Eich, T},
title = {Introducing the SAGE study: a multimodal protocol for testing a GABAergic mechanism of age-related episodic memory impairment across the sexes.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001546},
pmid = {42344858},
issn = {2632-6140},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder that severely hinders quality of life. Hippocampal hyperactivity is recognised as a biological marker of AD pathology and is associated with episodic memory impairments, the hallmark cognitive symptom of AD. What drives this hyperactivity, however, is not well understood. γ-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain. Animal models show that age-related GABAergic dysregulation drives hippocampal hyperactivity and cognitive impairment. However, whether this same mechanism translates to humans remains untested. Further, the role of biological sex has not been considered despite the fact that oestrogen modulates GABA receptor expression and GABA release in the hippocampus. Here, we introduce the Sex, Age, GABA, Episodic memory (SAGE) study, a protocol aimed to test an age and sex based GABAergic mechanism of memory impairment in humans.

METHODS AND ANALYSIS: The SAGE study, which will collect multimodal data from 300 healthy adults (100 per decade from age 50 years to 79 years, two-thirds women), aims to test whether age-related GABAergic dysregulation drives hippocampal hyperactivity and episodic memory decline in humans and whether this mechanism is moderated by sex.},
}

@article {pmid42344865,
year = {2026},
author = {Zhang, C and Zhang, J},
title = {6PPD-quinone exposure and Alzheimer's disease: insights from integrative network pharmacology, transcriptomics, machine learning, and molecular docking.},
journal = {Open medicine (Warsaw, Poland)},
volume = {21},
number = {1},
pages = {20261477},
pmid = {42344865},
issn = {2391-5463},
abstract = {OBJECTIVES: To systematically investigate the molecular associations between 6PPD-quinone (6PPD-Q), an environmental transformation product of the tire antioxidant 6PPD, and Alzheimer's disease (AD) pathogenesis.

METHODS: An integrative strategy combining network pharmacology, transcriptomic validation, and machine learning was employed. Intersecting targets were identified through multi-database mining, followed by functional enrichment and protein-protein interaction (PPI) network analyses. Transcriptomic validation, SHAP-based XGBoost analysis, Mendelian randomization, and molecular docking were performed to evaluate target expression, diagnostic value, causal associations, and binding affinities.

RESULTS: A total of 92 intersecting targets were identified, enriched in synaptic structures, kinase activity, neuroinflammation, and apoptotic pathways. PPI analysis revealed 23 core targets, with NFKB1, GSK3B, and PIK3CA as key hub genes enriched in the cerebral cortex and basal ganglia. Transcriptomic data confirmed differential expression of core targets in AD. SHAP analysis identified PTGS2, KIT, PIK3CA, NFE2L2, and NFKB1 as high-value diagnostic predictors. Mendelian randomization supported a causal association between NFKB1 brain expression and AD risk. Molecular docking confirmed strong binding of 6PPD-Q to PTGS2, GSK3B, and NFE2L2.

CONCLUSIONS: This study provides the first systematic characterization of the molecular mechanisms by which 6PPD-Q may contribute to AD pathogenesis, potentially through inducing oxidative stress, activating neuroinflammation, and disrupting kinase signaling networks.},
}

@article {pmid42344882,
year = {2026},
author = {Lutz, MW and Man, Z and Zheng, Y and Venkatesan, S and Chiba-Falek, O},
title = {A diagnostic plasma omics-biomarker for Alzheimer's disease informed by microglial single-cell transcriptomics: A pilot study.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70273},
pmid = {42344882},
issn = {2352-8737},
abstract = {BACKGROUND: The current biomarker framework for the diagnosis and staging of Alzheimer's disease (AD) relies mainly on neuropathological features; thus, its performance for diagnosis is limited prior to the initiation of neurodegeneration. Here, we leveraged transcriptomic data to develop a new framework for omic-informed blood-based diagnostic biomarkers for AD from an early stage.

METHODS: Microglial gene expression from single nucleus RNA sequencing (snRNA-seq) data was analyzed via six statistical methods to identify candidate panels of genes predictive of AD. A total of 78 gene panels, 30 to 2000 genes in size, were selected and evaluated for their ability to distinguish AD patients from controls. Three top-ranked panels of 300, 50, and 30 genes were transferred to blood (monocyte) transcriptomic data obtained from living subjects via a graph-based mapping approach based on optimal transport statistics.

RESULTS: The 300-panel method resulted in an area under the curve (AUC) of 0.7 and moderate accuracy (75%) in classifying AD; however, the accuracy in predicting cognitively normal patients was lower (53%). While the 300 genes provided high accuracy, inspection of the distribution of P values for the gene set revealed that the panel could be greatly reduced in size to capture the most significant differences between AD patients and cognitively normal individuals. The accuracy and specificity of the 50 and 30 panels demonstrated similar AUC values but improved the balance between the prediction of AD patients and normal controls. Specifically, the 50-gene panel resulted in an AUC of 0.7, with 65% AD accuracy and 71% normal accuracy.

CONCLUSIONS: Integrating multiomics datasets into the AD biomarker discovery pipeline offers a powerful modality to increase precision and comprehensiveness in AD research and clinical applications.},
}

@article {pmid42344884,
year = {2026},
author = {Roy, M and Fortier, M and St-Pierre, V and Morin, MC and Boré, A and Edde, M and Vandenberghe, C and Groulx, K and Croteau, É and Richard, G and Thoumyre, S and Fulop, T and Bocti, C and Rheault, F and Cuenoud, B and Descoteaux, M and Cunnane, SC},
title = {A combination of ketones and NAD[+] precursor preserves white matter integrity in mild cognitive impairment.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70278},
pmid = {42344884},
issn = {2352-8737},
abstract = {INTRODUCTION: Brain glucose metabolism declines and myelin deteriorates as Alzheimer's disease (AD) develops. Adequate energy supply to white matter (WM) is critical to maintain myelin integrity and axonal function. An exogenous source of ketones bypasses the glucose‑specific brain energy deficit and improves cognitive outcomes in mild cognitive impairment (MCI). The BREAK-AD (BRain Energy Activation with Ketones in AD) trial tested a ketone salt and nicotinamide adenine dinucleotide (NAD[+]) precursor mixture to compensate for reduced brain glucose uptake in MCI.

METHODS: Participants were randomized to a placebo (n = 15) or active supplement (β-hydroxybutyrate salts + nicotinamide riboside (NR); n = 15). Brain ketone and glucose metabolism (quantified by positron emission tomography [PET]), and cognitive performance were assessed before and at the end of the 6-month intervention. For WM analysis, seven tracts of interest were extracted using diffusion magnetic resonance imaging (MRI), and myelin density measures were derived from magnetization transfer (MT) imaging.

RESULTS: Total gray matter ketone uptake increased by 2.4-fold (p < 0.001) in the active group, with no change in gray matter glucose uptake in either group. In WM, ketone uptake increased in the active group by 3.1-3.6-fold across all seven tracts of interest (p < 0.001). In the placebo group, myelin density declined by up to 10% in specific regions of the fornix (p = 0.027), with no change in the active group. Improved processing speed was significantly associated with post-intervention change in myelin density (r = -0.39 to -0.59; p = 0.002-0.046) and ketone uptake (r = -0.40 to -0.52; p = 0.010-0.046) in WM tracts. Ketone uptake in specific WM tracts (fornix, uncinate and arcuate fasciculi), as well as in the composite of all tracts of interest was strongly associated with myelin density.

DISCUSSION: This study shows for the first time that improved myelin density may help explain the positive association between increased WM ketone uptake and improved processing speed in MCI after a ketone salt and NAD[+] precursor supplementation.},
}

@article {pmid42345500,
year = {2026},
author = {Drążyk, M and Pyc, Z and Pietrzyk, SJ and Gajda-Janiak, A and Godziszewski, F and Pioterek, O and Tulski, M and Mazurek, M and Domagała, ZA},
title = {Formaldehyde neurotoxicity: Effects on the mammalian brain, cognitive function, and neurodegenerative risk. A scoping review.},
journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University},
volume = {},
number = {},
pages = {},
doi = {10.17219/acem/209617},
pmid = {42345500},
issn = {1899-5276},
abstract = {Aqueous formaldehyde (FA) solution, known as formalin, is currently the primary agent used for preserving tissue samples and anatomical specimens. Formaldehyde is widely used in laboratories and the chemical industry; it also occurs as an air pollutant and endogenous cellular metabolite. The potential carcinogenic effects of formalin on the respiratory tract are well documented. A less recognized consequence of occupational exposure to FA is its detrimental effect on the central nervous system (CNS) and brain function. A literature review was conducted to investigate the effects of FA on the brain. Five databases were searched: PubMed, Web of Science (WoS), Embase, ScienceDirect, and Google Scholar. To describe the effects of FA exposure and endogenous FA generation, 35 relevant publications were collected and analyzed. The literature review demonstrated that inhalation is the most common route of FA exposure. Several studies have shown that FA may cause hippocampal damage, disrupt melatonin secretion, and induce a wide range of cognitive disorders with varying characteristics and severity. These disorders include memory impairment, disturbances in balance and spatial orientation, learning difficulties, sleep disturbances, impaired judgment, and prolonged reaction times to stimuli. Increased endogenous FA concentration has also been associated with a higher risk of neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis. The literature analysis demonstrated the high neurotoxicity of FA, which may lead to numerous neuropsychiatric disorders. We aim to draw attention to the risks associated with the routine use of formalin, particularly among anatomists and pathologists, and to encourage consideration of less harmful alternative preservation agents.},
}

@article {pmid42345506,
year = {2026},
author = {Cilia, J and Guillermin-Escobar, O and McCreary, AC and Virley, D and Li, J},
title = {Effects of pimavanserin, xanomeline and highly-purified plant-derived cannabidiol on MK-801-induced behaviours in mice relevant to psychosis.},
journal = {Journal of psychopharmacology (Oxford, England)},
volume = {},
number = {},
pages = {2698811261456216},
doi = {10.1177/02698811261456216},
pmid = {42345506},
issn = {1461-7285},
abstract = {BACKGROUND: Psychosis, as a comorbidity, is seen in many neuropsychiatric and neurodegenerative disorders and is often treated with dopamine D2 receptor (D2R) antagonists, which could aggravate Alzheimer's disease and Parkinson's disease (PD) symptoms. Hence, there is a need for new treatments with a non-D2R antagonist-related mechanism of action. Recently approved drugs for psychosis in PD, including pimavanserin (PIM), and for schizophrenia, xanomeline-trospium, offer advances since they lack D2R antagonism but both carry associated risks. The highly-purified, plant-derived form of cannabidiol (hpCBD; Epidiolex[®]) has a different safety profile, does not inhibit D2R and has demonstrated antipsychotic effects in patients with psychosis.

AIMS: To systematically assess the potential antipsychotic-like effects of hpCBD, alongside newer non-D2 antagonist drugs approved for PD psychosis (PIM) and schizophrenia psychosis (xanomeline oxalate (XAN)) in the same set of standardised preclinical assays.

METHODS: MK-801-induced hyperlocomotion and pre-pulse inhibition (PPI) deficits in male C57BL/6J mice were assessed following PIM (0.1, 0.3, 1 mg/kg s.c.), XAN (1, 3, 10 mg/kg s.c.) or hpCBD (50, 100, 200 mg/kg i.p.) administration. Locomotor activity was measured by infrared photobeams and Laboratory Animal Behaviour Observation Registration and Analysis System, and PPI was measured in acoustic startle chambers using a variable pre-pulse intensity protocol.

RESULTS: PIM, XAN (all doses) and hpCBD (200 mg/kg) attenuated MK-801 hyperlocomotion (p < 0.01). PPI deficits, at various pre-pulse intensities, were attenuated by PIM (all doses), XAN 10 mg/kg and hpCBD 200 mg/kg (p < 0.05).

CONCLUSION: These results suggest that hpCBD, like PIM and XAN, demonstrates putative antipsychotic-like activity in classic mouse assays relevant to psychosis, consistent with positive clinical data in patients with psychosis.},
}

@article {pmid42345513,
year = {2026},
author = {Goyal, A and Verma, A and Kumari, A and Mishra, MK},
title = {Battling Parkinson's and Alzheimer's: The Neuroprotective Power of Carnosic Acid.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {7},
pages = {e70991},
doi = {10.1002/jbt.70991},
pmid = {42345513},
issn = {1099-0461},
mesh = {*Abietanes/therapeutic use/pharmacology ; Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; *Parkinson Disease/drug therapy/metabolism/pathology ; Oxidative Stress/drug effects ; *Plant Extracts/therapeutic use ; },
abstract = {Neurodegenerative disorders have recently emerged as one of the most difficult worldwide health challenges. Neuronal cell injury is a major factor in neurodegenerative diseases. There seems to be rising interest in developing effective neuroprotective drugs from natural sources. Nutraceuticals, or compounds produced from natural sources have shown neuroprotective effects in both in vitro and in vivo models of neuronal cell death and neurodegeneration. Carnosic acid (CA), a natural compound majorly obtained from rosemary and other herbs, has emerged as a promising neuroprotective agent in neurodegenerative diseases, particularly Alzheimer's and Parkinson's. This review covers the latest findings on the methods by which carnosic acid mitigates key pathological features such as oxidative stress, neuroinflammation, apoptosis, and protein aggregation as well as other pathways related to Parkinson's and Alzheimer's disease induction. Furthermore, we describe preclinical and clinical research that demonstrates the ability of carnosic acid to improve cognitive function and motor performance. This study will give a detailed overview of carnosic acid as a possible therapeutic agent, opening the path for future research into viable therapies for Alzheimer's and Parkinson's disorders.},
}

*Abietanes/therapeutic use/pharmacology
Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Neuroprotective Agents/therapeutic use/pharmacology
Animals
*Parkinson Disease/drug therapy/metabolism/pathology
Oxidative Stress/drug effects
*Plant Extracts/therapeutic use

@article {pmid42345794,
year = {2026},
author = {Deng, Z and Chen, J and Li, J and Luo, X and Luo, Q and Ren, M and Li, X},
title = {Regulation of Neuronal Senescence by Srebf2 and Zmiz1 Reveals Mechanisms of Aging-Related Neurodegeneration.},
journal = {Biology},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/biology15120938},
pmid = {42345794},
issn = {2079-7737},
support = {No. 2021ZD0201004//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; No. 32400931//National Natural Science Foundation of China/ ; KJRC2023A03//Natural Science Foundation for Scientific and Technological Talents Innovation Programs of Hainan Province/ ; KJRC2023D28//Natural Science Foundation for Scientific and Technological Talents Innovation Programs of Hainan Province/ ; 2023WNLOKF014//Open Project Program of Wuhan National Laboratory for Optoelectronics/ ; },
abstract = {Neuronal senescence-like states are increasingly implicated in age-related neurodegeneration, yet the neuron-intrinsic regulators that drive these phenotypes remain poorly defined. Guided by prior transcriptomic analysis of aged basal forebrain cholinergic neurons, we investigated Srebf2 and Zmiz1 using primary basal forebrain neuronal cultures with adeno-associated virus-mediated gain- and loss-of-function, quantitative immunocytochemistry, and low-input transcriptomic profiling of fluorescence-activated cell sorting-isolated neurons. Both perturbation strategies produced the expected directional changes in target transcripts. Overexpression of either gene increased the other, whereas knockdown did not elicit reciprocal suppression, indicating asymmetric regulatory coupling. Phenotypically, Srebf2 showed a bidirectional association with senescence-like changes, as both overexpression and knockdown increased p16 and p21, whereas Zmiz1 acted more directionally, with overexpression increasing and knockdown reducing these markers. Transcriptomic profiling revealed broad direction-dependent remodeling, including a set of 55 genes that changed concordantly across perturbation directions. Pathway analysis further showed specialization, with Zmiz1 preferentially associated with an Alzheimer's disease-related signature and Srebf2 more strongly linked to cholinergic synapse programs. Together, these findings identify Srebf2 and Zmiz1 as coupled but non-equivalent regulators of a neuronal senescence-like program.},
}

@article {pmid42345905,
year = {2026},
author = {Huang, Y and Wang, N and Yi, X and Xia, N},
title = {Progress in (Photo)electrochemical Biosensors for the Detection of Amyloid-Beta Oligomer.},
journal = {Biosensors},
volume = {16},
number = {6},
pages = {},
pmid = {42345905},
issn = {2079-6374},
mesh = {*Biosensing Techniques ; *Amyloid beta-Peptides/analysis ; Humans ; *Electrochemical Techniques ; Alzheimer Disease/diagnosis ; Biomarkers ; },
abstract = {Alzheimer's disease (AD) has become a neurodegenerative disease with an increasing incidence rate and a large economic and social burden worldwide. Amyloid-beta oligomer (AβO) has been confirmed as a key neurotoxic species and a core diagnostic biomarker in AD. Traditional methods for AβO detection have drawbacks, such as cumbersome operation, high cost, and dependence on sophisticated instruments, hindering their transformation into fast and real-time detection techniques. (Photo)electrochemical biosensors have attracted much attention due to their inherent advantages, such as high sensitivity, low cost, portability, and ease of miniaturization. This review systematically summarizes the latest progress of (photo)electrochemical biosensors for AβO detection, mainly based on two sensing modes: direct detection and sandwich-type detection. We comprehensively elaborated on the sensing performances and recognition elements, such as antibodies, aptamers, peptides, and molecularly imprinted polymers. The integration of functional nanomaterials and signal amplification strategies was emphasized to improve the sensitivity, selectivity, and stability of biosensors. In addition, we discussed the existing challenges and looked forward to the future development direction for the early diagnosis of AD. This article aims to provide a systematic reference for the rational design and practical application of advanced biosensors in biomarker detection and AD-related precision medicine.},
}

*Biosensing Techniques
*Amyloid beta-Peptides/analysis
Humans
*Electrochemical Techniques
Alzheimer Disease/diagnosis
Biomarkers

@article {pmid42346084,
year = {2026},
author = {Czaniera, NJ and Schulten, W and Nowak, K and Pschik, D and Joneleit, J and Kaltschmidt, B and Kaltschmidt, C},
title = {Cholinergic Differentiation of Human iPSCs Reveals Early APOE4-Driven Dysregulation of Neuronal Markers, Synaptogenesis and Inflammatory Responses.},
journal = {Cells},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/cells15121057},
pmid = {42346084},
issn = {2073-4409},
mesh = {Humans ; *Apolipoprotein E4/metabolism/genetics ; *Cell Differentiation ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Inflammation/pathology/metabolism ; *Cholinergic Neurons/metabolism ; Tumor Necrosis Factor-alpha/pharmacology/metabolism ; *Synapses/metabolism ; *Biomarkers/metabolism ; *Neurogenesis ; Alzheimer Disease/metabolism ; Apolipoprotein E3/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by progressive memory impairment and cognitive decline. The APOE4 allele represents one of the most prominent genetic risk factors. In this study, we investigated the impact of APOE4 on the cholinergic neuronal development and on the neuronal inflammatory response to TNF-α stimulation. To address this, human induced pluripotent stem cells (hiPSCs) carrying a homozygous APOE4 genotype and an isogenic APOE3 control were differentiated into cholinergic-like induced neurons (iNs) by LHX8 overexpression. APOE4 was associated with accelerated early neuronal differentiation, as reflected by earlier downregulation of the progenitor marker Nestin. However, delayed expression of synaptophysin indicated impaired synaptic maturation. Functionally, APOE3 iNs exhibited a robust but temporally regulated response to TNF-α, whereas APOE4 iNs were characterized by a delayed yet sustained induction of inflammatory signaling. Moreover, APOE4 iNs displayed an enhanced stress-associated transcriptional response at early differentiation stages. Collectively, these findings suggest that APOE4 influences both neuronal development and the timing and persistence of inflammatory responses, potentially predisposing cholinergic neurons to later dysfunction in AD.},
}

Humans
*Apolipoprotein E4/metabolism/genetics
*Cell Differentiation
*Induced Pluripotent Stem Cells/metabolism/cytology
*Inflammation/pathology/metabolism
*Cholinergic Neurons/metabolism
Tumor Necrosis Factor-alpha/pharmacology/metabolism
*Synapses/metabolism
*Biomarkers/metabolism
*Neurogenesis
Alzheimer Disease/metabolism
Apolipoprotein E3/metabolism

@article {pmid42346090,
year = {2026},
author = {Marcoccia, S and Chiacchierini, G and Campolongo, P},
title = {Coordinating Cognition: The Entorhinal Cortex in Mnemonic, Temporal and Spatial Representation.},
journal = {Cells},
volume = {15},
number = {12},
pages = {},
pmid = {42346090},
issn = {2073-4409},
support = {B83C22002820006//European Union NextGenerationEU - Project ECS 0000024 Rome Technopole PNRR Mission 4, Component 2, Investment 1.5/ ; },
mesh = {*Entorhinal Cortex/physiology ; Humans ; Animals ; *Cognition/physiology ; *Memory/physiology ; Hippocampus/physiology ; },
abstract = {The entorhinal cortex (EC) is a central structure of the medial temporal lobe, functioning as the main cortical gateway to the hippocampus (HPC) and playing a crucial role in memory, spatial navigation, and temporal representation. This review outlines the distinct yet complementary contributions of its two main subdivisions, the medial (MEC) and lateral (LEC) entorhinal cortices. Despite being historically viewed as functionally segregated, they operate instead in close coordination to support the encoding and retrieval of multidimensional experiences. While the MEC is prominently involved in mapping spatial relationships and movement through specialized cell populations, and the LEC in processing object-related and contextual information, growing evidence shows substantial integration between these domains, challenging strict dichotomies. The MEC encodes elapsed time through persistent firing and time cell sequences, while the LEC signals temporal context via rate remapping; their convergent projections to the hippocampus enable the formation of temporally structured episodic memories. The review assesses recent findings on memory, navigation, and time processing, and highlights how the EC supports each through its layered architecture, local microcircuitry, and widespread interactions with HPC, cortical, and subcortical networks. Moreover, alterations in EC activity patterns emerge as the earliest signs of pathologies such as Alzheimer's disease and temporal lobe epilepsy. Altogether, this review offers an up-to-date view of the EC not as a set of parallel modules, but as a highly interactive and dynamic system essential for structuring experience across space, time, and context.},
}

*Entorhinal Cortex/physiology
Humans
Animals
*Cognition/physiology
*Memory/physiology
Hippocampus/physiology

@article {pmid42346109,
year = {2026},
author = {Huang, H and Xu, K and Lardellia, M},
title = {Ketone-Dependent Restoration of Autophagy and Mitochondrial Quality Control Through VPS35 in a Drosophila Model of C99-Induced Neurodegeneration.},
journal = {Cells},
volume = {15},
number = {12},
pages = {},
pmid = {42346109},
issn = {2073-4409},
mesh = {Animals ; *Mitochondria/metabolism/drug effects/ultrastructure ; *Autophagy/drug effects ; *Vesicular Transport Proteins/metabolism ; Disease Models, Animal ; *Ketones/pharmacology/metabolism ; Humans ; Neurons/metabolism/drug effects ; *Amyloid beta-Protein Precursor/metabolism ; Drosophila melanogaster/metabolism ; *Drosophila Proteins/metabolism ; Alzheimer Disease/metabolism ; },
abstract = {BACKGROUND: Early endolysosomal and autophagic defects are among the earliest cellular alterations observed in Alzheimer's disease (AD). However, the molecular mechanisms linking amyloid precursor protein (APP) metabolism to vesicle trafficking dysfunction remain incompletely understood. The APP-derived fragment C99 has emerged as a potential upstream mediator of intracellular toxicity, but its impact on organelle homeostasis and its modulation by metabolic interventions remain unclear.

METHODS: To investigate these mechanisms, we expressed human C99 in Drosophila neurons and examined intracellular pathology using ultrastructural analysis, fluorescent reporters of autophagy and mitochondrial turnover, and proteomic interactome mapping. The effects of the ketone body β-hydroxybutyrate (BHB) were evaluated to assess the impact of metabolic intervention.

RESULTS: Neuronal C99 expression induced pronounced vesicular abnormalities, impaired autophagic turnover, and disrupted mitochondrial quality control. Transmission electron microscopy revealed extensive accumulation of enlarged vesicular compartments, accompanied by reduced mitochondrial turnover and accumulation of aged mitochondria. BHB treatment restored autophagic cargo clearance, improved mitochondrial turnover, and normalized vesicular ultrastructure. These protective effects required neuronal ketone transport, indicating a neuron-intrinsic metabolic mechanism. Proteomic analysis of the C99-associated interactome revealed that ketone treatment remodels networks enriched for vesicle trafficking and proteostasis pathways. Network prioritization identified the retromer component VPS35 as a candidate regulatory hub. Functional analyses demonstrated that depletion of VPS35 abolished the BHB-dependent restoration of autophagy, mitochondrial turnover, and vesicle morphology.

CONCLUSIONS: Ketone treatment restores mitochondrial quality control and autophagic homeostasis through a VPS35-dependent mechanism in C99-induced neurodegeneration. These findings provide mechanistic insight into how metabolic interventions may restore intracellular homeostasis in Alzheimer's disease.},
}

Animals
*Mitochondria/metabolism/drug effects/ultrastructure
*Autophagy/drug effects
*Vesicular Transport Proteins/metabolism
Disease Models, Animal
*Ketones/pharmacology/metabolism
Humans
Neurons/metabolism/drug effects
*Amyloid beta-Protein Precursor/metabolism
Drosophila melanogaster/metabolism
*Drosophila Proteins/metabolism
Alzheimer Disease/metabolism

@article {pmid42346113,
year = {2026},
author = {Yao, Y and Zhou, S and Cheng, Z and Chen, S and Zhang, Y and Shi, J and Wei, D and Zhang, T and Duan, G and Gao, S},
title = {Investigating Alzheimer's Disease-Associated Genes Using Differential Splicing Frequency Analysis.},
journal = {Cells},
volume = {15},
number = {12},
pages = {},
pmid = {42346113},
issn = {2073-4409},
support = {32371153//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/genetics ; Humans ; Animals ; *Alternative Splicing/genetics ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice ; Protein Isoforms/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Cell Differentiation/genetics ; Neurons/metabolism ; Microglia/metabolism ; },
abstract = {Accurately quantifying the expression of individual transcript isoforms remains a formidable challenge, especially in contexts such as neurodegenerative diseases and cancers, which are characterized by high isoform diversity. The present study introduces a junction-based method, named differential splicing frequency analysis (DSFA), which enables more sensitive detection of differential splicing using RNA-seq data. Unlike the existing exon-, isoform-, and event-based methods, DSFA quantifies splice junction usage. We applied DSFA to Alzheimer's disease (AD)-associated genes through large-scale RNA-seq data mining. The present study is the first to establish that the APP770-, APP751-, APP695-, and APP752-encoding isoforms represent major isoforms of the APP gene. Three important findings are: (1) the APP752-encoding isoform exhibits immune cell specificity; (2) the relative proportion of the APP752-encoding isoform increases during the differentiation of induced pluripotent stem cells (iPSCs) into microglia, akin to the increase in relative proportion of the APP695-encoding isoform during iPSC differentiation into neurons; and (3) the APP751-encoding isoform predominates in both cancer and immune cells. Additionally, we identified APP/58417N and App/52804N as differentially expressed splice junctions in humans and mice, respectively. Through over-expression of U1 snRNA in human embryonic stem cell (hESC)-derived neurons, we found that U1 snRNA over-expression decreases the usage of APP/58417N in neurons, similar to the effects observed in AD samples. Our research highlights that the major isoforms of a gene can differ markedly in their expression across tissue and cell types.},
}

*Alzheimer Disease/genetics
Humans
Animals
*Alternative Splicing/genetics
Amyloid beta-Protein Precursor/genetics/metabolism
Mice
Protein Isoforms/genetics/metabolism
Induced Pluripotent Stem Cells/metabolism
Cell Differentiation/genetics
Neurons/metabolism
Microglia/metabolism

@article {pmid42346116,
year = {2026},
author = {Khan, SU and Chauhan, V and Chaudhary, AA and Khan, M},
title = {The Gut-Brain-Immune Axis: Multi-Omics Insights into Neurodegenerative and Metabolic Diseases.},
journal = {Cells},
volume = {15},
number = {12},
pages = {},
pmid = {42346116},
issn = {2073-4409},
support = {DDRSP-2601//Imam Mohammad ibn Saud Islamic University/ ; },
mesh = {Humans ; Multiomics ; *Neurodegenerative Diseases/immunology/metabolism ; Animals ; *Brain/immunology/metabolism ; *Metabolic Diseases/immunology/metabolism ; Gastrointestinal Microbiome ; Metabolomics ; },
abstract = {The axis linking the gut to the brain to the immune system connects all tissues involved-bacteria, immune cells, metabolism and the CNS-through a multidirectional communication network. Several studies have confirmed that when this axis is disrupted, it can be responsible for Alzheimer's disease, Parkinson's disease, obesity, type 2 diabetes, and NAFLD, and the main consequences come from increased systemic inflammation, altered regulation of immune cells, the production of microbial metabolites that alter signals to the immune cells and nervous system, increase in oxidative stress, breakdown of the gut barrier, and more. In recent years, advanced multi-omics technologies, such as metagenomics, transcriptomics, metabolomics, proteomics, and single-cell sequencing, have provided significant advancement in our understanding of all of the interacting nodes involved in the gut-brain-immune axis. These advanced sequencing technologies can characterize the microbial communities, host immune cells, metabolic profiles, and the degree of cell heterogeneity during a specific disease. Combining multi-omics information can reveal a few shared pathways between neurodegenerative and metabolic disorders, such as NF-κB, NLRP3 inflammasome activation, mitochondrial dysfunction, changes in SCFA metabolism, and the alteration of microbial populations in Alzheimer's and Parkinson's disease; metabolic dysbiosis and increased risk for Parkinson's disease; or changes in gut-to-brain-to-immune signaling contributing to diabetes complications and NAFLD. Artificial intelligence (AI) and machine learning are becoming promising tools for detecting biomarkers from these datasets, extracting knowledge, interpreting systems biology, and helping with developing precision medicine. In this review, we summarize current evidence that supports the role of the gut-brain-immune axis in neurodegenerative and metabolic diseases, highlighting results gained with the utilization of multi-omics approaches. We will describe the key microbial, immune, and metabolic pathways involved in pathogenesis and therapeutic approaches including psychobiotics, tailored nutrition, modulation of the microbiome, and metabolite interventions, discussing future perspectives of the translation of the gut-brain-immune axis knowledge into clinical practice.},
}

Humans
Multiomics
*Neurodegenerative Diseases/immunology/metabolism
Animals
*Brain/immunology/metabolism
*Metabolic Diseases/immunology/metabolism
Gastrointestinal Microbiome
Metabolomics

@article {pmid42346137,
year = {2026},
author = {Mikołajczak, K and Chmiel, J and Leszek, J},
title = {Neuroinflammation in Alzheimer's Disease (AD) and Glioblastoma (GBM): Shared Mechanisms and Therapeutic Insights.},
journal = {Cells},
volume = {15},
number = {12},
pages = {},
pmid = {42346137},
issn = {2073-4409},
mesh = {Humans ; *Alzheimer Disease/pathology/therapy ; *Glioblastoma/pathology/therapy ; Animals ; *Neuroinflammatory Diseases/pathology/therapy ; Microglia/metabolism/pathology ; *Brain Neoplasms/pathology ; Inflammasomes/metabolism ; Inflammation/pathology ; Cytokines/metabolism ; Blood-Brain Barrier/metabolism/pathology ; },
abstract = {INTRODUCTION: Neuroinflammation is a key feature of both Alzheimer's disease (AD) and glioblastoma, although it leads to different outcomes in each disorder. In AD, chronic activation of microglia and astrocytes by amyloid-β and tau contributes to neuronal injury and cognitive decline. In glioblastoma, tumor cells exploit inflammatory pathways to create an immunosuppressive microenvironment that supports tumor growth. This review compares the shared and distinct neuroinflammatory mechanisms in AD and glioblastoma and highlights their therapeutic relevance.

MATERIALS AND METHODS: This study was conducted as a narrative review based on a PubMed search performed by three reviewers. English-language articles on AD, glioblastoma, and neuroinflammatory pathways were included, covering original studies, reviews, meta-analyses, and experimental and clinical reports. Keywords included neuroinflammation, microglia, astrocytes, tumor-associated macrophages, inflammasomes, NLRP3, NF-κB, HIF-1α, cytokines, blood-brain barrier, and miRNAs. Due to study heterogeneity, findings were synthesized descriptively.

RESULTS: AD and glioblastoma share major neuroinflammatory mechanisms, including microglial and astrocytic activation, cytokine signaling, inflammasome activity, blood-brain barrier dysfunction, hypoxia-related changes, and miRNA regulation. In AD, these pathways promote chronic inflammation, synaptic loss, and neurodegeneration, with NLRP3, NF-κB, and M1-like microglial polarization playing central roles. In glioblastoma, similar pathways are redirected toward tumor progression through tumor-associated macrophages, reactive astrocytes, angiogenesis, immune evasion, and therapy resistance. Key overlapping mediators include IL-1β, TNF-α, NF-κB, HIF-1α, GSK-3β, and selected miRNAs.

CONCLUSIONS: AD and glioblastoma are connected by common neuroinflammatory pathways, but these processes result in neurodegeneration in AD and tumor support in glioblastoma. Understanding these shared and divergent mechanisms may guide the development of biomarkers and targeted therapies focused on microglia, inflammasomes, cytokines, and immune reprogramming in both diseases.},
}

Humans
*Alzheimer Disease/pathology/therapy
*Glioblastoma/pathology/therapy
Animals
*Neuroinflammatory Diseases/pathology/therapy
Microglia/metabolism/pathology
*Brain Neoplasms/pathology
Inflammasomes/metabolism
Inflammation/pathology
Cytokines/metabolism
Blood-Brain Barrier/metabolism/pathology

@article {pmid42346280,
year = {2026},
author = {Birsan, S and Roman-Filip, I and Rusu, M and Anca, F and Boicean, A and Sebastian, P and Blanca, G and Roman-Filip, C},
title = {Gastric Juice miR-106a-5p as a Non-Invasive Biomarker of Neuroinflammation and Neurodegeneration: A Prospective Observational Study.},
journal = {Diseases (Basel, Switzerland)},
volume = {14},
number = {6},
pages = {},
pmid = {42346280},
issn = {2079-9721},
abstract = {BACKGROUND: Neuroinflammation is a key contributor to the progression of several neurodegenerative disorders, including Alzheimer's disease, stroke, and small vessel disease. Emerging evidence highlights the role of circulating microRNAs (miRNAs) as non-invasive biomarkers of neuroinflammation and neuronal injury. miR-106a-5p, a member of the miR-17~92 cluster, is known to regulate inflammation, apoptosis, and vascular function. While typically studied in plasma or cerebrospinal fluid, gastric juice miRNAs represent a novel and underexplored source for biomarker discovery within the gut-brain axis. This exploratory study aimed to investigate the association between gastric juice miR-106a-5p expression and markers of neuroinflammation, including C-reactive protein (CRP), lactate dehydrogenase (LDH), and imaging-based evidence of neurodegeneration.

METHODS: A prospective, observational study was conducted on 38 participants (22 with neurodegenerative pathology and 16 healthy controls). Gastric juice samples were analyzed for miR-106a-5p using RT-qPCR, normalized to U6 snRNA. ΔCt values were used to determine relative expression. Statistical analyses included t-tests/Wilcoxon tests, ROC curve analysis, and correlation testing, with significance set at p < 0.05.

RESULTS: Patients with neurodegenerative changes exhibited significantly lower gastric miR-106a-5p expression compared to controls (p = 0.044). Elevated CRP and LDH levels were associated with higher ΔCt values (indicating lower expression), with p-values of 0.019 and 0.023, respectively. ROC analysis showed moderate diagnostic accuracy (AUC = 0.701) for miR-106a in identifying neurodegenerative status. miR-106a levels also correlated inversely with carotid intima-media thickness and brain MRI abnormalities, also reduced gastric miR-106a-5p expression is associated with systemic inflammation and neuroimaging evidence of neurodegeneration.

CONCLUSIONS: While causality cannot be inferred, these findings suggest that gastric miR-106a may serve as a promising non-invasive biomarker within the gut-brain axis framework. Further longitudinal and mechanistic studies are warranted to validate its clinical utility and explore its potential role in monitoring neuroinflammatory conditions.},
}

@article {pmid42346357,
year = {2026},
author = {Chen, J and Chen, X and Chen, T and Hu, J},
title = {Application of Plasma Metabolomic Biomarker Panels in Early Diagnosis and Disease Staging of Alzheimer's Disease.},
journal = {Metabolites},
volume = {16},
number = {6},
pages = {},
doi = {10.3390/metabo16060377},
pmid = {42346357},
issn = {2218-1989},
support = {LCYJZD2022006//Peking University Shenzhen Hospital/ ; },
abstract = {Background: Previous metabolomics studies on Alzheimer's disease (AD) have predominantly focused on Western populations, leaving Chinese cohorts and disease stage-specific data largely unexplored. Objectives: To characterize metabolic alterations across different clinical stages of AD in a Chinese population and identify early diagnostic biomarkers. Methods: We enrolled 172 participants, including patients with AD, mild cognitive impairment (MCI), subjective cognitive decline (SCD), vascular cognitive impairment (VCI), and healthy controls (HC). Untargeted metabolomics (LC-MS and GC-MS) was performed on plasma samples, integrated with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) assessments. Data were analyzed using multivariate statistics, pathway enrichment, and ROC modeling. Results: Distinct metabolic profiles emerged across disease stages, with phospholipids, ceramides, and glucose metabolites prominently enriched in glycerophospholipid, sphingolipid, and glucose pathways. A 16-metabolite panel achieved robust discrimination between AD+MCI and HC+VCI+SCD (AUC = 0.804). Specific metabolites, including ceramides, dihydroceramides, phosphatidylinositol, phosphatidylcholine, and glycodeoxycholic acid, correlated significantly with cognitive function and disease progression. Conclusions: This study reveals stage-specific metabolic dysregulation in Chinese AD patients and identifies potential plasma biomarkers for early detection, offering insights into AD pathogenesis. Trial registration number ChiCTR2400092653.},
}

@article {pmid42346588,
year = {2026},
author = {Kalam, AA and Roshanuddin, J and Gattu Linga, B and Ibrahim, FE and Hamdan, R and Farrell, T and Bu Shurbak, ZS and Mohamed, WMY and Al-Dewik, N},
title = {Associations of Vitamin D Receptor (ApaI, FokI, TaqI, BsmI) Polymorphisms with Neurodegenerative Diseases in the Middle East, North Africa and Turkiye (MENA&T) Region: A Systematic Review and Meta-Analysis Toward Population-Specific Precision Medicine.},
journal = {Journal of personalized medicine},
volume = {16},
number = {6},
pages = {},
pmid = {42346588},
issn = {2075-4426},
abstract = {Background: Vitamin D receptor (VDR) polymorphisms have been widely investigated as genetic determinants of neurodegenerative diseases, yet findings remain inconsistent and population-dependent. Evidence from the Middle East, North Africa, and Türkiye (MENA&T) regions, which is characterized by widespread vitamin D deficiency and distinct genetic backgrounds, has not been comprehensively synthesized. Methods: We conducted a systematic review and meta-analysis evaluating associations between four common VDR polymorphisms (ApaI rs7975232, FokI rs2228570, TaqI rs731236, and BsmI rs1544410) and the risk of multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD) in MENA&T populations. Six databases were searched from inception to November 2025. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using fixed- and random-effects models across multiple genetic contrasts. Subgroup analyses by ethnicity were conducted for MS. Study quality was assessed using the Newcastle-Ottawa Scale (NOS), and the certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: Nineteen unique case-control studies (20 reports), including 4744 participants, were included. For MS, the ApaI polymorphism showed consistent associations with increased risk across genetic models (random-effects ORs = 1.4-1.9), with stronger effects in Arab and Iranian populations and no association in Turkish cohorts. FokI showed associations with MS under selected genetic models, particularly recessive and homozygous contrasts, although findings were not consistent across all analytical approaches. TaqI showed model-dependent associations with substantial heterogeneity, while BsmI showed no significant association. For AD, a meta-analysis of two studies showed no significant associations. For PD, ApaI showed associations with increased risk across several models without heterogeneity; however, these findings were based on a limited number of studies. Overall certainty of evidence ranged from very low to moderate. Conclusions: In MENA&T populations, VDR ApaI polymorphism shows consistent evidence of association with MS susceptibility, while FokI may be associated under specific genetic models; evidence for AD and PD remains limited and should be considered exploratory. These findings highlight population-specific genetic heterogeneity and underscore the need for further large-scale studies to confirm these associations. These population-specific genetic associations underscore the importance of incorporating VDR genotyping into precision medicine frameworks for neurodegenerative disease risk stratification in MENA&T populations, where vitamin D deficiency is highly prevalent.},
}

@article {pmid42346783,
year = {2026},
author = {Gomes-Bispo, A and Cardoso, C and Afonso, C and Lourenço, HM and Pedro, S and Moniz, P and Bandarra, NM},
title = {Marine Lipids and Alzheimer's Disease: Biochemistry, Bioaccessibility/Bioavailability, Metabolism, and Health Effects.},
journal = {Marine drugs},
volume = {24},
number = {6},
pages = {},
pmid = {42346783},
issn = {1660-3397},
support = {MAR-016.9.1-FEAMPA-00008//Mar 2030/ ; 101060712//European Commission/ ; PRR - FF 483//Government of Portugal/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Lipids/chemistry/pharmacology/pharmacokinetics/therapeutic use ; *Aquatic Organisms/chemistry ; Biological Availability ; Lipid Metabolism ; },
abstract = {Due to its high prevalence and significant impact on modern society, Alzheimer's disease (AD) is one of the most important neurodegenerative disorders. It is more common among individuals over the age of 65, and its incidence has increased sharply as a result of rising life expectancy. Several factors have made it challenging to identify an effective treatment for AD. One major difficulty lies in its complexity, as the mechanisms involved in its progression are not yet fully understood. Nevertheless, the role of diet and lipids has been highlighted by numerous studies, underscoring their potential influence on this pathology. Due to the intricacy of its biochemical and metabolic interactions, this subject continues to be of particular interest, highlighting the need for further research. In this sense, this comprehensive and updated review aimed to elucidate these aspects, especially regarding marine-derived lipids, whose bioactive potential may become an irreplaceable tool in the management of AD, whether in terms of its treatment or prevention.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
Animals
*Lipids/chemistry/pharmacology/pharmacokinetics/therapeutic use
*Aquatic Organisms/chemistry
Biological Availability
Lipid Metabolism

@article {pmid42347116,
year = {2026},
author = {Miyata, S and Shimizu, S and Ishino, Y},
title = {Transcriptional Heterogeneity of Oligodendrocytes: Molecular Basis of Diversity Across Development, Brain Regions, and Neurological Diseases.},
journal = {Neurology international},
volume = {18},
number = {6},
pages = {},
doi = {10.3390/neurolint18060108},
pmid = {42347116},
issn = {2035-8385},
abstract = {Oligodendrocytes (OLs) are specialized glial cells essential for the formation and maintenance of the myelin sheath within the central nervous system (CNS). Historically, OLs were considered a functionally homogeneous population. However, the advent and widespread application of single-cell and single-nucleus RNA sequencing (scRNA-seq/snRNA-seq) technologies since 2015 have revealed substantial transcriptional heterogeneity, varying according to developmental stage, anatomical region, and disease state. In this review, we synthesized current advances in the understanding of OL heterogeneity. Nine OL cell classes have been identified in the mouse somatosensory cortex and hippocampal CA1 region, later expanding to 13 distinct subpopulations across ten CNS regions. Furthermore, we characterized disease-associated oligodendrocytes (DAOs)/disease-associated oligodendrocyte lineages (DOLs), identified in various neurological diseases, including multiple sclerosis (MS), Alzheimer's disease (AD), and spinal cord injury, focusing on their molecular markers, spatial distribution, and pathophysiological roles. We summarized key transcriptional regulatory networks underlying DAO induction, including the signal transducer and activator of transcription (STAT)/interferon regulatory factor (IRF) family, the Yin Yang 1 (YY1)/nuclear factor kappa B (NF-κB) axis, and the SOX9/SOX10 regulatory system. The utility of region-specific brain analyses using spatial transcriptomics (ST) in conjunction with these approaches was also discussed. Finally, we compiled the implications of patient stratification according to white matter glial response patterns derived from large-scale snRNA-seq analyses of patients with progressive MS. Our synthesis shows that oligodendrocytes consist of multiple distinct subtypes that vary across development, brain regions, and disease conditions. In pathological states, they adopt specific disease-associated programs that reflect context-dependent responses and may influence disease progression and repair. This work provides a framework for understanding how oligodendrocyte diversity contributes to neurological disease and may support the development of targeted remyelination therapies.},
}

@article {pmid42347121,
year = {2026},
author = {Xiao, D and Duvvuri, A and Makrigiannis, LV and Fuller, C},
title = {The Neuroprotective Role of Exercise in Alzheimer's Disease: An Integrative Review of Animal and Human Studies.},
journal = {Neurology international},
volume = {18},
number = {6},
pages = {},
doi = {10.3390/neurolint18060113},
pmid = {42347121},
issn = {2035-8385},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by progressive cognitive decline along with hallmark brain pathologies including amyloid-beta accumulation, hyperphosphorylated tau, neuroinflammation and neuronal mitochondrial dysfunction. As current pharmaceutical treatments only provide modest symptomatic improvement, there is an urgent need for effective non-pharmaceutical treatment options for the prevention or slowing down of this disease. This review synthesizes results from randomized controlled trials, observational studies, and animal model research on the ability of exercise to influence cognitive functions, brain structural changes, inflammatory processes, and neuroplasticity-related pathways. Exercise has demonstrated the capacity to enhance neurotrophic signaling, improve the regulation of mitochondria, improve cerebrovascular function and reduce pro-inflammatory cytokine levels in preclinical and mild cognitive impairment (MCI) subjects. Additionally, aerobic and resistance training has been shown to enhance physical performance and functional capacity. Furthermore, mind-body, dual-task and multimodal types of interventions may also provide additional cognitive and psychological benefits. Although the overall cognitive effect of exercise in individuals with established AD is generally small, it has been demonstrated that exercise can contribute to maintaining brain health through multiple interconnected metabolic, vascular and molecular pathways, thereby preserving cognitive reserve and slowing disease progression, particularly when initiated during early to midlife prior to the onset of AD symptoms. Therefore, future research will require establishing stage-specific exercise recommendations based on modality type, intensity and duration to achieve optimal clinical outcomes.},
}

@article {pmid42347402,
year = {2026},
author = {Li, Z and Luo, Y and Wang, S and Xue, D and Zhang, Y},
title = {Molecular Mechanisms of 6PPD and 6PPD-Q Toxicity in Neurodegenerative Diseases: A Network Toxicology and Experimental Validation Study.},
journal = {Toxics},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/toxics14060504},
pmid = {42347402},
issn = {2305-6304},
support = {2026zzts0639//the Postgraduate Research and Innovation Project of Central South University/ ; },
abstract = {6PPD is a widely used tire antioxidant that readily transforms into its more toxic ozonation product, 6PPD-quinone (6PPD-Q). Both compounds are emerging environmental contaminants with potential neurotoxic risks, yet their molecular mechanisms in Alzheimer's disease (AD) and Parkinson's disease (PD) remain unclear. This study integrated network toxicology, molecular docking, transcriptomic validation, and experimental models to investigate their neurotoxic effects. In silico analyses predicted significant neurotoxicity and blood-brain barrier permeability for both compounds. Target prediction and PPI network analysis identified 145/121 overlapping targets with AD/PD for 6PPD and 120/100 for 6PPD-Q. Functional enrichment analysis suggested that 6PPD-associated targets were mainly enriched in axon regeneration-, p75NTR-, and AGE-RAGE-related pathways, whereas 6PPD-Q-associated targets were enriched in MAPK cascade-, endosomal TLR signaling-, and amyloid-β formation-related pathways. Molecular docking suggested favorable binding affinities between these compounds and several core targets, including MAP2K1, EGFR, GSK3B, and CYCS. Transcriptomic validation in GEO datasets prioritized multiple hub genes. In vivo experiments showed activation of apoptosis-related signaling in the brain, while in vitro assays demonstrated ROS accumulation and neuroinflammatory activation (elevated TNF-α, IL-1β, IL-6, IFN-γ). CYCS and MAP2K1 emerged as key convergent nodes. Our findings reveal distinct yet synergistic neurotoxic mechanisms of 6PPD and 6PPD-Q in AD and PD, highlighting tire-derived pollutants as potential environmental risk factors for neurodegenerative diseases.},
}

@article {pmid42347525,
year = {2026},
author = {Caires, GA and Pereira, IS and DeOcesano-Pereira, C and Pimenta, DC and Kerkis, I and Sciani, JM and Vigerelli, H},
title = {Enhancing Neuronal Networks with Rhinella schneideri Skin Secretion Molecules: Implications for Neurodegenerative Disorders.},
journal = {Toxins},
volume = {18},
number = {6},
pages = {},
doi = {10.3390/toxins18060271},
pmid = {42347525},
issn = {2072-6651},
support = {130247/2021-9//National Council for Scientific and Technological Development/ ; },
mesh = {Animals ; *Neurodegenerative Diseases/drug therapy ; *Skin/metabolism ; *Neurons/drug effects ; *Bufonidae ; *Nerve Net/drug effects ; },
abstract = {Neurodegenerative disorders, including Parkinson's and Alzheimer's diseases, are hallmarked by the progressive degeneration of neuronal networks. Given the lack of disease-modifying cures, current therapies are limited to symptomatic relief. Here, we investigated the neurotrophic potential of the skin secretion (SS) from Rhinella schneideri, its polar fraction (PF) and nonpolar (NPF) fraction, and respective subfractions on the morphology of neuron-like cells. Following initial H2O-CH2CL2 partitioning, PF and NPF subfractions were isolated via RP-HPLC. Chemical characterization using LC-MS-IT-TOF identified eight distinct molecules, notably bufotenine and marinobufagin. Cytotoxicity screening established safe working concentrations (100-250 ng/mL for SS/PF; 250-500 ng/mL for NPF and subfractions) for downstream morphological evaluations using High Content Screening (HCS). The subfraction polar 5 (SfP5) elicited a robust neurotrophic response, significantly enhancing all assessed morphometric parameters: total neurite outgrowth (+72%), branching points (+120%), maximum process length (+60%), and total number of processes (+35%). Our data show that Rhinella schneideri SS contains molecules that improve in vitro neuronal networks, serving as a promising source for preliminary screening of neuroprotective effects.},
}

Animals
*Neurodegenerative Diseases/drug therapy
*Skin/metabolism
*Neurons/drug effects
*Bufonidae
*Nerve Net/drug effects

@article {pmid42347564,
year = {2026},
author = {Chen, J and Ding, X and Guan, D and Zhu, S and Zhang, X and Xie, L and Zhou, J and Zhang, H},
title = {Design, Synthesis, and Performance Characterization of BODIPY-Based NIR Probes for Aβ42 Aggregate Detection.},
journal = {ChemPlusChem},
volume = {91},
number = {6},
pages = {e70196},
doi = {10.1002/cplu.70196},
pmid = {42347564},
issn = {2192-6506},
mesh = {*Amyloid beta-Peptides/analysis/metabolism/chemistry ; *Boron Compounds/chemistry/chemical synthesis ; Animals ; *Fluorescent Dyes/chemistry/chemical synthesis ; PC12 Cells ; *Peptide Fragments/analysis ; Rats ; Fluorescent Chemosensor Compounds ; Alzheimer Disease/diagnostic imaging ; Humans ; Protein Aggregates ; *Drug Design ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with typical pathological features including β-amyloid (Aβ) plaques. Achieving early and accurate detection of cerebral Aβ aggregates is essential for timely intervention in AD, but the process is challenging. To address the lack of high-sensitivity and high signal-to-noise ratio near-infrared imaging tools for the early pathological detection of Aβ, we designed and synthesized two BODIPY-quinoline-based fluorescent probes, BQ-1 and BQ-2, for targeting Aβ42 aggregates. BQ-1 showed high affinity (KD = 48.81 nM), high sensitivity (LOD = 52 nM), and high signal-to-noise ratio (189.5-fold) for Aβ42 aggregates. Based on the twisted intramolecular charge transfer (TICT) mechanism, BQ-1 showed near-infrared fluorescence emission (λex/λem = 612/669 nm, Stokes shift 57 nm) after binding to Aβ42 aggregates, which showed good optical properties. Cell imaging experiments showed that BQ-1 could label Aβ42 aggregates in PC12 cells with high selectivity and low cytotoxicity. This study demonstrates that BQ-1 is a near-infrared (NIR) fluorescent probe with excellent performance and provides a potential tool for early pathological imaging diagnosis of AD.},
}

*Amyloid beta-Peptides/analysis/metabolism/chemistry
*Boron Compounds/chemistry/chemical synthesis
Animals
*Fluorescent Dyes/chemistry/chemical synthesis
PC12 Cells
*Peptide Fragments/analysis
Rats
Fluorescent Chemosensor Compounds
Alzheimer Disease/diagnostic imaging
Humans
Protein Aggregates
*Drug Design

@article {pmid42347716,
year = {2026},
author = {Zheng, M and Hou, B and Ma, R and Tan, Z},
title = {Methyltransferase-like 14 alleviates neuronal ferroptosis in Alzheimer's disease by regulating the peroxiredoxin 6/apoptosis signal-regulating kinase 1 signaling pathway.},
journal = {Neuroreport},
volume = {37},
number = {11},
pages = {430-441},
doi = {10.1097/WNR.0000000000002282},
pmid = {42347716},
issn = {1473-558X},
mesh = {Humans ; *Alzheimer Disease/metabolism ; *Ferroptosis/physiology ; *Methyltransferases/metabolism/blood/genetics ; Signal Transduction/physiology ; Cell Line, Tumor ; *Peroxiredoxin VI/metabolism ; *Neurons/metabolism ; Amyloid beta-Peptides ; Reactive Oxygen Species/metabolism ; *MAP Kinase Kinase Kinase 5/metabolism ; Peptide Fragments ; },
abstract = {BACKGROUND: Alzheimer's disease is a neurodegenerative disorder, in which ferroptosis contributes to its pathogenesis and progression. This study explored the precise mechanisms of ferroptosis in the pathological development of Alzheimer's disease.

METHODS: Amyloid beta 1-42 oligomer-treated SH-SY5Y cells were used to simulate Alzheimer's disease in vitro. Ferroptosis was evaluated by detecting the levels of reactive oxygen species (ROS), malonaldehyde, glutathione, Fe2+, and ferroptosis-related proteins. Cell viability was assessed by a Cell Counting Kit-8 assay. Total RNA N6-methyladenosine (m6A) levels were detected using an RNA methylation quantification kit, and peroxiredoxin 6 (PRDX6) m6A levels were analyzed by m6A RNA immunoprecipitation. The binding of methyltransferase-like 14 (METTL14) to PRDX6 was investigated by a dual-luciferase reporter assay.

RESULTS: METTL14 levels were decreased in the serum of Alzheimer's disease patients and in an in-vitro model of Alzheimer's disease, and serum levels correlated with the degree of cognitive impairment. METTL14 overexpression significantly inhibited amyloid beta 1-42 oligomer-induced ferroptosis and cytotoxicity in SH-SY5Y cells. Mechanistically, METTL14-mediated m6A modification increased PRDX6 mRNA stability, which inactivated the ROS-apoptosis signal-regulating kinase 1/p38 pathway. Rescue experiments demonstrated that PRDX6 overexpression reversed sh-METTL14-induced ferroptosis and neurotoxicity.

CONCLUSION: METTL14 suppressed neuronal ferroptosis to delay Alzheimer's disease progression through m6A modification of PRDX6 to inactivate the ROS-apoptosis signal-regulating kinase 1/p38 pathway. Our observations provide a potential therapeutic strategy for Alzheimer's disease.},
}

Humans
*Alzheimer Disease/metabolism
*Ferroptosis/physiology
*Methyltransferases/metabolism/blood/genetics
Signal Transduction/physiology
Cell Line, Tumor
*Peroxiredoxin VI/metabolism
*Neurons/metabolism
Amyloid beta-Peptides
Reactive Oxygen Species/metabolism
*MAP Kinase Kinase Kinase 5/metabolism
Peptide Fragments

@article {pmid42347970,
year = {2026},
author = {Huang, G and Zhang, Z and Ding, F},
title = {BRICHOS-Biased Inhibition Contributes to Aβ42 Dominance in Parenchymal Plaques Despite Higher Aβ40 Abundance and Coaggregation Capability.},
journal = {Biomacromolecules},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biomac.6c00811},
pmid = {42347970},
issn = {1526-4602},
abstract = {The predominance of Aβ42 fibrils in parenchymal plaques of Alzheimer's disease (AD), despite the higher abundance of Aβ40 capable of coaggregation with Aβ42, remains an open question of the disease. We postulate that the molecular chaperone Bri2 BRICHOS, an endogenous substoichiometric inhibitor of Aβ aggregation, may contribute to this mystery. Using atomistic replica-permutation discrete molecular dynamics simulations, we investigated the modulatory effects of BRICHOS on the fibril growth of both Aβ42 and Aβ40 by comparing their self- and cross-seeding processes. Aβ42 fibrils exhibited a higher fibrillization rate and greater thermal stability than Aβ40 fibrils, consistent with their higher amyloidogenicity. Both Aβ42 and Aβ40 fibrils were capable of efficiently cross-seeding the aggregation of the other variant, with fibril growth pathways determined by the seed morphology rather than the type of incoming monomer. However, BRICHOS showed a pronounced competitive advantage over Aβ40 monomer for binding Aβ40 fibril, thereby effectively capping the growth of Aβ40. The same effect, albeit much weaker, was also observed for Aβ42 fibrillization. This differential inhibition provides a possible mechanistic explanation for the scarcity of Aβ40 in fibrillar form in the AD brain despite its greater abundance and capability for cross-aggregation. Our findings highlight the combined influence of intrinsic fibril properties and selective environmental modulators in shaping amyloid deposit composition, providing new insights into AD pathogenesis and potential therapeutic strategies.},
}

@article {pmid42347999,
year = {2026},
author = {Hosseinpouri, A and Sadegh, K and Zarei-Behjani, Z and Dehghan, Z and Karbalaei, R},
title = {Correction to: Identification of critical genes and drug repurposing targets in entorhinal cortex of Alzheimer's disease.},
journal = {Neurogenetics},
volume = {27},
number = {1},
pages = {},
doi = {10.1007/s10048-026-00914-2},
pmid = {42347999},
issn = {1364-6753},
}

@article {pmid42348024,
year = {2026},
author = {Kurz, C and Hattenkofer, D and Pihale-Haug, M and Hufnagel, A and Gürsel, SÜ and Brendel, M and Rauchmann, BS and Levin, J and Höglinger, G and Perneczky, R},
title = {Head-to-head comparison of neurodegeneration biomarkers across two analytical platforms in Alzheimer's disease.},
journal = {Aging clinical and experimental research},
volume = {},
number = {},
pages = {},
doi = {10.1007/s40520-026-03420-5},
pmid = {42348024},
issn = {1720-8319},
abstract = {BACKGROUND: Blood-based biomarkers are increasingly used to support the identification of Alzheimer's disease (AD) in clinical and research settings. However, variability between analytical platforms limits their interchangeability and may affect their clinical interpretation. Direct head-to-head comparisons across assays and their alignment with clinical phenotypes remain limited.

OBJECTIVE: To compare the inter-test agreement of blood-based biomarkers measured using Roche and Fujirebio assays and to determine which biomarker shows the most robust analytical concordance and clinical relevance in AD.

METHODS: Participants with AD (n = 86) and cognitively healthy controls (HC; n = 56) underwent blood biomarker assessment using Roche and Fujirebio platforms. Plasma phosphorylated tau at threonine 217 (pTau217), plasma phosphorylated tau at threonine 181 (pTau181), Amyloid-β42 (Aβ42), amyloid-β40 (Aβ40), and the amyloid-β42/amyloid-β40 ratio (Aβ42/Aβ40) and glial fibrillary acidic protein (GFAP) were analyzed. Inter-test agreement was assessed using intraclass correlation coefficients, concordance analyses, and regression-based methods. Clinical relevance was evaluated by association with measures of cognitive and functional impairment evaluated using the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB). Analyses were adjusted for age and sex and complemented by sensitivity and stability analyses.

RESULTS: Inter-test agreement varied across biomarkers, with pTau217 demonstrating the highest and most stable concordance between Roche and Fujirebio assays. Among the evaluated markers, pTau217 also showed the strongest and most consistent associations with global cognition measures across diagnostic groups and best discriminated between individuals with AD and HC. GFAP demonstrated robust inter-test agreement but weaker alignment with clinical measures, while amyloid-based markers showed lower concordance and greater variability across platforms.

CONCLUSIONS: Head-to-head comparison of Roche and Fujirebio assays revealed biomarker-specific differences in inter-test agreement, limiting the direct interchangeability of measurements across platforms. Plasma pTau217 showed the most consistent analytical concordance and clinical associations in this setting, supporting its potential utility in cross-platform applications. However, these findings also highlight the need for assay-specific calibration and cautious interpretation of biomarker thresholds in clinical and research use and the need for further validation across diverse populations.

TRIAL REGISTRATION: NCT05059158, NCT05317871.},
}

@article {pmid42348056,
year = {2026},
author = {Zhang, C and Long, W and Ni, J and Chen, Z and Wu, X and Li, M and Du, F and Zhao, Y and Shen, J and Cho, CH and He, X and Xiao, Z},
title = {The Biological Basis, Mechanisms of Action, and Optimization Strategies of Exosomes Derived from Mesenchymal Stem Cells for the Treatment of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42348056},
issn = {1559-1182},
mesh = {*Exosomes/metabolism/transplantation ; Humans ; *Alzheimer Disease/therapy/metabolism/pathology ; Animals ; *Mesenchymal Stem Cells/metabolism ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathological process involves multiple mechanisms, including Aβ deposition, tau protein abnormalities, neuroinflammation, synaptic damage, and neuronal loss. Current therapeutic approaches remain ineffective in halting disease progression; therefore, the development of multi-targeted, low-immunogenicity therapeutic strategies with efficient brain delivery is of great significance. Mesenchymal stem cell-derived exosomes (MSC-derived exosomes) inherit the immunomodulatory, neuroprotective, and tissue-repairing properties of MSCs, and possess good biocompatibility and the potential to cross the blood-brain barrier. Studies have shown that MSC-derived exosomes exert therapeutic effects by modulating neuroinflammation, promoting neurogenesis and synaptic plasticity, reducing Aβ deposition and tau pathology, and regulating multiple AD-related signaling pathways. At the same time, the molecular composition and functions of MSC-derived exosomes derived from different tissues exhibit heterogeneity, and their therapeutic efficacy is influenced by factors such as the source cells, culture conditions, preparation processes, and administration methods. In recent years, strategies such as engineered surface modification, functional molecule loading, three-dimensional culture, microenvironment pretreatment, large-scale production, as well as intranasal administration and biomaterial delivery systems have provided new directions for enhancing the brain-targeting ability, stability, yield, and therapeutic efficacy of MSC-derived exosomes. This review summarizes the biological basis of MSC-derived exosomes, their mechanisms of action in AD treatment, and optimization strategies, providing a reference for their further development and translational application as a cell-free therapeutic approach for AD.},
}

*Exosomes/metabolism/transplantation
Humans
*Alzheimer Disease/therapy/metabolism/pathology
Animals
*Mesenchymal Stem Cells/metabolism

@article {pmid42348083,
year = {2026},
author = {Yildirim, C and Cevik, S and Bal, R and Kaplan, DS and Yilmaz, SG and Ulusal, H and Bekerecioglu, S},
title = {Vitexin Protects Against Scopolamine-Induced Cognitive Impairment by Preserving Synaptic Integrity and Modulating Nrf2/HO-1 and NF-κB Signaling Pathways.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42348083},
issn = {1559-1182},
mesh = {Animals ; *Apigenin/pharmacology/therapeutic use ; Male ; *NF-kappa B/metabolism ; *Signal Transduction/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Synapses/drug effects/metabolism/pathology ; Rats, Wistar ; *Cognitive Dysfunction/chemically induced/drug therapy/prevention & control/metabolism ; Scopolamine ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Heme Oxygenase-1/metabolism ; Rats ; Maze Learning/drug effects ; *Heme Oxygenase (Decyclizing)/metabolism ; Hippocampus/drug effects/metabolism/pathology ; },
abstract = {Alzheimer's disease is characterized by progressive cognitive decline driven by oxidative stress, neuroinflammation, and synaptic dysfunction. This study investigated the neuroprotective effects of vitexin in a scopolamine (Sco)-induced rat model of cognitive impairment. Forty-two male Wistar rats were randomly assigned to six groups (n = 7 per group): saline, Sco (2 mg/kg/day, i.p.), Sco + vitexin (30 mg/kg/day, oral), Sco + donepezil (1.5 mg/kg/day, i.p.), vitexin alone, and donepezil alone. All treatments were administered for 14 consecutive days. Behavioral assessments using the morris water maze and elevated plus maze revealed that Sco significantly impaired spatial learning and memory while increasing anxiety-like behaviors. Vitexin treatment markedly improved these deficits, with efficacy comparable to donepezil. Biochemically, Sco elevated acetylcholinesterase activity, lipid peroxidation, and oxidative/nitrosative stress markers (TOS, OSI, MDA, Peroxynitrite, NO, and NOS) while decreasing total antioxidant status (TAS). Vitexin reversed these changes. Western blot and immunofluorescence analyses demonstrated that Sco reduced hippocampal BDNF, GDNF, PSD95, and synaptophysin levels and increased GFAP, IL-6, TNF-α, NF-κB p65, and COX-2 expression. Vitexin restored neurotrophic and synaptic proteins, suppressed astrocyte activation and inflammatory signaling, and activated the Nrf2/HO-1 pathway. These findings were further supported by qRT-PCR analysis of BDNF, GDNF, GPX4, and NF-κB. In conclusion, vitexin exerts significant neuroprotective and synaptoprotective effects against Sco-induced cognitive impairment by simultaneously restoring redox balance, suppressing neuroinflammation, and preserving synaptic integrity. These results position vitexin as a promising therapeutic candidate for neurodegenerative disorders, including Alzheimer's disease.},
}

Animals
*Apigenin/pharmacology/therapeutic use
Male
*NF-kappa B/metabolism
*Signal Transduction/drug effects
*NF-E2-Related Factor 2/metabolism
*Synapses/drug effects/metabolism/pathology
Rats, Wistar
*Cognitive Dysfunction/chemically induced/drug therapy/prevention & control/metabolism
Scopolamine
Oxidative Stress/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
*Heme Oxygenase-1/metabolism
Rats
Maze Learning/drug effects
*Heme Oxygenase (Decyclizing)/metabolism
Hippocampus/drug effects/metabolism/pathology

@article {pmid42348207,
year = {2026},
author = {Mrhar, A and Carballo-Casla, A and Grande, G and Gregorio, C and Triolo, F and Valletta, M and Fredolini, C and Gregoric Kramberger, M and Kuhar, A and Winblad, B and Fratiglioni, L and Calderón-Larrañaga, A and Vetrano, DL},
title = {Diet Quality and Dementia Risk in Older Adults With Alzheimer Pathology.},
journal = {JAMA network open},
volume = {9},
number = {6},
pages = {e2620254},
doi = {10.1001/jamanetworkopen.2026.20254},
pmid = {42348207},
issn = {2574-3805},
mesh = {Humans ; Female ; Aged ; Male ; *Alzheimer Disease/epidemiology/pathology ; Sweden/epidemiology ; *Dementia/epidemiology ; Biomarkers/blood ; Cohort Studies ; Middle Aged ; Glial Fibrillary Acidic Protein/blood ; *Diet ; Aged, 80 and over ; Risk Factors ; Diet, Mediterranean ; tau Proteins/blood ; *Diet, Healthy ; },
abstract = {IMPORTANCE: Higher diet quality has been linked to reduced dementia incidence, but whether it buffers dementia onset in individuals with Alzheimer disease (AD) pathology or broader neurobiological risk is unclear.

OBJECTIVE: To explore the association of diet quality with dementia risk across biomarker levels of AD pathology (phosphorylated tau at threonine 217 [p-tau217]) and broader neurodegenerative and glial processes (neurofilament light chain [NFL], glial fibrillary acidic protein [GFAP]).

This cohort study analyzed data from adults without dementia aged 60 years or older from the population-based Swedish National Study on Aging and Care in Kungsholmen, which enrolled participants between March 2001 and August 2004 and examined them up to 6 times until February 2016 to November 2019. Adherence to 3 dietary patterns was examined: the Alternate Mediterranean Diet (AMED), Alternative Healthy Eating Index (AHEI), and reversed Empirical Dietary Inflammatory Index (rEDII). Data were analyzed between September 2024 and August 2025 and reanalyzed in March and April 2026.

EXPOSURES: Baseline serum p-tau217, NFL, and GFAP concentrations and repeated adherence over 6 years to the AMED, AHEI, and rEDII dietary patterns.

MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause dementia identified by clinical diagnosis, medical records, and death certificates. The secondary outcome was AD-related dementia. Dementia risk was analyzed using adjusted Cox regression models. Ten-year dementia probabilities and restricted mean time lost due to dementia were also estimated.

RESULTS: A total of 1865 participants were included (mean [SD] age at baseline, 70.5 [9.3] years; 1125 female [60.3%]). Over a mean follow-up of 8.4 years (range, <0.1 to 15.9 years), 240 participants developed dementia. Higher adherence to healthier dietary patterns was associated with lower dementia risk in participants with elevated AD and neurobiological risk biomarkers. For rEDII, each 1-z-score increase in adherence was associated with lower dementia risk among those with elevated p-tau217, NFL, and GFAP levels, with hazard ratios of 0.71 (95% CI, 0.58-0.88), 0.79 (95% CI, 0.66-0.95), and 0.73 (95% CI, 0.60-0.89), respectively. Associations of AMED and AHEI with lower dementia risk were generally found only among participants with lower biomarker levels. Similar findings were observed for AD-related dementia.

CONCLUSIONS AND RELEVANCE: This cohort study of older adults found that adherence to a dietary pattern with lower inflammatory potential was associated with lower dementia risk among individuals with AD pathology and broader neurobiological risk. These findings reinforce the importance of targeted dietary dementia prevention strategies not only for the general population but also for individuals already at elevated risk.},
}

Humans
Female
Aged
Male
*Alzheimer Disease/epidemiology/pathology
Sweden/epidemiology
*Dementia/epidemiology
Biomarkers/blood
Cohort Studies
Middle Aged
Glial Fibrillary Acidic Protein/blood
*Diet
Aged, 80 and over
Risk Factors
Diet, Mediterranean
tau Proteins/blood
*Diet, Healthy

@article {pmid42348373,
year = {2026},
author = {Perley, AS and Coleman, TP},
title = {A Dynamic Mutual Information Measure of Phase-Amplitude Coupling with Uncertainty Quantification.},
journal = {IEEE transactions on bio-medical engineering},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TBME.2026.3705664},
pmid = {42348373},
issn = {1558-2531},
abstract = {Phase-amplitude coupling (PAC)-in which the phase of a low-frequency rhythm modulates the amplitude of a higher-frequency oscillation-is widely observed across the brain and has been linked to cognition as well as neurological disorders including Parkinson's disease, epilepsy, and depression. Standard PAC metrics typically aggregate over long windows and return a single summary statistic, obscuring transient structure. Although recent work pursues time-resolved PAC via windowed analyses, these methods often fail to capture fast, sample-level fluctuations in coupling strength. To overcome these limitations, we introduced a dynamic state space model with a latent Gauss state space model for regression weights and a Gamma generalized linear model for measurements. Upon estimation, a mutual information measure of PAC at any time point provides our dynamic PAC formulation. Our approach yields interpretable, smoothly evolving PAC trajectories and allows multiple trials to be incorporated in a unified probabilistic framework. Our key contribution in this work is to extend this paradigm into a unified modeling framework by developing methodology for hyperparameter tuning, multi-trial PAC estimation and uncertainty quantification. To tune key hyperparameters, we introduce an expectation- maximization (EM) algorithm that uses a Laplace approximated posterior to perform tractable updates. Furthermore, we develop the ability of our model to accommodate multi-trial analyses that are ubiquitous in neuroscience, and demonstrate the ability to detect when PAC phenomena are repeatable. We further describe a Bayesian uncertainty-quantification procedure based on the Laplace approximation, enabling computation of credible intervals for every PAC trajectory and offering an explicit measure of confidence in dynamic estimates. Using synthetic data with ground-truth time-varying coupling, we show that the proposed method more accurately tracks rapid changes and discriminates coupled from uncoupled periods. Applied to human sleep EEG, the approach reliably detects PAC during spindle events-highlighting its potential relevance for biomarkers of neurophysiological disorders, including Alzheimer's disease. Overall, this dynamic PAC framework provides a flexible, statistically grounded tool for basic and clinical neuroscience, and may support future applications in adaptive neurostimulation and real-time brain-computer interfaces.},
}

@article {pmid42348392,
year = {2026},
author = {Thomas, TM and Yang, CY and Zhang, K and Wetzel, L and Bugybayeva, D and Ferguson, J and Hasan, MM and Samsa, W and Patil, N and Dash, A and Gowda, T and Zhu, X and Cheng, F and Liu, T},
title = {CHCHD10 Mitigates Alzheimer's Disease-Related Phenotypes in Association With Epigenetic Remodeling in Directly Reprogrammed Neurons.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76205},
doi = {10.1002/advs.76205},
pmid = {42348392},
issn = {2198-3844},
support = {R01AG086365 to T.L R21AG070299 to T.L R21AG095389 to T.L R03AG084948 to T.L/AG/NIA NIH HHS/United States ; RF1NS133812/NS/NINDS NIH HHS/United States ; ALZDISCOVERY-1051936//Alzheimer's Association award/ ; },
abstract = {Mitochondrial dysfunction and chromatin dysregulation are interconnected contributors to neuronal vulnerability in Alzheimer's disease (AD), yet the molecular mechanisms linking these processes remain poorly understood. CHCHD10, a mitochondrial intermembrane space protein, has been implicated in neurodegenerative disorders, but its role in AD has not been defined. Here, we identify CHCHD10 as a previously unrecognized modulator of neuronal epigenomic stability in AD. Using direct fibroblast-to-neuron reprogramming, which preserves patient-specific epigenetic signatures, we show that AD neurons recapitulate genome-wide hypomethylation patterns observed in postmortem AD cortex. CHCHD10 expression is significantly reduced in AD neurons and across multiple human brain datasets, including single-cell and bulk RNA sequencing, proteomics, and human cortical tissue analyses. Restoration of CHCHD10 in AD neurons reduces amyloid-β and insoluble tau accumulation while reversing AD-associated differentially methylated regions across CpG islands, promoters, and regulatory elements. CHCHD10-responsive methylation changes overlap with those observed in human AD brain regions and colocalize with significant AD loci and cortex-specific eQTL loci, including MAPT and ABCA7. Finally, we identify KATNAL2 as a CHCHD10-responsive effector whose loss enhances tau phosphorylation and seeding, whereas its restoration mitigates tau pathology. Together, these findings support a CHCHD10-associated neuroprotective pathway linking mitochondrial dysfunction, epigenomic instability, and tau pathology in AD.},
}

@article {pmid42348482,
year = {2026},
author = {Xue, D and Peng, J and Yue, L and Qi, W},
title = {Understanding Discrepancies and Predictors of Self- versus Proxy-Rated Quality of Life in Chinese Community-Dwelling Older Adults with Mild Dementia: A Cross-Sectional Study.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1-19},
doi = {10.1159/000553237},
pmid = {42348482},
issn = {1421-9824},
abstract = {BACKGROUND: Accurate evaluation of quality of life (QoL) is essential for optimal dementia management, yet notable discrepancies exist between patient self-rated and proxy-rated QoL. This study aimed to analyse the discrepancies and agreement between self-rated and proxy-rated QoL and identify their independent predictors among community-dwelling persons with mild dementia (PwMD).

METHODS: This cross-sectional study included 129 PwMD and their primary caregivers. Assessments included sociodemographic information, the QoL-Alzheimer's Disease scale, Mini-Mental State Examination, Geriatric Depression Scale, Activities of Daily Living, Functional Activities Questionnaire and Neuropsychiatric Inventory Questionnaire. Differences and agreement were analyzed using Wilcoxon tests, Spearman correlations, and intraclass correlation coefficients (ICC). Independent predictors were identified through multiple linear regression.

RESULTS: Patients rated their QoL significantly higher than their caregivers did, with poor-to-fair agreement at the total, dimensional and item levels (ICC = 0.11-0.50). Higher depressive symptoms (β = -0.354, p = 0.001), lower severity of elation (β = 0.214, p = 0.013), and greater disinhibition (β = -0.174, p = 0.041) independently predicted poorer self-rated QoL. By contrast, greater neuropsychiatric symptom severity (β = -0.283, p < 0.001), poorer Activities of Daily Living function (β = -0.230, p = 0.006), and polypharmacy (β = -0.208, p = 0.009) predicted lower proxy-rated QoL.

CONCLUSION: Self- and proxy-rated QoL reflect distinct evaluative perspectives in PwMD. Self-reports are influenced by emotional and psychological states, whereas proxy ratings are shaped by observable symptoms, functional dependency and treatment burden. These findings suggest the need to integrate both assessment perspectives in clinical practice.},
}

@article {pmid42348502,
year = {2026},
author = {Madden, KM and Feldman, B and Jimenez, D and Khokhar, M and Li, Q and Nguyen, M and Zhu, J},
title = {Design of an artificial intelligence model to screen spontaneous speech to detect Alzheimer's Disease.},
journal = {PLOS digital health},
volume = {5},
number = {6},
pages = {e0001444},
doi = {10.1371/journal.pdig.0001444},
pmid = {42348502},
issn = {2767-3170},
abstract = {There is a shortage of physicians trained in the specialized care of Alzheimer's disease (AD). One possible solution is to use machine learning (ML)/artificial intelligence (AI) techniques to screen for the effects of AD on speech patterns, a technique that has the potential for automation. Our objective was to evaluate the ability of various language processing/artificial intelligence (AI) techniques to classify subjects into AD and controls. Our study used the Pitt dataset (n = 549), from DementiaBank, a shared dataset of audio files of spontaneous speech using the standardized Cookie Theft Picture Description task. The dataset was divided into training (n = 337), development (n = 115) and test (n = 97) datasets. A series of language processing techniques were tested on their ability to classify subjects into AD and controls, including classical (Tfidf, Term Frequency-Inverse Document Frequency), hybrid (Tfidf + text embeddings), neural classification and large language models. The hybrid model (Tfidf + text embeddings) was the best performing one, with accuracy and recall of 0.92 and 0.93 respectively on the test dataset. However, when tested on an independently collected validation dataset it only achieved 0.70 accuracy and 0.44 recall, performing well in identifying controls but missing some true AD cases. The model also demonstrated similar performance in identifying controls in a dataset that included a high proportion of diverse cognitive conditions, similar to referrals to a specialized memory clinic. AI techniques have demonstrated some utility for the classification of spontaneous speech audio files into those with AD and controls although these techniques could benefit from having enlarged datasets.},
}

@article {pmid42348506,
year = {2026},
author = {Accorroni, A and Clavien, C and Frisoni, GB},
title = {Just Semantics? How Diagnostic Criteria Influence Physician-Patient Narratives in Alzheimer's Disease.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-33},
doi = {10.1159/000552764},
pmid = {42348506},
issn = {1660-2862},
abstract = {INTRODUCTION: The current diagnosis of Alzheimer's disease (AD) is shaped by the Alzheimer's Association (AA) and the International Working Group (IWG) criteria. While both frameworks lead to similar physician-patient conversations when disclosing biomarker results to patients with cognitive impairment, they diverge significantly for cognitively unimpaired individuals. The aim of this paper is to explore these differences and their associated epistemological and ethical implications, through simulated, case-based physician-patient conversations.

METHODS: The conversations were developed on the basis of clinical experience, exchanges with patients and carers, insights from a targeted narrative literature review and were subsequently refined with large language model assistance.

RESULTS: Our analysis highlights that the AA framework reinforces a deterministic narrative by equating amyloid biomarker positivity with disease and raising a misunderstanding with illness. In contrast, the IWG framework is consistent with the incomplete penetrance of AD pathology and frames biomarker positivity in cognitively unimpaired individuals as a risk condition. We acknowledge that the IWG framework enables more complex but also more realistic physician-patient conversations.

CONCLUSION: Physician-patient conversations employing a carefully selected lexicon, reflecting patient-centred outcomes, may promote patient engagement, compliance with medical recommendations, and, ultimately, societal trust in medicine and physicians.},
}

@article {pmid42348624,
year = {2026},
author = {De La Roca, AY and Lafo, JA and Rosen, RK and Davis, JE and Arias, I and Korthauer, LE},
title = {Adaptation of a Multidomain Behavioral Intervention for Dementia Prevention in Hispanic/Latino Adults: Protocol to Guide an Evidence-Based Cultural Adaptation.},
journal = {Rhode Island medical journal (2013)},
volume = {109},
number = {7},
pages = {27-31},
pmid = {42348624},
issn = {2327-2228},
mesh = {Humans ; *Hispanic or Latino/psychology ; *Dementia/prevention & control/ethnology ; Rhode Island ; Adult ; Middle Aged ; Aged ; Culturally Competent Care ; *Behavior Therapy/methods ; Female ; Research Design ; Alzheimer Disease/prevention & control/ethnology ; },
abstract = {OBJECTIVE: Alzheimer's disease and related dementias (ADRD) pose a growing public health challenge, with 45% of cases attributable to 14 modifiable risk factors. Midlife represents a critical window for prevention. Hispanic/Latino adults face disproportionate ADRD risk, compounded by health inequities such as limited healthcare access and higher prevalence of cardiovascular and metabolic conditions. In Rhode Island, where 17.6% of residents identify as Hispanic/Latino, culturally tailored interventions are urgently needed. This study aims to inform the cultural adaptation of the TEACH intervention (Tailored Education for Aging and Cognitive Health), an evidence-based, multidomain behavioral intervention designed to reduce ADRD risk through lifestyle modification, to ensure its cultural relevance for Hispanic/ Latino adults.

DESIGN AND METHODS: The research team will follow the Cultural Adaptation Process (CAP) model to guide the adaptation of the TEACH intervention, emphasizing linguistic and cultural relevance for Hispanic/Latino adults in southern New England by incorporating the views and perspectives of key stakeholders. We will conduct semi-structured qualitative interviews with bilingual stakeholders (N=6-8) and Hispanic/Latino adults aged 40-69 (N=10-12) recruited from clinical and community settings. Interviews will explore brain health beliefs, perceived intervention needs, barriers, and cultural values. Qualitative data will be analyzed using framework matrix and applied thematic analysis approaches to identify adaptation priorities across language, content, and delivery.

RESULTS: This project was funded in September 2023. Data collection began in 2024, and analysis is projected to be completed in 2026.

CONCLUSIONS: Findings will guide cultural adaptation of the TEACH intervention using the CAP model. This work addresses a critical gap in ADRD prevention for U.S. Hispanic/Latino populations and lays the foundation for a future randomized controlled trial to evaluate efficacy of the adapted intervention.},
}

Humans
*Hispanic or Latino/psychology
*Dementia/prevention & control/ethnology
Rhode Island
Adult
Middle Aged
Aged
Culturally Competent Care
*Behavior Therapy/methods
Female
Research Design
Alzheimer Disease/prevention & control/ethnology

@article {pmid42348734,
year = {2026},
author = {Böken, D and Wu, Y and Zhang, J and Xia, Z and Beltran-Lobo, P and Croft, CL and Weerasekera, S and Heslegrave, A and Zetterberg, H and Keshavan, A and Schott, JM and Jimenez-Sanchez, M and Duffy, DC and Klenerman, D},
title = {Profiling Protein Aggregate Size Using Single-Molecule Array Technology.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c03315},
pmid = {42348734},
issn = {1520-6882},
abstract = {Protein aggregation is a central feature of many neurodegenerative diseases, yet methods to characterize aggregate size in complex biological samples remain limited. Here, we show that fluorescence intensity from individual single-molecule array (Simoa) microwells encodes size-dependent information beyond conventional digital quantification. Using defined synthetic tau assemblies, we establish that increasing aggregate size produces higher microwell brightness. Applying this technique to human brain homogenate reveals a shift toward larger tau aggregates in Alzheimer's disease compared to age-matched controls, in agreement with orthogonal measurements by single-molecule super-resolution microscopy. Brightness profiling further captures time-dependent aggregate size increase in a neuronal cell model, demonstrating sensitivity to dynamic changes in aggregation. Although resolution is limited between similarly sized small species, Simoa brightness robustly reports population-level shifts in aggregate size distributions. These findings repurpose a widely used ultrasensitive detection platform to provide high-throughput structural as well as quantitative insight into protein aggregation in biological systems.},
}

@article {pmid42349060,
year = {2026},
author = {Changchien, TC and Zul, DD and Cheng, KD and Mathurin, TV and Dagbue, AC and Fang, YY and Liang, CS and Yeh, WC and Hsu, TW},
title = {Lithium versus valproate in bipolar disorder: Associations with dementia, mortality, suicide attempt, and end-stage renal disease in adults aged 45 years and older - a propensity score-matched retrospective cohort study.},
journal = {Psychiatry research},
volume = {364},
number = {},
pages = {117284},
doi = {10.1016/j.psychres.2026.117284},
pmid = {42349060},
issn = {1872-7123},
abstract = {BACKGROUND/OBJECTIVE: Patients with bipolar disorder (BD) are at increased risk of dementia. However, few studies have directly compared subsequent dementia risk between BD patients treated with lithium and valproate, the two first-line mood stabilizers.

METHODS: This retrospective cohort study used the TriNetX collaborative network, which aggregates de-identified electronic health records across the United States. Adults aged≧45 years with BD who initiated lithium or valproate for the first time between 2000 and 2025 were included. 1:1 propensity score matching was applied. The primary outcome was all-cause dementia, and secondary outcomes were Alzheimer's disease, vascular dementia, unspecified dementia (ICD10 code: F03), mortality, suicide attempt, and ESRD.

RESULTS: After applying exclusion criteria and matching, 3056 patients remained in each group. Lithium use was associated with a lower risk of all-cause dementia than valproate use (207 [7.1%] vs 311 [10.8%]; Relative risk [RR], 0.658; 95% confidence interval [CI], 0.556-0.778; Hazard ratio [HR], 0.689; 95% CI, 0.578-0.822; both P<.001). Lithium use was also associated with lower risks of unspecified dementia (HR, 0.677; 95% CI, 0.530-0.865; P=.002) and suicide attempt (HR, 0.594; 95% CI, 0.399-0.885; P=.010). Although the relative risk of Alzheimer disease was lower in the lithium group, the adjusted hazard ratio did not reach statistical but marginal significance. No significant between-group differences were observed for vascular dementia, mortality, or ESRD.

LIMITATIONS: Residual confounding may persist due to the observational design, and dementia diagnoses relied on clinical coding within electronic health records.

CONCLUSIONS: In this large, compliance-verified cohort, lithium treatment was associated with lower risks of dementia compared to valproate, without excess ESRD or mortality risk. These findings support lithium as a preferred long-term mood stabilizer for preserving cognitive outcomes in older adults with bipolar disorder, though observational data preclude causality inferences.},
}

@article {pmid42349104,
year = {2026},
author = {Chellali, R and Tan, S and Khemtemourian, L},
title = {Optimizing grid preparation methods for TEM imaging of amyloid-forming proteins.},
journal = {Biophysical chemistry},
volume = {337},
number = {},
pages = {107676},
doi = {10.1016/j.bpc.2026.107676},
pmid = {42349104},
issn = {1873-4200},
abstract = {Transmission electron microscopy (TEM), together with Thioflavin T (ThT) fluorescence assays, is widely used to visualize amyloid fibrils and to characterize the kinetics of amyloid formation. However, discrepancies between ThT fluorescence data and TEM observations are sometimes reported, which may arise from limitations in fibril visualization by TEM. In particular, TEM imaging can be strongly influenced by the sample loading procedure on the grid, which governs fibril deposition and retention. In this work, five different grid preparation methods were compared to evaluate their efficiency in detecting and visualizing human islet amyloid polypeptide (hIAPP) fibrils, which are present in 95% of patients with type 2 diabetes mellitus. The methods were assessed based on detection speed, morphological representation, fibril abundance and grid contamination. The two best-performing methods were further evaluated for detecting early hIAPP aggregates and subsequently applied to another amyloid forming protein, namely amyloid-β 42 (Aβ42), which is involved in Alzheimer's disease. Among the tested approaches, method 2 (a droplet-deposition protocol) and method 3 (a centrifugation-based loading protocol) provided the most efficient fibril detection and morphological representation. Method 2 was identified as the best compromise between rapid detection, experimental simplicity, and low grid contamination, and was further tested under different buffer conditions. Overall, this comparative study demonstrated that variations in grid preparation protocols can significantly influence TEM observations and provide practical guidance for selecting optimal conditions for amyloid fibril imaging depending on experimental objectives.},
}

@article {pmid42349149,
year = {2026},
author = {Fan, Z and Yan, X and Zheng, Q and Zhu, Z and Song, B and Feng, X and Pan, S and Lv, C and Shi, P},
title = {Clioquinol inactivates thiamine pyrophosphate by increasing cellular oxidative stress.},
journal = {Redox biology},
volume = {95},
number = {},
pages = {104258},
doi = {10.1016/j.redox.2026.104258},
pmid = {42349149},
issn = {2213-2317},
abstract = {Clioquinol (CQ), a prescribed oral antibiotic, was withdrawn from use following its association with the incidence of subacute myelo-optic neuropathy (SMON) in Japan. The neurotoxicity associated with CQ may be linked to thiamine deficiency. However, their relationship and underlying mechanisms remain unclear. In this study, we identified thiamine pyrophosphate (TPP) as a key metabolite affected by CQ via metabolomics analysis. Analysis of related thiamine transport, TPP synthesis, and oxidative stress pathways revealed that CQ promoted TPP inactivation through oxidative modification. The Seahorse metabolic analyzer data showed that CQ-induced TPP deficiency led to diminished mitochondrial oxidative phosphorylation, accompanied by enhanced glycolysis. Morphological examination of mitochondria further indicated that CQ elicited mitochondrial damage in a TPP-dependent manner. In an Alzheimer's disease murine model, CQ administration similarly provoked oxidative stress, decreased cerebral TPP concentrations, and induced neuronal injury. Notably, supplementation with TPP or N-acetylcysteine (NAC) mitigated CQ-associated neurotoxicity and potentiated CQ-mediated clearance of amyloid plaques. Our findings elucidate that CQ is involved in mitochondrial dysfunction and metabolic reprogramming by inactivating TPP, providing valuable insights into the neurotoxicity of CQ.},
}

@article {pmid42146353,
year = {2026},
author = {Xu, Z and Wang, K},
title = {LongAllele: a joint inference framework for allele-specific analysis on long-read bulk and single-cell RNA sequencing.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.05.722992},
pmid = {42146353},
issn = {2692-8205},
abstract = {Allele-specific analysis from RNA-seq is a powerful approach to characterize cis -regulatory effects. However, existing methods remain limited in both haplotype inference and allelic testing. Their haplotype-inference workflows separate variant calling, haplotype phasing, and read-haplotype assignment into sequential steps, failing to fully exploit within-read single-nucleotide variant (SNV) linkage information and propagating errors into downstream allelic analysis. At the testing stage, they ignore non-phasable reads lacking heterozygous SNVs, biasing calls and inflating false positives, and remain incomplete across gene-, isoform-, and local-event-level variant effects. Here, we present LongAllele, a statistical framework that employs an expectation-maximization algorithm to jointly infer heterozygous variants, haplotype structure, and read-haplotype assignments from long-read bulk and single-cell RNA sequencing. LongAllele further introduces phasability-aware testing that explicitly accounts for non-phasable reads, avoiding inflated false-positive calls when haplotype information is incomplete. It also enables comprehensive allelic testing across gene-level allele-specific expression (ASE), isoform-level allele-specific transcript usage (ASTU), and local-event-level haplotype-associated exon and junction usage (HAEU and HAJU), providing a multi-scale view of cis -regulation across biological contexts. We applied LongAllele to long-read RNA-seq datasets spanning GTEx (multi-tissue bulk), peripheral blood mononuclear cells (single-cell), human hippocampus (single-nucleus), and human cortex from two Alzheimer's disease (AD) case-control cohorts (bulk, Oxford Nanopore and PacBio). LongAllele consistently revealed greater context dependence in expression-level than isoform-level allelic regulation across tissues, cell types, and disease states, and pinpointed high-impact regulatory variants including rare splice-site mutations missed by standalone variant callers. It further showed that purifying selection constrains allelic imbalance at both gene and isoform levels and resolved AD-associated variant effects in individual transcriptomes across long-read platforms.},
}

@article {pmid42335444,
year = {2026},
author = {Gallaccio, G and Müller, A and Wang, M and Diekmann, LM and Otto, C and Dinoto, A and Chiodega, V and Schwake, C and Jarius, S and Usnich, T and Sperber, PS and Anderhalten, L and Ongphichetmetha, T and Byars, A and Subasic, D and Kunkel, D and Ayzenberg, I and Mariotto, S and Samadzadeh, S and Paul, F and Böttcher, C},
title = {Immuno-Proteomic Features Associated to Relapse Risk in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.},
journal = {Neurology(R) neuroimmunology & neuroinflammation},
volume = {13},
number = {4},
pages = {e200615},
doi = {10.1212/NXI.0000000000200615},
pmid = {42335444},
issn = {2332-7812},
mesh = {Humans ; *Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease/immunology/cerebrospinal fluid/blood/diagnosis ; Female ; Male ; Proteomics ; Recurrence ; Middle Aged ; Adult ; *Alzheimer Disease/immunology/blood/cerebrospinal fluid ; *Multiple Sclerosis/immunology/blood/cerebrospinal fluid ; Biomarkers/blood/cerebrospinal fluid ; Myelin-Oligodendrocyte Glycoprotein/immunology ; },
abstract = {BACKGROUND AND OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory demyelinating disorder that overlaps clinically with multiple sclerosis (MS) but immunopathologically distinct. Although often considered an acute inflammatory disease, recurrent attacks in MOGAD can lead to demyelination, axonal injury, and secondary neurodegeneration. Reliable biomarkers associated with relapse risk and disease subphenotypes, including optic neuritis, remain limited. Here, we aimed to define molecular and cellular signatures that distinguish MOGAD from MS as a prototypical neuroinflammatory disease and from Alzheimer disease (AD) as a proxy of neurodegeneration and to identify candidate immune-proteomic features associated with relapse frequency and clinical phenotype in MOGAD.

METHODS: CSF, serum, and whole-blood samples from patients with MOGAD (n = 67), MS (n = 49), and AD (n = 36) were profiled using NULISAseq™ CSF proteomics, Olink Explore 3072 CSF and serum proteomics, and high-dimensional mass cytometry for immune cell characterization. In MOGAD, longitudinal clinical data, including total attack counts from the earliest documented attack through follow-up, were integrated with immune and proteomic profiles to assess associations with disease course and clinical phenotype.

RESULTS: CSF and blood proteomic profiling revealed distinct inflammatory and cardiometabolic proteomic profiles in MOGAD, differentiating it from both MS and AD. Compared with MS, MOGAD showed relative reductions in lymphocyte populations with regulatory phenotypes. Within MOGAD, relapsing disease was associated with reduced frequencies of CD8[+]CCR7[+]CD31[+]CTLA4[+] T cells and concurrent expansion of double-negative γδ T-cell subsets. IL-13 correlated positively with relapse frequency and inversely with circulating regulatory T cells, whereas IL-32 and CASP4 showed opposite associations, correlating negatively with relapse count and positively with Treg frequency. IL-13 was also inversely associated with CD31-expressing CD8[+] T cells. Phenotype-stratified analyses suggested that these immune-proteomic relationships differed according to clinical presentation, including optic neuritis vs nonoptic neuritis phenotypes.

DISCUSSION: This integrative immune-proteomic analysis identifies cellular and molecular features associated with relapsing vs monophasic MOGAD, suggesting a model of impaired peripheral immune regulation in relapsing disease. While exploratory, these findings generate a concrete hypothesis for future longitudinal and functional studies aimed at refining biomarker-based monitoring and informing individualized therapeutic strategies in MOGAD.},
}

Humans
*Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease/immunology/cerebrospinal fluid/blood/diagnosis
Female
Male
Proteomics
Recurrence
Middle Aged
Adult
*Alzheimer Disease/immunology/blood/cerebrospinal fluid
*Multiple Sclerosis/immunology/blood/cerebrospinal fluid
Biomarkers/blood/cerebrospinal fluid
Myelin-Oligodendrocyte Glycoprotein/immunology

@article {pmid42335451,
year = {2026},
author = {Liao, Q and Wang, X and Duan, Y and Guo, L and He, S and Lyu, W and Shi, J and Fu, R and Zhang, H and Han, Y and Li, Q},
title = {Discovery of New Butyrylcholinesterase Inhibitors and Evaluation of Their Biological Activity against Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00302},
pmid = {42335451},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a degenerative disease of the central nervous system (CNS), which is relatively common in the elderly population and is the main cause of senile dementia. Its typical pathological features mainly lie in hyperphosphorylated tau proteins in the form of neurofibrillary tangles (referred to as tau tangles) and β-amyloid plaques. Using DrugCLIP website, we investigated the effects of butyrylcholinesterase (BChE) inhibitors on AD. From virtual screening, molecule W1 (inhibitory concentration (IC50) = 0.63 ± 0.19 μM) was identified as the lead compound of this research. Subsequently, the lead compound molecule was obtained through chemical synthesis, and its structure was modified to synthesize and evaluate 21 derivatives. Derivatives W3 and W13 also showed micromolar-level BChE inhibitory activity (W3: IC50 = 0.28 ± 0.14 μM, W13: IC50 = 0.03 ± 0.02 μM), with W13 demonstrating superior inhibitory activity. The results of binding patterns demonstrated that both compounds can bind to the target and form multiple interactions with amino acid residues. From the enzyme kinetics results, it can be observed that both compounds were BChE inhibitors in a mixed manner, which was consistent with the docking results. Due to W3 not occupying the acyl-binding pocket, its activity was inferior to W13. In pharmacodynamic studies, W3 and W13 protected nerve cells from toxicity, hydrogen peroxide (H2O2), and Aβ1-42 stimulation in vitro, reduced the production of reactive oxygen species, and alleviated Aβ-induced cognitive impairment in mice. In addition, optimal compound W13 presented considerable pharmacokinetic properties, with a high oral bioavailability (80%). Moreover, it could penetrate the blood-brain barrier and take effect in the CNS. Therefore, these findings support further investigation of W3 and W13 as potential therapeutic candidates for advanced AD.},
}

@article {pmid42335456,
year = {2026},
author = {Ha, J and Bok, J and Lee, Y and Kim, YS and Kim, JS and Kim, HJ and Jang, Y},
title = {Noninvasive Electrophysiological Biomarkers of Olfactory Responses Across Cognitive States in Alzheimer Dementia: Cross-Sectional Study.},
journal = {JMIR mHealth and uHealth},
volume = {14},
number = {},
pages = {e76245},
doi = {10.2196/76245},
pmid = {42335456},
issn = {2291-5222},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/physiopathology/complications/psychology/diagnosis ; Aged ; *Biomarkers/analysis ; Cross-Sectional Studies ; Electroencephalography/methods/instrumentation ; Cognitive Dysfunction/physiopathology/diagnosis ; *Cognition/physiology ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is characterized by progressive cognitive decline, with olfactory dysfunction emerging among its earliest symptoms. Conventional olfactory tests rely on subjective self-reports and patient cooperation, limiting their clinical applicability. Noninvasive olfactory bulb (OB) recordings may provide objective physiological measures for early detection of cognitive decline.

OBJECTIVE: This study investigated the relationship between olfactory dysfunction and cognitive decline across the AD spectrum and evaluated whether noninvasive OB recordings obtained via a wearable electroencephalography-based device could serve as digital biomarkers for early detection and home-based monitoring.

METHODS: We recruited 71 participants, including individuals who were cognitively normal (CN; n=18), patients with mild cognitive impairment (MCI) subdivided into early MCI (n=30) and late MCI (n=9), and patients with dementia of the Alzheimer type (n=14). OB activity was recorded noninvasively during odor stimulation using a 6-channel wearable electroencephalography system. Behavioral olfactory function was assessed using a culturally adapted 6-item modified Brief Smell Identification Test and compared with electrophysiological responses. Time-frequency analyses identified disease-related components via nonparametric permutation testing (1000 iterations; P<.05). A support vector machine classifier was applied for group discrimination. Structural brain integrity was assessed through diffusion tensor imaging and magnetic resonance imaging, and cognitive performance was evaluated using comprehensive neuropsychological testing. Beta-band power (reflecting top-down cortical feedback) and gamma-band power (representing OB activity) were analyzed to characterize neural communication patterns.

RESULTS: Beta-band power progressively declined from CN to dementia of the Alzheimer type, while gamma-band power decreased and response latency increased beginning in late MCI. Behavioral olfactory testing failed to differentiate CN from early MCI (P=.77), whereas electrophysiological recordings revealed significant differences (P=.02). The support vector machine classifier achieved 83.1% accuracy in distinguishing all groups based on olfactory spectral features. Reduced beta-band power showed a trend-level association with cingulum-hippocampal tract diffusivity (R²=0.28; P=.061), whereas gamma-band power correlated with OB volume in later disease stages (R²=0.21; P<.001). Electrophysiological features explained 91.7% of the variance in cognitive scores (Seoul Neuropsychological Screening Battery II; P<.001). The brief 5 to 10-minute testing protocol, requiring less than 2 minutes to fit the device, supports its feasibility for repeated, home-based assessments.

CONCLUSIONS: Bidirectional interactions between the OB and higher-order brain regions appear altered early in the AD continuum, with beta-band changes emerging first and gamma-band alterations occurring later. Digital OB recordings offer objective, noninvasive biomarkers for detecting cognitive decline before overt structural changes. Their portability and short duration make this approach ideal for longitudinal, home-based cognitive assessments within mobile health frameworks and for evaluating therapeutic efficacy in future interventional studies.},
}

Humans
Female
Male
*Alzheimer Disease/physiopathology/complications/psychology/diagnosis
Aged
*Biomarkers/analysis
Cross-Sectional Studies
Electroencephalography/methods/instrumentation
Cognitive Dysfunction/physiopathology/diagnosis
*Cognition/physiology
Aged, 80 and over
Middle Aged

@article {pmid42335710,
year = {2026},
author = {Bruno, D and Jauregi-Zinkunegi, A and Studer, RL and Wilson, R and Zetterberg, H and Johnson, SC and Mueller, KD},
title = {A multiverse analysis of the logical memory test and plasma biomarkers of Alzheimer's disease.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {202},
number = {},
pages = {181-192},
doi = {10.1016/j.cortex.2026.06.005},
pmid = {42335710},
issn = {1973-8102},
abstract = {BACKGROUND: Alzheimer's disease (AD) detection with blood-based biomarkers promises to revolutionise dementia diagnosis. However, blood testing is still a challenge in remote settings. Cognitive testing that is sensitive to plasma biomarker levels can be a useful proxy. A common test for dementia assessment is the logical memory test (LMT) - where a story is read out loud to the individual and then freely recalled. Alongside standard metrics, item-based metrics, such as recall of proper names and serial positions, are effective at detecting AD-related pathology. We set out to compare a range of LMT metrics against plasma AD biomarkers, and examine differences between men and women.

METHODS: The Wisconsin Registry for Alzheimer's Prevention cohort was used for analysis: participants (n = 1195, 69% women; mean age = 67.2, SD = 7.7) were free from dementia. Data included logical memory performance, demographics, clinical and genetic information, and plasma biomarkers. Analyses were cross-sectional with a maximum of two years between assessment and biomarker extraction. We carried out multiverse analyses to allow comparison of alternative models with permutations of covariates.

RESULTS: In the full sample, associations were most stable between LMT scores and p-tau217, and were significant across all models, while associations with other plasma biomarkers were generally less reliable. In the stratified analyses, associations were overall more robust and consistent in women than in men.

DISCUSSION: Current findings show LMT metrics are consistently associated with in vivo levels of pathology as measured by plasma p-tau217. The discrepancies observed between men and women require further investigation.},
}

@article {pmid42336030,
year = {2026},
author = {Bagri, K and Damde, P and Bhatia, A and Deshmukh, R},
title = {From Synapses to Tangles: PDE Inhibitors as Therapeutic Modulators in Alzheimer's Disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {179084},
doi = {10.1016/j.ejphar.2026.179084},
pmid = {42336030},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD), historically characterized by amyloid plaques and tau tangles, is increasingly recognized as a disorder of intracellular signalling failure-where second messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) become silent before memory does. These cyclic nucleotides are critical for synaptic plasticity, memory consolidation, and neurovascular function, operating through tightly regulated pathways involving protein kinases such as protein kinase A (PKA) and protein kinase G (PKG), transcription factors like cAMP response element-binding protein (CREB), and phosphodiesterases (PDEs). In the healthy brain, cAMP and cGMP orchestrate gene transcription, long-term potentiation, and cerebral blood flow. However, in AD, these signalling networks are progressively disrupted. Although it is not clear, whether failures in cyclic nucleotide signalling lead to amyloid beta and tau pathology or these pathological hallmarks disrupt the signalling mechanisms and lead to synaptic failure. However, the evidence suggests both of these possibilities. Amyloid-β oligomers and tau pathology impair adenylyl and guanylyl cyclase activity, reduce CREB phosphorylation, and disrupt nitric oxide (NO) signalling. Concurrently, overexpression of PDEs accelerates cyclic nucleotide degradation, silencing downstream pathways essential for neuronal resilience and plasticity. Dysregulated cyclic nucleotide signalling has been linked to neurovascular dysfunction, and cognitive decline. The present review is significant as it reframes AD as a signalling failure disorder rather than solely a protein aggregation disease. By identifying cyclic nucleotide dysregulation as a central and druggable mechanism, it establishes a strong translational rationale for targeting PDE-mediated degradation. This mechanism-driven perspective provides a focused platform for therapeutic innovation aimed at restoring synaptic integrity and improving cognitive outcomes in AD.},
}

@article {pmid42336161,
year = {2026},
author = {Zhang, Y and Zhang, X and Huang, J and Sun, Z},
title = {Lamivudine ameliorates neuropathology in 5×FAD mice via coordinated inhibition of the cGAS-STING pathway with enhancement of mitophagy.},
journal = {Brain research bulletin},
volume = {243},
number = {},
pages = {112014},
doi = {10.1016/j.brainresbull.2026.112014},
pmid = {42336161},
issn = {1873-2747},
abstract = {Alzheimer's disease is a neurodegenerative disorder for which there is currently no effective treatment available. Epidemiological and clinical evidence suggests that lamivudine, a nucleoside reverse transcriptase inhibitor, is associated with a reduced risk of Alzheimer's disease and shows potential in alleviating neuroinflammation. This study therefore aims to employ AD mouse models to further investigate the molecular mechanisms by which lamivudine ameliorates AD-related phenotypes. In this study, we showed that lamivudine administration inhibited cGAS-STING activation and attenuated mitochondrial damage in the 5 ×FAD mouse model, as supported by improved mitochondrial morphology and enhanced mitophagy. These changes were associated with improved spatial memory, alongside reduced neuronal apoptosis and synaptic loss. Our findings underscore the neuroprotective potential of lamivudine in AD via coordinated preservation of mitochondrial integrity and suppression of innate immune signaling, suggesting its promise for clinical translation in neurodegenerative disorders.},
}

@article {pmid42336262,
year = {2026},
author = {Bhagat, PP and Sharma, TG and Shirasath, KR and Goyal, SN and Awathale, SN},
title = {Bromodomain protein 4 (BRD4) as a central epigenetic regulator in neuropsychiatric and neurodegenerative disorders.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.033},
pmid = {42336262},
issn = {1873-7544},
abstract = {Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, is a central epigenetic regulator that links histone acetylation-dependent chromatin remodelling to transcriptional control. Through recognition of acetylated lysine residues and recruitment of transcriptional machinery, it is increasingly recognised as a critical regulator of neuronal and glial functions, influencing synaptic plasticity, neuroinflammation, learning, memory, and behavioural adaptation. A wide range of neurological, neurodevelopmental, and neuropsychiatric diseases are linked to abnormal BRD4 signalling. BRD4 coordinates common pathogenic pathways, such as dysregulated transcriptional networks, by binding to acetylated histones and recruiting positive transcription elongation factor b to stimulate RNA polymerase II-dependent transcription of genes associated with central nervous system (CNS) diseases such as Alzheimer's and post-traumatic stress disorder. These convergent roles of BRD4 positioned it as a molecular hub that connects CNS dysfunction and epigenetic control. In this review, we focus on involvement of BRD4 in various CNS disorders and provide a thorough overview of its structure, transcriptional mechanisms, and physiological and pathogenic functions in the CNS. Here, the emphasis is on common BRD4-dependent mechanisms that span multiple neurological conditions and the therapeutic opportunities and challenges associated with targeting BRD4. Collectively, current evidence supports BRD4 as a promising target for precision epigenetic therapies aimed at restoring neuronal homeostasis and modifying disease progression.},
}

@article {pmid42336284,
year = {2026},
author = {Steiner, H and Breimann, S and Kamp, F and Frishman, D},
title = {From mechanism to substratome: unraveling mysteries of γ-secretase.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113287},
doi = {10.1016/j.jbc.2026.113287},
pmid = {42336284},
issn = {1083-351X},
abstract = {γ-Secretase is a pivotal membrane-embedded protease, which cleaves more than 150 single-span membrane proteins within their transmembrane domains. While γ-secretase is involved in a wide range of physiological processes, it is best known for its critical role in Alzheimer´s disease, where it cleaves a C-terminal fragment of the amyloid precursor protein into small aggregation-prone and neurotoxic peptides. However, how γ-secretase recognizes and recruits its substrates, how it binds and unfolds them, where drug-binding sites are located, and what the full range of its substrates and functions is, have all remained unknown. These long-standing questions have been at the forefront of research for the past decade and are now increasingly being solved. In this review, we outline how recent advances in structural biology, biochemistry, and computational biology have helped to elucidate these mysteries. We also highlight future research directions needed to achieve a comprehensive understanding of this fascinating enzyme, a major therapeutic target for which Alzheimer's disease drugs are now on the horizon.},
}

@article {pmid42336347,
year = {2026},
author = {Custodio, N and Montesinos, R and Custodio, B and Malaga, M and Uribe, A and Nuñez, M and Bartolo, P and Yauri, Z and Agüero, K and Verastegui, G and Huilca, J},
title = {Cognitive impairment on the Alzheimer's Disease Centers' Uniform Data Set Version 3 Neuropsychological Test Battery in a Peruvian population with progressive supranuclear palsy.},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {5},
pages = {1-9},
doi = {10.1055/s-0046-1824433},
pmid = {42336347},
issn = {1678-4227},
mesh = {Humans ; Female ; Peru ; Male ; *Neuropsychological Tests ; Cross-Sectional Studies ; *Supranuclear Palsy, Progressive/physiopathology/complications/psychology ; Aged ; Middle Aged ; *Cognitive Dysfunction/physiopathology/diagnosis/etiology ; Aged, 80 and over ; Reference Values ; Cognition Disorders/physiopathology ; },
abstract = {BACKGROUND: Research on the cognitive profile in progressive supranuclear palsy (PSP) has been scarce in Latin America.

OBJECTIVE: To outline the demographic, clinical, and cognitive profile of Peruvian PSP patients living in Lima, Peru. We sought to determine the relationship between first clinical symptoms and specific cognitive abilities.

METHODS: A cross-sectional study of 34 PSP subjects. We used the Uniform Data Set Version 3 Neuropsychological Battery (UDS3-NB), which possesses normative data for the Peruvian population, to assess global and specific cognitive functions. We also performed correlation analyses to determine the relationship between presenting clinical symptoms (parkinsonism, postural instability, and cognitive impairment) and cognitive functioning.

RESULTS: The mean age was 68 years, and mean schooling was 12.1 years in this cohort. The most common initial clinical symptom was parkinsonism (55.9%), followed by postural instability (23.5%) and dementia (20.6%). Our cohort showed poor performance on global cognition, with selective impairment of processing speed, executive function, and episodic memory. Attentional and visuospatial skills were mildly affected, with partial preservation of naming. There was no significant relationship between the initial clinical symptoms and global cognition, except for a slight correlation between parkinsonism and visuospatial function (r = 0.18; p < 0.05).

CONCLUSION: We found that PSP patients in Peru had extensive impairment in executive function, processing speed, and episodic memory, with relatively preserved naming, consistent with other international cohorts. We did not find a correlation between initial clinical signs and cognitive profile, suggesting that an interdisciplinary approach is needed to evaluate patients with suspicion for PSP. Longitudinal studies are needed to more clearly define the progression of neuropsychiatric symptoms in PSP patients.},
}

Humans
Female
Peru
Male
*Neuropsychological Tests
Cross-Sectional Studies
*Supranuclear Palsy, Progressive/physiopathology/complications/psychology
Aged
Middle Aged
*Cognitive Dysfunction/physiopathology/diagnosis/etiology
Aged, 80 and over
Reference Values
Cognition Disorders/physiopathology

@article {pmid42336352,
year = {2026},
author = {Mitsuoka, Y and Morimoto, T and Bando, K and Hara, S and Fujita, K and Nishida, K},
title = {Label-Free Detection of Cellular Aβ Accumulation and Mitochondrial Dysfunction in AD Cell Models via Raman Microscopy.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c06200},
pmid = {42336352},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) is a neurocognitive disorder characterized by the accumulation of amyloid beta (Aβ) in senile plaques in the brain. Aβ accumulates in nerve cells, causing cellular dysfunction through various mechanisms, including mitochondrial dysfunction, leading to apoptosis. AD cell models are being studied to elucidate the neurotoxic effect of Aβ; however, conventional methods such as immunostaining and fluorescent molecular labeling require extensive sample manipulation and may produce artifacts not reflective of natural states. In this study, we employed Raman microscopy on AD cell models and simultaneously detected Aβ accumulated in cells and associated mitochondrial dysfunction through cytochrome distribution changes. This label-free method enables the observation of AD cell models in a more natural state and is expected to contribute to elucidating the mechanism of cell damage caused by Aβ. Furthermore, applying this system to experiments involving Aβ inhibitor administration enables rapid, label-free evaluation of drug activity, which is highly valuable in drug development.},
}

@article {pmid42336662,
year = {2026},
author = {Rajender, R and Foth, N and Eggert, S and Schilling, S and Fäßler, M and Ott, C and Mühlhaus, T and Sommer, F and Schroda, M and Maritzen, T and Banicevic, M and Bengelsdorff, V and Kiss, E and Buchholz, CJ and Müller, UC and Kins, S},
title = {Trans-dimerization of Amyloid Precursor Protein family members induces pre- and postsynaptic differentiation through distinct signaling pathways.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.0701-25.2026},
pmid = {42336662},
issn = {1529-2401},
abstract = {The amyloid precursor protein (APP), a key factor in Alzheimer's disease (AD) pathology, and its two mammalian homologues, amyloid precursor like proteins 1 and 2 (APLP1 and APLP2), are considered as members of the synaptic adhesion molecule (SAM) family. They are localized to the pre- and postsynapse, form trans-cellular dimers and have been shown to induce presynaptic differentiation in a heterologous synapse formation assay.We demonstrate that expression of all APP family members in non-neuronal cells also promotes dendritic excitatory postsynaptic differentiation in primary mouse neurons of either sex, similar to Neurexin1β and other SAMs. Synaptogenic activity was decreased by deletion of the E1 domain and increased upon inhibition of soluble APP (sAPP) generation, reinforcing that trans-cellular interaction of APP/APLPs can induce synaptogenesis. Consistent with this, the capacity of heterologously expressed APP to induce postsynaptic specializations in contacting dendrites was reduced by the absence of APP family members at the postsynaptic site and was lost in conditional triple knockout (cTKO) neurons. Pharmacological analyses revealed that heterologous formation of pre- and postsynapses relies on proper microtubule- and actin cytoskeleton dynamics, as well as the MAP kinase pathway, similar to what has been shown for Neurexin1β and Neuroligin1. However, inhibition of the PI3K/Akt pathway selectively impaired APP-induced postsynaptic differentiation, suggesting that distinct APP signaling pathways are required for pre- and postsynaptic differentiation. Collectively, our data highlight the role of all APP family members as SAMs in trans-synaptic signaling, providing key insights into their physiological function and advancing our understanding of AD-related synaptopathies.Significance Statement Our data show that all three amyloid precursor protein (APP) family members induce besides presynaptic also postsynaptic differentiation through distinct signaling pathways. Specifically, the c-Jun N-terminal kinase pathway is involved at pre- and postsynaptic sites, whereas the Akt pathway is selectively required for postsynaptic differentiation. Furthermore, mutagenesis studies demonstrate that pre- and postsynaptic differentiation is mediated independent of secreted APP. Finally, our analyses on knockout neurons lacking all APP family members strongly suggest that synaptogenic activity of APP is mostly mediated by APP or Amyloid precursor like proteins (APLPs) dimerization partner located at the opposing postsynaptic site. Together, these data support the hypothesis that synaptogenic activity of APP/APLPs is predominantly driven by heterotypic trans-cellular interaction as synaptic adhesion molecules.},
}

@article {pmid42336817,
year = {2026},
author = {Vari, HR and Praticò, D},
title = {Necroptosis in Down Syndrome.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-09035-y},
pmid = {42336817},
issn = {2041-4889},
abstract = {Necroptosis is a form of controlled cell death implicated in neuronal loss observed in neurodegenerative diseases such as Alzheimer's disease. Down syndrome (DS) is also characterized by the presence of neuronal cell loss, but the underlying mechanisms remain unclear. Brain tissue from a mouse model of DS, Ts65dn mice, and subjects with DS were assessed for levels of necroptosis markers including receptor-interactive protein kinase 1 and 3, necroptosis executor mixed lineage kinase domain-like protein and long non-coding RNA MEG. While no differences were observed between the Ts65dn and wild type mice at a young age, levels of these markers were significantly elevated in the brains of old DS mice when compared with matched wild type controls. Assessment of post-mortem brains from DS subjects also revealed a significant increase in these necroptosis markers. Our study is the first report showing the presence of necroptosis markers in the brains of a mouse model of DS and in DS subjects. These findings support the novel idea that this form of cell death should be also considered for developing novel therapeutic strategies for DS.},
}

@article {pmid42336952,
year = {2026},
author = {Arabhalvaei, V and Rajaei, SN and Alinaghi, MM and Talebi, M and Dashti, F and Abachi, SF and Khodayar, Z and Jafroodi, AR and Jamalaldin, M and Mehboodi, M and Maleki, MH and Rahimi, A and Baziyar, P},
title = {Investigation of the effects of sodium butyrate on SH-SY5Y neurons treated with amyloid beta42 and lipopolysaccharide: A computational and experimental study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-59446-2},
pmid = {42336952},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid beta42 (Aβ42) aggregation, neuroinflammation, and synaptic dysfunction. This study combines computational and experimental approaches to investigate the neuroprotective effects of sodium butyrate (NaB). Differentiated SH-SY5Y neurons were exposed to lipopolysaccharide (LPS) and Aβ1-42 to model AD-like conditions, and the potential protective effects of NaB were evaluated. MD simulations indicated that NaB may be associated with destabilization of organized Aβ42 fibrils. Alterations in RMSD, Rg, and SASA values indicated structural instability of Aβ42 fibrils in the presence of NaB. Treatment with NaB (10 and 50 µM) significantly improved cell viability compared to the LPS + Aβ group (p < 0.001) and attenuated apoptosis, as evidenced by reduced expression of Bax, Caspase-3, and FOXO3a (p < 0.0001), alongside upregulation of the anti-apoptotic marker Bcl-2 (p < 0.01). Moreover, NaB markedly increased the expression of neuroprotective and antioxidant genes, including BDNF, Nrf2, SIRT1, and CREB (p < 0.001), thereby restoring pathways involved in neuronal survival, oxidative stress defense, and synaptic plasticity. Collectively, these effects mitigated LPS + Aβ-induced cytotoxicity, suggesting that NaB exerts its neuroprotective action through epigenetic regulation of stress-response and plasticity networks. Our findings provide robust evidence supporting sodium butyrate as a promising therapeutic candidate for preventing or slowing AD-related neuronal degeneration and highlight its potential translational relevance for future in vivo and clinical investigations.},
}

@article {pmid42337012,
year = {2026},
author = {Li, Z and Miao, Y and Zhang, X and Ma, Y and Jin, L},
title = {Metabolomic signatures of brain aging: A multimodal and genetic study.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42337012},
issn = {1476-5578},
abstract = {Accelerated brain aging is increasingly recognized as a transdiagnostic risk factor for neuropsychiatric and neurodegenerative disorders, yet its metabolic underpinnings remain poorly understood. Here we integrated multimodal neuroimaging (MRI), plasma metabolomics, and genomic data from the UK Biobank to identify metabolic markers of brain aging and evaluate their causal relevance. Using 1079 imaging-derived phenotypes (IDPs) from 4333 healthy participants, we trained and validated machine learning models for brain age prediction, with a least absolute shrinkage and selection operator (LASSO) regression model achieving the best performance (mean absolute error = 3.26 years, R[2] = 0.68). Brain age gap (BAG) was then estimated in 37,458 participants. Association analyses in 21,780 individuals identified nine plasma metabolites significantly linked to BAG after Bonferroni correction, with glucose showing the strongest effect (β = 0.32, P = 9.90 × 10[-12]). Genome-wide association studies (GWAS) identified 392 BAG-associated single-nucleotide polymorphisms (SNPs) (P < 5 × 10[-8]), and two-sample Mendelian randomization (MR) provided evidence supporting a potential causal role of glucose in accelerating brain aging. Clinically, elevated plasma glucose was positively associated with seven brain disorders, including all-cause dementia, Alzheimer's disease, vascular dementia, Parkinson's disease, stroke, depression, and anxiety, and negatively associated with cognitive performance, movement function, and mental health outcomes. Higher glucose concentrations were also associated with reduced regional brain volumes across 80 cortical, subcortical, and cerebellar regions. These findings implicate glucose metabolism as a modifiable pathway in brain aging, with implications for early intervention strategies aimed at preserving brain health across the lifespan.},
}