@article {pmid41772480,
year = {2026},
author = {Lv, H and Cai, Y and Mo, D and Gao, X and Wei, M and Xu, J and Jing, F and Zhang, Y and Fang, X and Wu, W and Xiang, Y and Ma, X},
title = {The relationship between low birth weight and neurological disorders: a prospective cohort study in the UK Biobank.},
journal = {BMC neurology},
volume = {26},
number = {1},
pages = {},
pmid = {41772480},
issn = {1471-2377},
support = {cstc2021ycjh-bgzxm0008//Chongqing Talents: Exceptional Young Talent Project/ ; },
abstract = {BACKGROUND: Birth weight as a marker of fetal growth has been linked to later health outcomes, but its relationship with adult neurological disorders is less well characterised, and few large studies have evaluated multiple neurological disorders within a unified analytical framework.

METHODS: We analyzed 279,842 UK Biobank participants with self-reported birth weight. Birth weight was modeled continuously (per 1-kg increment) and categorically (low < 2.5 kg, reference 2.5–4.0 kg, high ≥ 4.0 kg). Incident multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, migraine and cerebrovascular disease (CVD) were ascertained from hospital and registry records (ICD-10). Logistic regression estimated OR and 95% CI, adjusting for age, sex, education, race, and socioeconomic status, with stratification by sex and age.

RESULTS: Low birth weight was associated with higher risk of AD (OR = 1.31, 95% CI 1.14–1.51), epilepsy (OR = 1.37, 95% CI 1.24–1.51), and CVD (OR = 1.32, 95% CI 1.25–1.40). AD showed a U-shaped pattern, with high birth weight increasing risk (OR = 1.19, 95% CI 1.04–1.36). Each 1-kg increase in birth weight corresponded to 12% lower odds of epilepsy (OR = 0.88, 95% CI 0.84–0.93) and 11% lower odds of CVD (OR = 0.89, 95% CI 0.85–0.94). Findings were consistent across sex and age strata, and no associations were observed for MS, PD, or migraine after full adjustment.

CONCLUSIONS: Low birth weight was independently associated with increased risk of AD, epilepsy, and CVD in adulthood, but not with MS, PD, or migraine, after adjustment for measured confounders. These observational findings, which remain susceptible to residual confounding and measurement error, support the Developmental Origins of Health and Disease framework and underscore the enduring influence of early-life growth on neurological health. Future research should incorporate objective birth records, encompass more diverse populations, and explore how birth weight can be integrated into life-course risk prediction models and prenatal preventive strategies.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12883-026-04761-4.},
}

@article {pmid41776475,
year = {2026},
author = {Mekonen, EW and Endalew, SA and Ferede, YA and Birhan, GW},
title = {Antibacterial and antioxidant activities of Inula confertiflora extracts.},
journal = {BMC complementary medicine and therapies},
volume = {26},
number = {1},
pages = {},
pmid = {41776475},
issn = {2662-7671},
abstract = {BACKGROUND: Antimicrobial-resistant pathogenic microorganisms are disease causing microbes that cause several diseases in humans, animals, and plants. Currently, these microorganisms cause more than a quarter of the reported diseases worldwide. The other current global health risk is the imbalance generation of free radicals in human physiology, which exposes several millions to oxidative stress diseases like Alzheimer, Cancer, and Diabetes.

OBJECTIVE: The objective of this study was to evaluate the antibacterial and antioxidant activities of Inula confertiflora roots, stems, and leaves extracts.

METHOD: The methanolic, ethyl acetate, and petroleum ether extracts of the roots, stems, and leaves of this plant were separately evaluated against the Gram-positive bacteria strains Enterococcus faecalis, Staphylococcus aureus, and Gram-negative bacteria Klebsiella pneumonia using the agar well diffusion method. Each crude extract was also evaluated by an invitro antioxidant activity test against DPPH free radical reagent.

RESULT: The crude extrats showed moderate to high activities against two Gram-positive bacterial strains, S. aureus and E. faecalis. The petroleum ether extract of the leaves showed the highest activity (39.97 ± 0.12 mm inhibition diameter) against S. aureus. All crude extracts also showed strong free radical scavenging activity, with a maximum percentage scavenging value. The root petroleum ether extracts showed 99.18 ± 0.06% scavenging activity at 1000 (µg/ml) concentration.

CONCLUSION: Extracts from this plant are potentially effective against S. aureus and E. faecalis; they also have strong free radical scavenging activities.},
}

@article {pmid41776637,
year = {2026},
author = {Wang, L and Wang, F and Wang, X and Chen, X and Li, C and Shan, K and Zhou, H and Wu, G and Xu, Z and Kong, X and Wei, P},
title = {The lung-brain axis: elucidating the mechanisms of pulmonary-driven neurological disorders.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41776637},
issn = {1742-2094},
support = {22201164//National Natural Science Foundation of China/ ; 82571352//National Natural Science Foundation of China/ ; QDZDZK-2025064//the Qingdao Key Health Discipline Development Fund/ ; ZR2024QH041//the Natural Science Foundation of Shandong Province/ ; QDKY2023ZD02//the Scientific Research Foundation of Qilu Hospital of Shandong University/ ; 2024M761822//China Postdoctoral Science Foundation/ ; },
abstract = {The brain and lungs represent two of the most vital organs in the human body. The conceptualization of the lung-brain axis has advanced our understanding of the bidirectional communication between the respiratory and central nervous systems. Accumulating evidence indicates that pulmonary diseases, including chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome and infections such as bacterial pneumonia, influenza and Coronavirus Disease 2019, along with airborne environmental exposures, constitute significant risk factors for various neurological disorders. The lung-brain axis is primarily mediated by microbial, immune, neural, metabolic and hormonal pathways. These mechanisms contribute to the disruption of blood-brain barrier integrity, the activation of neuroglial cells and the dysfunction of the cerebrovascular system, ultimately causing neuronal injury and diverse neurological conditions. Environmental factors, notably airborne particulate matter and chemical pollutants, further amplify the crosstalk among these mechanisms, extending the neurological risk. Here, we summarize the current knowledge regarding the association between pulmonary dysfunction and the development and progression of neurodegenerative diseases (such as Alzheimer’s disease and Parkinson’s disease), stroke, anxiety/depression, epilepsy, and migraine. Additionally, potential therapeutic strategies targeting the lung–brain axis are discussed to foster further research in this emerging field. Elucidating the complex interactions within the lung–brain axis will not only deepen our understanding of the shared pathophysiological mechanisms but also open novel avenues for the early diagnosis, prevention, and treatment of related neurological diseases.},
}

@article {pmid41862973,
year = {2026},
author = {Marei, HE},
title = {Enhancer-based gene therapy: a new path for precision medicine.},
journal = {Hereditas},
volume = {163},
number = {},
pages = {},
pmid = {41862973},
issn = {1601-5223},
abstract = {Enhancers are critical cis-regulatory elements that regulate gene expression in a context-dependent manner by integrating transcription factor binding, chromatin state, and the three-dimensional organization of the genome. Recent advances in functional genomics and synthetic biology have increased interest in harnessing enhancer activity to regulate the expression of therapeutic genes. Unlike traditional approaches that rely on promoter-driven gene regulation, enhancer-based approaches can bias transgene expression toward specific cellular states or disease contexts; however, this control remains probabilistic and highly dependent on the chromatin environment. This review summarizes current knowledge of enhancer biology, discusses new strategies for utilizing enhancer function directly, and examines the potential benefits and drawbacks of using enhancer-based strategies for gene therapy applications. Often delivered using adeno-associated virus (AAV) vectors with tailored capsids, enhancers in gene therapy can be included into expression cassettes. Astrocyte- or microglia-specific enhancers in the brain enable enriched or preferential distribution of neuroprotective or immunomodulatory genes, hence lowering unintentional expression in non-target cell types. It is important to control gene expression for specific cell types for the treatment of neurodegenerative conditions such as Alzheimer’s or Parkinson’s disease, were unintentional gene expression results in negative consequences. However, the uses of enhancer-guided gene therapy go beyond the central nervous system. In cancer, therapeutic constructs are designed to inhibit oncogenic expression or induce tumor suppression pathways, using enhancers in either malignant or immune cells as a target. Similarly, through the use of tissue-specific enhancers in cardiovascular and regenerative medicine, lineage-enriched genes can be used to promote repair of damaged tissues and enhance functional recovery. Enhancer-based systems that modulate the levels of gene expression (enhancer systems that adjust gene expression to levels that are physiologically appropriate for a given cell type) may also be useful in diseases caused by imbalances of gene dosage (e.g., haploinsufficiency and copy number variations). However, despite the potential promise of enhancer-driven gene therapy, many technical and translational hurdles remain. Mapping and validating the function of cell-type-specific enhancers is hampered by the dynamic, context-dependent regulation of chromatin. The identification of enhancers across a variety of developmental stages and clinical states is being accelerated through the combination of recent advances in single-cell epigenomic techniques (e.g., ATAC-seq, ChIP-seq, and multi-omic integration). Recent advances in non-viral delivery methods and AAV capsid engineering are improving the safety, efficacy, and scalability of enhancer-driven gene therapies. However, there must be careful regulatory oversight to avoid unintentional activation of enhancers and ensure continuing efficacy of enhancer-guided therapies. This paper provides an overview of the conceptual basis of enhancer-driven gene therapies, the currently available applications, and barriers to their clinical application. We show how the combination of delivery technology, synthetic biology, and genomics is enabling new possibilities for tailored gene therapy particular to cell- and disease-specific. Enhancer-driven gene therapy could become an important component of next-generation precision medicine by addressing current challenges and using creative technology.},
}

@article {pmid41951582,
year = {2026},
author = {Kimura, T and Yamakawa, A and Mitsumori, R and Niida, S and Ozaki, K and Shigemizu, D},
title = {Whole-genome sequencing reveals an East Asian-specific rare variant of INPP5J associated with Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04027-0},
pmid = {41951582},
issn = {2158-3188},
abstract = {Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly, yet no curative treatments are available. Although genome-wide association studies (GWASs) have identified numerous genetic risk factors, these factors often differ among ethnic groups, and the mechanisms driving LOAD onset remain poorly understood. Most GWASs of LOAD have been conducted in European populations; the expansion of future studies to non-European populations should uncover novel genetic factors underlying LOAD pathogenesis. To identify novel LOAD-susceptible genes, we conducted whole-genome sequencing data analysis on 1928 Japanese individuals including 325 patients with LOAD and 1603 cognitively normal elderly controls. A GWAS for common variants identified a statistically significant association signal in rs429358, within the apolipoprotein E gene (APOE), which defines the APOEε4 haplotype. This association was successfully replicated in an independent Japanese replication cohort of 4768 samples, genotyped using the Asian Screening Array. For rare variants, a gene-based association study identified two rare variants, rs769490815 and rs1921732305, in Inositol polyphosphate 5-phosphatase (INPP5J) as potential candidates for LOAD association. Due to their extremely low allele frequencies, these variants were not included on the genotyping array and could not be evaluated in the replication cohort. However in vitro functional analyses revealed that the ethnicity-specific p.K687T mutation (rs1921732305) significantly reduced the phosphatase activity of INPP5J, suggesting a potential pathogenic role in LOAD.},
}

@article {pmid41951598,
year = {2026},
author = {Zhao, S and Ye, R and Tang, QY and Attaallah, B and Toniolo, S and Saleh, Y and Rouse, MA and Garrard, P and Broulidakis, MJ and Thompson, S and Manohar, SG and Irani, SR and Ang, YS and Lockwood, P and Apps, MAJ and Hu, P and Wang, K and Rowe, JB and Le Heron, C and Husain, M},
title = {The social dimension of apathy: evidence for a distinct domain from 11,243 individuals across health and neurocognitive disorders.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04023-4},
pmid = {41951598},
issn = {2158-3188},
support = {226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 220258/WT_/Wellcome Trust/United Kingdom ; 226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 82171917//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82471271//National Natural Science Foundation of China (National Science Foundation of China)/ ; MR/V007173/1//RCUK | Medical Research Council (MRC)/ ; MC_UU_00030/14//RCUK | Medical Research Council (MRC)/ ; SUAG/092 G116768//RCUK | Medical Research Council (MRC)/ ; 02/2019//Canterbury Medical Research Foundation (CMRF)/ ; },
abstract = {Apathy is a highly prevalent and disabling neuropsychiatric syndrome, but its multi-dimensional structure is a challenge for progress towards better identification and treatment. A crucial unresolved question is whether social disengagement reflects a distinct deficit in social motivation or a by-product of diminished initiative or emotional blunting. Previous studies have been constrained by modest sample sizes and limited use of apathy-specific instruments or phenotypically narrow cohorts. Here, we analysed item-level data from 11,243 individuals recruited across multiple centres, including 1154 neurological patients with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, autoimmune encephalitis and small vessel disease, alongside people with depression and healthy adults. Across exploratory and confirmatory factor analyses, symptom-level network modelling, and lifespan analyses, social apathy consistently emerged as a coherent and separable dimension. This pattern was preserved across health, psychiatric, and neurocognitive cohorts, from adolescence through late life. Recognising social apathy as an independent domain reframes a central aspect of mental health-the motivation to connect, care, and act for others-and provides a foundation for more precise assessment and for interventions targeting both social and neurobiological mechanisms.},
}

@article {pmid41951832,
year = {2026},
author = {Islam, N and Akçesme, B},
title = {Single nucleotide polymorphisms affecting galantamine binding to acetylcholinesterase in Alzheimer's disease: a structural bioinformatics study.},
journal = {Journal of computer-aided molecular design},
volume = {40},
number = {1},
pages = {},
pmid = {41951832},
issn = {1573-4951},
mesh = {*Galantamine/chemistry/metabolism ; Humans ; *Alzheimer Disease/drug therapy/genetics/enzymology ; *Acetylcholinesterase/chemistry/genetics/metabolism ; *Cholinesterase Inhibitors/chemistry/metabolism/pharmacology ; Molecular Dynamics Simulation ; *Polymorphism, Single Nucleotide ; Molecular Docking Simulation ; Protein Binding ; Computational Biology ; Binding Sites ; Ligands ; Catalytic Domain ; Thermodynamics ; },
abstract = {Galantamine, an acetylcholinesterase (AChE) inhibitor used for symptomatic treatment of Alzheimer's disease (AD), shows substantial inter-individual variability in clinical response. Missense single nucleotide polymorphisms (SNPs) within the AChE active-site gorge may modulate inhibitor recognition. In this computational study, binding residues were defined from human AChE inhibitor co-crystal structures and cross-referenced with dbSNP missense variation, followed by in-silico predictions of variant impact, evolutionary conservation and folding stability, and assessment of ligand engagement by docking and molecular dynamics (MD) with MM/GBSA binding-energy estimation. Using complexes containing galantamine (GNT) and a donepezil-like ligand (E20), 11 of 807 AChE missense variants overlapped binding-site residues, highlighting Phe294 (UniProt Phe326) and His447 (UniProt His479). ConSurf classified His447 as highly conserved, and MUpro predicted decreased folding stability for His447 substitutions. SwissDock docking indicated that His447Gln retains a plausible GNT binding pose and yielded the least favourable docking score among the tested variants, consistent with a potential reduction in binding strength. MD simulations (200 ns) of wild-type and His447Gln AChE-GNT complexes supported preserved global structural integrity of the complex over the simulated timescale, while indicating local remodelling of the GNT binding microenvironment. MM/GBSA estimates from terminal snapshots suggested a modestly less favourable theoretical binding free energy for His447Gln relative to wild-type (approximately 2.0 kcal mol[-1]). Given that His447 is the catalytic triad histidine, such substitutions may have consequences for catalysis in addition to inhibitor binding; these in-silico findings require experimental validation using site-directed mutagenesis with kinetic and binding assays.},
}

*Galantamine/chemistry/metabolism
Humans
*Alzheimer Disease/drug therapy/genetics/enzymology
*Acetylcholinesterase/chemistry/genetics/metabolism
*Cholinesterase Inhibitors/chemistry/metabolism/pharmacology
Molecular Dynamics Simulation
*Polymorphism, Single Nucleotide
Molecular Docking Simulation
Protein Binding
Computational Biology
Binding Sites
Ligands
Catalytic Domain
Thermodynamics

@article {pmid41951843,
year = {2026},
author = {Komy, MHE and Aldosari, BN and Zaki, RM and Bafail, R and Yusif, RM and Abdelgawad, MA and Elmowafy, M and Abuhelwa, AY and Eid, HM},
title = {Intranasal co-delivery of riluzole and berberine via chitosan-coated PLGA nanoparticles for synergistic neuroprotection in Alzheimer's disease: formulation, characterization, and pharmacokinetics analysis.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41951843},
issn = {1432-1912},
support = {DGSSR-2024-01-02058//Al Jouf University/ ; },
abstract = {This study presents an intranasal chitosan-coated PLGA nanoparticle system co-loaded with riluzole (RLZ) and berberine (BER) to achieve synergistic neuroprotection and enhanced brain targeting for Alzheimer's disease therapy. Chitosan-coated PLGA nanoparticles containing riluzole and berberine (RLZ-BER-CTS-PLGA) were prepared via a modified single emulsion-solvent evaporation method using 0.9% PLGA and 1% PVA, and 0.99% chitosan. The optimized formulation exhibited a size of 203.5 nm, zeta potential of + 34.7 mV, and high entrapment efficiencies of 73.9% (RLZ) and 71.4% (BER). In vitro release showed sustained delivery, with only 36.3% BER and 28.4% RLZ released after 2 h compared to 82.6% and 57.3% from suspensions. Ex vivo nasal permeation demonstrated 2.8-fold (BER) and 2.1-fold (RLZ) increases in permeability coefficients relative to drug suspensions. Pharmacokinetic evaluation confirmed superior brain delivery, with intranasal RLZ-BER-CTS-PLGA achieving Cmax levels of 596 ng/mL for BER and 1345 ng/mL for RLZ, versus only 213 ng/mL and 385 ng/mL from intranasal suspensions. Direct transport percentage (DTP) reached 81.4% for BER and 56.4% for RLZ, with corresponding drug targeting efficiencies (DTE) of 536.6% and 229.3%. Histopathology confirmed nasal safety with no mucosal irritation. These results establish chitosan-functionalized PLGA nanocarriers as a promising noninvasive co-delivery platform for multifunctional Alzheimer's therapeutics.},
}

@article {pmid41952326,
year = {2026},
author = {Youssef, H and Gatto, RG and Ghayal, NB and Estades Ayuso, V and Jansen-West, KR and Dunmore, JA and Song, Y and Yue, M and Cook, CN and DeTure, M and Rawlinson, BD and Castanedes-Casey, M and Jack, CR and Petersen, RC and Dickson, DW and Petrucelli, L and Whitwell, JL and Prudencio, M and Josephs, KA},
title = {Biochemical and Immunohistochemical Associations of TDP-43 and Cryptic RNA With Hippocampal and Amygdala Volumetrics in Alzheimer's Disease.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78223},
pmid = {41952326},
issn = {1531-8249},
abstract = {OBJECTIVE: Immunohistochemically (IHC) measured transactive response DNA-binding protein 43 (TDP-43) inclusions are observed in Alzheimer's disease (AD) and are associated with medial temporal lobe atrophy. Accumulation of cryptic exons occurs in AD in response to TDP-43 pathology. We aimed to assess relationships between IHC and biochemically measured insoluble TDP-43 and cryptic exons and assess associations with hippocampal and amygdala volume loss and atrophy rates on magnetic resonance imaging (MRI).

METHODS: Eighty-one neuropathologically diagnosed AD cases were analyzed. For biochemistry, insoluble TDP-43 was quantified using a Meso-scale discovery (MSD) immunoassay. IHC-TDP burden was quantified with digital histopathology. Cryptic RNAs were assessed via quantitative real-time polymerase chain reaction (qRT-PCR). Thirty-eight cases had serial brain MRI. Hippocampal and amygdala volumes were calculated using FreeSurfer. Regression models were used to investigate associations among IHC-TDP-43 status/burden, MSD-TDP status/levels, cryptic RNAs, and hippocampal and amygdala volumes and atrophy rates.

RESULTS: IHC-TDP(+) cases exhibited elevated levels of MSD-TDP and cryptic RNAs (KCNQ2, STMN2, and UNC13A) and increased MSD-TDP levels were associated with increased cryptic RNA levels, in the hippocampus and amygdala. IHC-TDP(+) cases had smaller hippocampal and amygdala volumes compared to IHC-TDP(-) cases. MSD-TDP(+) cases had smaller hippocampal volumes and faster amygdala rates of atrophy compared with MSD-TDP(-) cases. Higher KCNQ2 and UNC13A levels were associated with smaller amygdala volumes.

INTERPRETATION: MSD-TDP level is a reliable surrogate for IHC-based TDP-43 status. Both TDP-43 and cryptic RNA levels are associated with reduced medial temporal volumes, suggesting cryptic exons may be playing a role in brain volume loss in AD. ANN NEUROL 2026.},
}

@article {pmid41952419,
year = {2026},
author = {Jiang, X and Toomey, CE and Lashley, T and Gatt, A},
title = {Widespread hnRNP K Mislocalisation Suggests Differential Neuronal Vulnerability in the Neurodegenerative and Ageing Human Brain.},
journal = {Neuropathology and applied neurobiology},
volume = {52},
number = {2},
pages = {e70072},
doi = {10.1111/nan.70072},
pmid = {41952419},
issn = {1365-2990},
support = {579/ALZS_/Alzheimer's Society/United Kingdom ; //Alzheimer's Research UK/ ; //Association of Frontotemporal Dementia/ ; //BRAIN non-clinical post-doctoral fellowship/ ; //My Name'5 Doddie Foundation/ ; },
mesh = {Humans ; *Brain/pathology/metabolism ; Male ; Aged ; Female ; *Aging/pathology/metabolism ; *Neurons/metabolism/pathology ; *Heterogeneous-Nuclear Ribonucleoprotein K/metabolism ; Aged, 80 and over ; Middle Aged ; *Neurodegenerative Diseases/pathology/metabolism ; Alzheimer Disease/pathology/metabolism ; Frontotemporal Lobar Degeneration/pathology/metabolism ; },
abstract = {Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a widely distributed RNA-binding protein in the human brain, playing a crucial role in post-transcriptional regulation, including mRNA metabolism and neuroplasticity. We have previously identified an increase in neuronal hnRNP K mislocalisation in cases of frontotemporal lobar degeneration (FTLD) compared to controls, where loss of nuclear hnRNP K was linked to alternative splicing events. However, the broader distribution of hnRNP K mislocalisation across different brain regions, other diseases and its pathological significance remains unclear. This study systematically examined hnRNP K mislocalisation across 13 brain regions from 19 cases, including different pathological subtypes of FTLD, Parkinson's disease (PD), Alzheimer's disease (AD) and age-matched neurologically normal controls, using immunohistochemistry and quantitative image analysis. The results of the study show that hnRNP K mislocalisation is observed throughout the brain, characterised by nuclear depletion and cytoplasmic aggregation. In the cerebral cortex, mislocalisation was most pronounced in the frontal lobe and least in the occipital lobe, with significant predominance in the depth of sulci compared to gyri. Notably, the basal ganglia, thalamus, medulla and cerebellum exhibited particular vulnerability to hnRNP K pathology. In contrast, Purkinje cells within the cerebellum and CA1-CA2 pyramidal neurons within the hippocampus showed lower levels of mislocalisation. Furthermore, levels of hnRNP K mislocalisation within the putamen correlated significantly with motor symptoms, suggesting a potential link between hnRNP K pathology and motor dysfunction. These findings highlight the propensity of hnRNP K mislocalisation in neurodegenerative diseases and the aged brain and underscore the need for further investigation into its functional consequences.},
}

Humans
*Brain/pathology/metabolism
Male
Aged
Female
*Aging/pathology/metabolism
*Neurons/metabolism/pathology
*Heterogeneous-Nuclear Ribonucleoprotein K/metabolism
Aged, 80 and over
Middle Aged
*Neurodegenerative Diseases/pathology/metabolism
Alzheimer Disease/pathology/metabolism
Frontotemporal Lobar Degeneration/pathology/metabolism

@article {pmid41952807,
year = {2026},
author = {Burns, B and Xue, Y and Scharre, DW and Ning, X},
title = {Flexible Multimodal Neuroimaging Fusion for Alzheimer's Disease Progression Prediction.},
journal = {Applications of medical artificial intelligence. AMAI (Workshop) (4th : 2024 : Taejon-si, Korea)},
volume = {16206},
number = {},
pages = {235-245},
pmid = {41952807},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with high inter-patient variance in rate of cognitive decline. AD progression prediction aims to forecast patient cognitive decline and benefits from incorporating multiple neuroimaging modalities. However, existing multimodal models fail to make accurate predictions when many modalities are missing during inference, as is often the case in clinical settings. To increase multimodal model flexibility under high modality missingness, we introduce PerM-MoE, a novel sparse mixture-of-experts method that uses independent routers for each modality in place of the conventional, single router. Using T1-weighted MRI, FLAIR, amyloid beta PET, and tau PET neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we evaluate PerM-MoE, state-of-the-art Flex-MoE, and unimodal neuroimaging models on predicting two-year change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores under varying levels of modality missingness. PerM-MoE outperforms the state of the art in most variations of modality missingness and demonstrates more effective utility of experts than Flex-MoE.},
}

@article {pmid41952858,
year = {2026},
author = {Calderón-Garcidueñas, L and Hernández-Luna, J and Galaz-Montoya, CI and Clouston, SAP and Aiello-Mora, MV and Amaro de Gante, J and Stommel, EW and Torres-Jardón, R and Nalbantoglu, OU},
title = {Cortical, subcortical, and cerebellar atrophy and cognition deficits in Metropolitan Mexico City teens and young adults exposed to fine particulate matter (PM2.5) - neurodegeneration is in progress.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1772916},
pmid = {41952858},
issn = {1664-2295},
abstract = {Exposure to environmental fine particulate matter (PM2.5), ultrafine PM (UFPM) and nanoparticles (NPs) are associated with accumulation of amyloid-β1-42 peptides, phosphorylated-Tau, alpha-synuclein and transactive response DNA binding-protein-43 misfolded aberrant proteins, consistent with the biological definitions of overlapping Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) in 99% of ≤40-year-old Metropolitan Mexico City (MMC) forensic autopsies. Structural and volumetric brain responses in vivo are critical in young MMC residents. We performed volumetric and whole-brain correlation analyses in 75 healthy volunteers: 45 MMC 31.2 ± 14.7 y old and 30 low-pollution 31.8 ± 4.8 y old controls, matched by ethnicity, socioeconomic status, nutrition, and BMI. MMC residents exhibited fronto-parietal and temporal lobes, precentral gyrus, hippocampi, basal ganglia, thalamus, amygdala and cerebellar atrophy. The most common atrophy pattern was cortical first parietal and fronto-parietal lobes, combined with gray matter (GM) atrophy in cerebellar lobules IV and V left and right III, IV and V and VI.MMC participants had mild cognitive impairment (Montreal Cognitive Assessment Score 22.8 ± 3.2). GM atrophy involving right globus pallidus and pulvinar and cerebellar white matter (WM) bilaterally were associated with lower cognitive performance and high BMI to subiculum, posterior orbital gyrus and insula, inferior temporal gyrus, supplementary motor cortex, and cuneus WM atrophy. PM2.5 exposure and BMI appear to play key roles in early neurodegenerative disease biology and may contribute to adverse effects on academic and occupational performance, neuropsychiatric disorders, behavioral regulation, risk of substance use initiation, and psychopathy. Neuroradiologists across the world need to know cortical and subcortical, including extensive hippocampal, stratium and cerebellar atrophy identifies overlapping patterns of regional atrophy associated with MCI, AD, bvFTD, PD and ALS, in young urbanites. There is an urgent need for early pediatric neuroprevention interventions, non-invasive AD, PD and TDP-43 biomarkers, in-depth characterization of emission pollutants exposures and their effective control. Denial is no longer an option.},
}

@article {pmid41952870,
year = {2026},
author = {Liu, W and Bai, Y and Qu, W and Zhang, X and Zhou, S and Luo, H and Zhu, M and Li, D and Fang, X},
title = {Intervention of ginseng-derived macromolecular drugs in Alzheimer's disease: exploring mechanisms and assessing potential.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1752446},
pmid = {41952870},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder for which effective treatments remain elusive. This review aims to explore the roles, mechanisms, and therapeutic potential of three principal ginseng components, including ginseng polysaccharides (GPS), ginseng proteins (GP), and ginseng glycoproteins (GGP), in the prevention and management of AD. We systematically reviewed recent literature related to these components in AD research. By analyzing evidence from cellular experiments, animal models, and preliminary clinical studies, we evaluated their effects on core pathological processes. These ginseng-derived compounds exert neuroprotective effects via multiple pathways. Specifically, they inhibit the aggregation of amyloid-β (Aβ) and reduce the hyperphosphorylation of tau protein. Furthermore, they demonstrate significant anti-neuroinflammatory and antioxidant activities, which protect neurons from damage and enhance cognitive functions, including memory and learning. The efficacy of these components has been consistently demonstrated across various AD experimental models. In conclusion, GPS, GP, and GGP exhibit promise as multitarget therapeutic agents against AD, underscoring a potential pathway for developing novel natural product-based treatments. Although current preclinical results are promising, further rigorous clinical trials are necessary to validate their efficacy and safety in humans. Therapeutic strategies targeting these components may therefore offer new hope for AD patients.},
}

@article {pmid41952872,
year = {2026},
author = {Burgio, F and Pezzetta, R and Gooijers, J and Nordio, S and Mantini, D},
title = {Neural and motor mechanisms of handwriting: from healthy aging to neurodegenerative disorders.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1758541},
pmid = {41952872},
issn = {1663-4365},
abstract = {Handwriting is a complex cognitive and motor skill supported by a distributed brain network involving cortical, subcortical, and cerebellar regions responsible for planning, execution, and sensorimotor integration. Beyond its communicative role, handwriting provides biologically meaningful information about brain function and motor control, serving as a sensitive marker of both normal and pathological changes. Age-related alterations, such as reduced fine motor precision, impaired sensory feedback, and cognitive slowing, contribute to the progressive decline in handwriting fluency and legibility. Importantly, distinctive handwriting patterns may be associated with early signs of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and Multiple Sclerosis, reflecting disease-specific alterations in motor and cognitive circuits. Advances in digital technology now enable high-resolution, quantitative analysis of handwriting kinematics, offering promising and scalable tools for diagnosis, longitudinal monitoring, and personalized rehabilitation. Furthermore, interventions incorporating fine motor and visuomotor coordination exercises, adaptive writing, and cognitive training may help preserve handwriting abilities and promote adaptive neural changes. In this review, we synthesize current evidence on the neural, behavioral, and technological mechanisms underlying handwriting across aging and neurodegenerative conditions. We provide an integrated overview of neural substrates, age- and disease-related alterations, and emerging digital approaches for assessment and intervention, highlighting their relevance for research and clinical practice. Overall, handwriting has the potential to offer a powerful, non-invasive window into brain health, bridging neuroscience, aging research, and digital medicine.},
}

@article {pmid41952873,
year = {2026},
author = {Misrani, A and Ngwa, C and Liu, F},
title = {Mitochondrial dysfunction in Alzheimer's disease and related sex differences.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1761702},
pmid = {41952873},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), the most common form of dementia, accounts for 70% of cases and remains a major healthcare challenge due to its rising prevalence and lack of disease-modifying treatments. Clinically, AD is a sexually dimorphic disease. Women exhibit more rapid cognitive decline and accelerated brain atrophy during mild cognitive impairment and early dementia, whereas men more frequently present cardiovascular comorbidities, earlier mitochondrial dysfunction, and greater neuropsychiatric symptoms. AD is marked by amyloid-β (Aβ) plaques, neurofibrillary tangles, neuroinflammation, and neuronal loss, with mitochondrial dysfunction emerging as a key early contributor that exhibits sex specific phenotypes. Mitochondria are vital for neuronal function by generating ATP, maintaining calcium homeostasis, and regulating oxidative stress. However, mitochondria in AD exhibit impaired ATP synthesis, excessive reactive oxygen species (ROS) production, calcium dysregulation, and disrupted fission-fusion dynamics. AD mitochondrial dysfunction can be measured by molecular markers, such as increased expression of fission-related protein Drp1, decreased biogenesis regulator PGC-1α, and elevated oxidative stress markers like malonaldehyde, nitotyrosine and protein carbonyls. Accumulating data suggest that sex differences in mitochondrial dysfunction are attributed to either sex hormonal or sex chromosomal effects, which eventually contribute to sex dichotomic phenotypes of AD. This review collected data regarding mitochondrial dysfunction in AD, with an emphasis on sex differences in oxidative stress, energy metabolism, and regulatory pathways.},
}

@article {pmid41953002,
year = {2026},
author = {Chen, C and He, Y and Ni, Y and Song, D and Chu, M and Zhang, W},
title = {Machine learning and free energy clustering reveal PAH protein binding linked to AD risk.},
journal = {iScience},
volume = {29},
number = {4},
pages = {115311},
pmid = {41953002},
issn = {2589-0042},
abstract = {This study develops a computational framework integrating bioinformatics, machine learning, and ΔG clustering to prioritize polycyclic aromatic hydrocarbons (PAHs) for Alzheimer's disease (AD)-associated neurotoxicity. PAH targets were predicted from ChEMBL/STITCH databases; AD-related differentially expressed genes (DEGs) were identified via WGCNA and differential expression analysis of GEO datasets. Protein-protein interaction (PPI) networks, GO/KEGG enrichment, and XGBoost feature selection identified PARP1, PTPN1, and ITGA4 as candidate core PAH targets enriched in neuroinflammation, microglial activation, lipid metabolism, and atherosclerosis pathways. Molecular docking produced ΔG heatmaps for clustering 16 PAHs into eight toxicity-similarity categories. Category-average ΔG values correlated linearly with literature LD50/BMDL data (ρ = 1, p = 0.0417), yielding an empirical relationship BMDL = 1.723 × ΔG + 22.602. Zebrafish motility assays provided preliminary support (Spearman ρ = -1.0, p = 0.167; n = 3). This pipeline provides initial insights into PAH mechanisms and potential therapeutic targets, pending experimental validation.},
}

@article {pmid41953054,
year = {2026},
author = {Zhuang, YY and Yan, JM and Wu, TC and Xu, WS and Wu, B and Xie, X and Wang, WJ and Lin, HW and Jian, JW and Wang, JZ and Jiang, T and Chen, LM and Qiu, YX and Hu, ZY and Zhou, YH and Yang, T and Yang, MG and Zhu, JF and Tao, J and Chen, LD and Li, WG and Yan, K and Liu, WL},
title = {tDCS improves early Alzheimer's disease by synaptic vesicle fusion and release.},
journal = {Military Medical Research},
volume = {13},
number = {1},
pages = {100003},
pmid = {41953054},
issn = {2054-9369},
mesh = {*Alzheimer Disease/therapy/physiopathology ; Animals ; Mice ; *Transcranial Direct Current Stimulation/methods/standards ; *Synaptic Vesicles/physiology/metabolism ; Mice, Transgenic ; Prefrontal Cortex/physiopathology ; Disease Models, Animal ; Male ; Memory, Short-Term ; Humans ; },
abstract = {BACKGROUND: Working memory deficits, one of the earliest hallmarks of Alzheimer's disease (AD), are closely linked to abnormal neural activity in the dorsolateral prefrontal cortex (DLPFC). Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation therapy, has been shown to ameliorate early AD working memory deficits by modulating excitatory activity in the DLPFC, yet the underlying mechanisms remain incompletely understood.

METHODS: This investigation was structured around 3 experimental phases. We initially applied tDCS to stimulate the left prefrontal cortex (PFC) of transgenic mice with 5 familial AD (5×FAD) 5 d per week for 4 weeks. Subsequently, we employed optogenetic (Opt) techniques to modulate left PFC glutamatergic neurons. Finally, we inhibited soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) expression in the left PFC to elucidate the essential function of SNARE complex assembly with chaperone molecules in orchestrating synaptic vesicle release.

RESULTS: tDCS treatment improved working memory deficits in early-stage AD mice. This was accompanied by increased cerebral blood flow, enhanced neuronal excitability, amelioration of neurochemical metabolic disorders, and reduced amyloid β-protein (Aβ) deposition in the left PFC. Opt stimulation of PFC glutamatergic neurons similarly improved working memory, indicating the association between tDCS's therapeutic effects and synaptic plasticity of excitatory neurons. Crucially, tDCS facilitated synaptic vesicle fusion and release, evidenced by increased vesicle numbers, enhanced release probability, improved synaptic transmission efficacy, and upregulation of the SNARE complex, Snap25, and Syt1. Inhibiting SNARE expression in the left PFC attenuated the tDCS-induced improvements in synaptic vesicle release and working memory.

CONCLUSION: These findings collectively demonstrate that left PFC-targeted tDCS modulates interactions between the SNARE complex and chaperone molecules, thereby promoting synaptic vesicle fusion and release. This mechanism underlies the amelioration of early AD-like working memory impairment by tDCS.},
}

*Alzheimer Disease/therapy/physiopathology
Animals
Mice
*Transcranial Direct Current Stimulation/methods/standards
*Synaptic Vesicles/physiology/metabolism
Mice, Transgenic
Prefrontal Cortex/physiopathology
Disease Models, Animal
Male
Memory, Short-Term
Humans

@article {pmid41953111,
year = {2026},
author = {Hunt, CJ and Zabriskie, BN and Coulter, EJ and McClellan, MC and Templeton, G and Erbstoesser, R and MacLean, S and Miller, CH and Moss, J and Carter, C and Gale, SD and Moore, JD and Farrer, TJ and Hedges, DW},
title = {Herpes simplex virus 2 and dementia risk: a systematic review and meta-analysis.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1737068},
pmid = {41953111},
issn = {2813-3919},
abstract = {INTRODUCTION: Several potentially modifiable risk factors for dementia have been identified, including infectious diseases. Among the infectious diseases potentially associated with dementia is herpes simplex virus type-2 (HSV-2).

METHODS: To better characterize the association between HSV-2 and dementia, we conducted a meta-analysis of published peer-reviewed studies reporting HSV-2 exposure and dementia outcomes.

RESULTS: Of 626 identified primary studies, eight met our inclusion criteria, with one of these excluded due to overlapping data with another study, yielding seven independent studies (total N = 751,156). Meta-analyses found no significant association between HSV-2 infection and Alzheimer's disease (pooled odds ratios ≈ 1.1, 95% confidence intervals included the null across all methods). Similarly, when pooling odds ratios across studies examining all-cause dementia, results were non-significant (pooled odds ratios ≈ 1.2, 95% confidence intervals included 1). In contrast, pooled hazard ratios from three studies for all-cause dementia suggested a possible increased risk among individuals with HSV-2 (DerSimonian and Laird pooled hazard ratio = 1.37, 95% CI: 1.00-1.89; Hartung-Knapp-Sidik-Jonkman pooled hazard ratio = 1.35, 95% CI: 0.58-3.14), driven primarily by two significant studies.

DISCUSSION: Overall, the available evidence indicates no clear association between HSV-2 and Alzheimer's disease and only one of the two meta-analytic methods shows evidence of a potential relationship with all-cause dementia. These findings support continued investigation into the association between HSV-2 and dementia.},
}

@article {pmid41953170,
year = {2026},
author = {Yousefzadeh, N and Sharma, O and Oliver, A and O'Keefe, H and Robertson, EG and Harris, B and Spiers, GF and Craig, D},
title = {Diagnostic Blood-Based Biomarkers of Amyloid-β and Tau Pathologies Prior to Alzheimer's Disease Diagnosis: a Rapid Umbrella Review.},
journal = {SN comprehensive clinical medicine},
volume = {8},
number = {1},
pages = {109},
pmid = {41953170},
issn = {2523-8973},
abstract = {BACKGROUND: Amyloid-β plaques and tau tangles are established hallmarks of Alzheimer's disease (AD). Early detection of these pathological changes in preclinical and prodromal stages can enable timely intervention and improve outcomes. This umbrella review synthesises evidence from systematic reviews examining diagnostic blood-based biomarkers (BBMs) predictive of amyloid-β and tau pathologies prior to clinical AD diagnosis.

METHODS: We conducted an umbrella review of systematic reviews published between 2018 and 2024, selecting those that synthesised data on BBMs associated with amyloid-β or tau pathologies in adults in preclinical or prodromal AD stages. Searches were performed across Medline, Embase, Cochrane databases, CINAHL, Web of Science, Epistemonikos, and grey literature. A narrative synthesis approach was used. AMSTAR2 was applied for quality appraisal.

RESULTS: Eighteen systematic reviews were included. Eight reviews were rated high or moderate quality using AMSTAR 2. Across the 18 reviews, 556 primary studies were represented, and overlap was low (38 studies; 6.8%). Forty‑four blood-based biomarkers (BBMs) were reported as associated with amyloid-β and/or tau pathology, but only three reviews reported diagnostic or prognostic performance metrics (e.g., sensitivity/specificity, PPV/NPV or AUC). Evidence with the clearest translational signal supported use of panels combining amyloid measures (e.g., plasma Aβ42/Aβ40 ratio) with APOE4 + status and/or phosphorylated tau, and plasma GFAP as an aid to distinguish amyloid-positive from amyloid-negative individuals in symptomatic populations.

CONCLUSIONS: BBMs have the potential to widen access to amyloid and tau pathology assessment earlier in the diagnostic pathway. However, limitations in consistently reported accuracy metrics, heterogeneous populations and assays, and the small number of clinically validated tests mean that clear recommendations for routine clinical implementation cannot yet be made. Future evidence syntheses should prioritise (i) standardised reporting of diagnostic accuracy against reference standards (Aβ-PET/CSF), (ii) head‑to‑head comparisons of leading candidates (p‑tau isoforms, Aβ42/Aβ40, GFAP, NfL) and (iii) evaluation in real‑world diagnostic pathways (primary care, memory clinics).

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42399-026-02319-6.},
}

@article {pmid41953385,
year = {2026},
author = {Nemoto, M and Nemoto, K and Ota, M and Sasai, H and Midorikawa, H and Sekine, A and Kitabatake, A and Arai, T},
title = {Real-World Multimodal Day-Care Intervention for Mild Cognitive Impairment with Lewy Bodies: A Prospective 3-Year Comparative Cognitive Trajectory Study.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {16},
number = {1},
pages = {11-20},
pmid = {41953385},
issn = {1664-5464},
abstract = {INTRODUCTION: Mild cognitive impairment with Lewy bodies (MCI-LB) is generally associated with more rapid cognitive decline than mild cognitive impairment due to Alzheimer's disease (MCI-AD). However, evidence regarding the potential cognitive trajectories of individuals with MCI-LB participating in structured non-pharmacological multimodal programs remains limited. The aim of the study was to preliminarily examine cognitive changes over time among individuals with MCI-LB and MCI-AD undergoing a multimodal intervention.

METHODS: Conducted at the University of Tsukuba Hospital between April 2013 and February 2020, this prospective study enrolled 74 participants (MCI-LB: 14; MCI-AD: 60) in the Cognitive Improvement Day-Care (CIDC) program. The CIDC was a multimodal intervention offering structured sessions including physical exercise, cognitive training, music therapy, and art-based activities. Participants attended the program, mostly once a week, and underwent annual cognitive assessments for up to 3 years using the Japanese version of Mini-Mental State Examination (MMSE-J). Linear mixed-effects models were used to analyze longitudinal changes in MMSE-J scores.

RESULTS: The overall annual cognitive decline was -0.36 points/year (95% CI: -0.63, 0.10). The annual decline was -0.44 points/year (95% CI: -0.95, 0.06) for the MCI-LB group and -0.34 points/year (95% CI: -0.64, -0.03) for the MCI-AD group. No significant group-by-time interaction was observed over the 3-year follow-up (p = 0.97).

CONCLUSIONS: These findings suggest that individuals with MCI-LB exhibited longitudinal cognitive trajectories under a structured multimodal intervention that were comparable to those observed in individuals with MCI-AD, at least as assessed by the MMSE-J. Future studies with larger samples and more detailed cognitive assessments are needed to clarify potential subtype-specific responses.},
}

@article {pmid41953573,
year = {2026},
author = {Amato, LG and Lassi, M and Grippo, A and Moschini, V and Giacomucci, G and Padiglioni, S and Morinelli, C and Nacmias, B and Mazzoni, A and Bessi, V and Vergani, AA},
title = {EEG recordings during visuo-attentive task reduce sex bias in Alzheimer's disease diagnosis.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70245},
pmid = {41953573},
issn = {2352-8737},
abstract = {INTRODUCTION: Pathological cognitive decline affects roughly 15% of older adults, presenting relevant sex differences, being a stronger predictor of Alzheimer's disease in females. Yet, sex-specific neural markers that support a balanced early diagnosis remain limited. Event-related potentials (ERPs) derived from task-based electroencephalograph (EEG) offer a non-invasive window into cognitive processing, but their sex-specific diagnostic value in subjective cognitive decline (SCD) has not been explored.

METHODS: We recorded EEG during a visuo-attentive task in elders with SCD (n = 119) and age-matched healthy controls (n = 19) to extract ERP components reflecting stimulus encoding and decision processes. We investigated sex-specific associations between ERP features and task performance and trained separate machine learning models for SCD diagnosis in males and females. Diagnostic models were constructed using either clinical features alone or a combination of clinical and ERP features to quantify the added value of ERPs over standard assessments.

RESULTS: ERP analyses revealed distinct sex-specific associations between neural responses and behavioral performance, suggesting partially divergent neurocognitive mechanisms underlying attentional processing in aging males and females. Diagnostic models based solely on clinical data produced significantly unbalanced performance between sexes (area under the curve [AUC]: 0.75 males, AUC: 0.63 females; p < 0.00001). When ERP features were incorporated, classification accuracy improved in both groups and the sex imbalance was eliminated (AUC: 0.77 males, AUC: 0.75 females; p = 0.31). ERP features consistently demonstrated higher sensitivity to subtle cognitive alterations, particularly in females.

DISCUSSION: Task-related ERPs provide complementary, sex-specific neural information that mitigates diagnostic disparity arising from clinical assessments alone. Incorporating ERP features supports a more equitable early identification of cognitive decline and may improve screening strategies for populations usually under-recognized in preclinical Alzheimer's disease pathways.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05569083.

HIGHLIGHTS: Task-based electroencephalograph (EEG) reveals sex-specific neural mechanisms in early Alzheimer's disease (AD) stages.Event-related potentials (ERP) features improve subjective cognitive decline (SCD) diagnosis and eliminate sex bias in classification.Combining cognitive data with task-EEG enhances overall diagnostic accuracy.Visuo-attentive EEG offers a non-invasive, unbiased tool for early AD detection.},
}

@article {pmid41953574,
year = {2026},
author = {Maestre, GE and Blangero, J and Manusov, EG and de Erausquin, GA and Fernández, F and Mejía-Arango, S and Diego, V and López-Alvarenga, JC and Alaniz, C and García, N and Pirela, RV and Tsin, A and Mahaney, MC},
title = {Decentralizing dementia research to the US-Mexico border: the Rio Grande Valley AD-RCMAR as a model for translational equity.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70238},
pmid = {41953574},
issn = {2352-8737},
abstract = {Translational equity means ensuring that diagnostics, treatments, care models, and prevention strategies are developed and implemented so they work for populations with the greatest burden and least access to care. In Alzheimer's disease and related dementias (ADRD), where most evidence derives from highly educated, non-Hispanic White participants at large academic centers, translational equity is critical to prevent misclassification, limited access, and widening disparities and to ensure that underrepresented communities shape how new knowledge moves into practice. Hispanic and other populations in the United States are disproportionately affected by ADRD yet remain underrepresented in research, with gaps especially pronounced in high-poverty border regions such as the Rio Grande Valley (RGV) of South Texas. We describe the design and early outcomes of the Rio Grande Valley Alzheimer's Disease Resource Center for Minority Aging Research (RGV AD-RCMAR), a National Institute on Aging-funded P30 center located at a new, R2, Hispanic-Serving Institution. Drawing on program documents, center evaluation data, and alignment with national RCMAR statistics, we examine how the RGV AD-RCMAR's three cores, the Leadership and Administrative Core, Analysis Core, and Community Liaison and Recruitment Core (CLRC), and the Research Education Component (REC) were structured to decentralize where dementia research questions are generated, who leads that work, and how benefits flow back to the community. During the 2018 to 2023 cycle, the RGV center supported 14 early-career investigators, representing ∼5% of all scientists in the national RCMAR/AD-RCMAR portfolio and ∼12% of all AD-RCMAR scientists. The REC maintained 50% female representation, retained 70% of scholars at the institution after pilot funding, and saw scholars secure National Institutes of Health (NIH) K- and R-level awards. The CLRC has built a registry of over 600 residents interested in participation and documented hundreds of engagement activities and community changes, positioning the RGV AD-RCMAR as a border-based model for translational equity in AD/ADRD.},
}

@article {pmid41953673,
year = {2026},
author = {Espinosa-Garcia, C and Srivastava, U and Kumar, P and Kour, D and Malepati, S and Tobin, BR and Xiao, H and Sunna, S and Bowen, CA and Cheng, L and Bagchi, P and Duong, DM and Whitworth, TJ and Liu, X and Seyfried, NT and Wood, LB and Faundez, V and Rangaraju, S},
title = {Neuroinflammatory stress preferentially impacts synaptic MAPK signaling and mitochondria in excitatory neurons.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {17},
pmid = {41953673},
issn = {3059-4944},
abstract = {BACKGROUND: Understanding synapse-specific effects of neuroinflammation can provide mechanistic and therapeutically relevant insights across the spectrum of neurological diseases.

METHODS: We applied neuron-specific proteomic biotinylation in vivo, differential centrifugation of brain for crude synaptosome enrichment (P2 fraction) and mass spectrometry (MS) analysis of biotinylated proteins to derive native-state proteomes of Camk2a-positive neurons and their corresponding P2 synaptic compartments. Next, in an in vivo model of systemic lipopolysaccharide (LPS) dosing, we examined the effects of neuroinflammation on whole neuron and synaptic compartments using a combination of MS, network analysis, confirmatory biochemical and ultrastructural assays and integrative approaches across our mouse-derived and existing human datasets.

RESULTS: Ultrastructural and biochemical analyses of P2 fractions verified enrichment in synaptic elements, including synaptic vesicles and mitochondria. MS of biotinylated proteins from Camk2a-specific bulk brain homogenates (whole neuron) and P2 fractions (synaptosome) showed enrichment of > 1000 proteins, consistent with neuron-specific biotinylation, also confirmed by immunofluorescence microscopy. Camk2a-specific synaptic proteome revealed molecular signatures related to mitochondrial function, synaptic transmission, protein translation. LPS-treated mice displayed body weight loss and neuroinflammation, characterized by glial activation, increased pro-inflammatory cytokine levels and upregulated expression of Alzheimer's disease (AD)-related microglial genes. LPS-induced neuroinflammation exerted distinct effects on the synaptic proteome, including increased mitochondrial and reduced cytoskeletal-synaptic proteins, while suppressed synaptic MAPK signaling. Importantly, these changes were not observed at the whole neuron level, indicating unique vulnerability of the synapse to neuroinflammation. In line with synapse proteomic and signaling changes, LPS altered the ultrastructure of asymmetric synapses, suggesting dysregulation of excitatory neurotransmission. Co-expression network analysis of Camk2a neuronal proteins further resolved mitochondria- and synapse-specific protein modules, some of which were neuroinflammation-dependent. Neuroinflammation increased levels of a mitochondria-enriched module, and decreased levels of a pre-synaptic vesicle module, without impacting a post-synaptic membrane module. LPS-dependent mitochondrial and LPS-independent post-synaptic modules in mouse neurons mapped to post-mortem human AD brain proteomic modules which were decreased in cases with AD dementia and positively correlated to cognitive function, including pro-resilience markers for AD.

CONCLUSION: Our findings using native-state proteomics of Camk2a neurons combined with synaptosome enrichment identify proteome-level mechanisms of early synaptic vulnerability to neuroinflammation relevant to AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-026-00024-1.},
}

@article {pmid41953799,
year = {2026},
author = {Kim, EH and Lee, YJ and Moon, YS and Kwon, DR},
title = {Investigating the Neuroprotective Effects of Peripheral Nerve Microcurrent Stimulation in a Mouse Model of Parkinson's Disease.},
journal = {Brain & NeuroRehabilitation},
volume = {19},
number = {1},
pages = {e3},
pmid = {41953799},
issn = {2383-9910},
abstract = {Parkinson's disease (PD) is a neurodegenerative disorder characterized by neuroinflammation and motor dysfunction. Current treatments primarily provide symptomatic relief. Microcurrent (MC) stimulation has recently emerged as a promising noninvasive technique for Alzheimer's disease; however, its therapeutic potential in PD remains underexplored. This study investigated the effects of MC therapy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Female C57BL/6 mice were divided into 3 groups: control, MPTP treated, and MPTP plus MC treated. A step-form waveform (5 V, 7 Hz base frequency with 44 kHz superposition) was applied for 4 weeks. Motor function was evaluated using rotarod and open field tests, and neuropathological changes were assessed by analyzing tyrosine hydroxylase, poly (ADP-ribose) polymerase (PARP), Toll-like receptor (TLR) proteins, caspase-3, and immunohistochemistry. MC therapy significantly improved motor activity in MPTP-treated mice, with increased latency to fall compared to the MPTP-only group. In the substantia nigra, the MC-treated mice had reduced tyrosine hydroxylase neuronal degradation and α-synuclein accumulation. Western blot analysis further revealed that the MC-treated mice had attenuated neuroinflammation by downregulating the TLR4 pathway and reducing PARP and cleaved caspase-3 expression. These findings suggest that MCs preserve dopaminergic neurons by suppressing neuroinflammation in a mouse model of PD, highlighting their potential as a therapeutic modality for PD.},
}

@article {pmid41953934,
year = {2026},
author = {Willis, DR and Summanwar, D and Fowler, NR and Brosch, JR and Hammers, DB},
title = {The primary care brain health navigator: A perspective on implementation.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70323},
pmid = {41953934},
issn = {2352-8729},
abstract = {Gaps in primary care (PC) early detection are caused by systems-based issues that require a systems-based solution. A PC brain health navigator (BHN) can mitigate the time limitations of PC providers, standardize high-quality PC-based evaluation of cognitive impairment, and improve the appropriateness of specialty care referrals. The design of the BHN role and function should be part of the patient-centered PC medical home team and integrated wholly within the PC space to achieve its potential. Sustainability of a PC BHN relies upon advanced payment models and requires further research and policy evaluation. The role and function of the PC BHN is the linchpin necessary to enable feasibility of early detection of Alzheimer's disease and related dementias in PC by creating capacity and capability of the primary care team. To be effective, the PC BHN must be intentionally and contextually developed, implemented, and supported within PC and with PC leaders.},
}

@article {pmid41954048,
year = {2026},
author = {Yang, NV and Wang, S and Li, B and Simms, J and Dinh, L and Huang, A and Oei, JH and Yassine, HN and Krauss, RM},
title = {TOMM40 suppression promotes neuronal cholesterol imbalance and molecular and behavioral phenotypes of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71306},
pmid = {41954048},
issn = {1552-5279},
support = {//Jordan Family Foundation/ ; R01AG067063/NH/NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; Mitochondrial Precursor Protein Import Complex Proteins ; *Cholesterol/metabolism ; Humans ; *Neurons/metabolism ; *Membrane Transport Proteins/metabolism/genetics ; Mice ; *Brain/metabolism/pathology ; Mitochondria/metabolism ; Amyloid beta-Peptides/metabolism ; Phenotype ; Induced Pluripotent Stem Cells/metabolism ; Disease Models, Animal ; Male ; },
abstract = {INTRODUCTION: While the apolipoprotein E (APOE) ε4 allele is a major risk factor for Alzheimer's disease (AD), the role of translocase of outer mitochondrial membrane 40 (TOMM40)-an adjacent gene involved in mitochondrial protein import-is not known.

METHODS: Human brain tissue, human induced pluripotent stem cell-derived neurons (iNeurons), and mice were used for study of gene expression, cholesterol metabolism, mitochondrial function, and animal cognition.

RESULTS: Human brain transcriptomics showed reduced TOMM40 expression that correlated with cholesterol regulatory gene expression, amyloid burden, and clinical AD diagnosis. In human iNeurons, TOMM40 knockdown (KD) disrupted mitochondria-endoplasmic reticulum contact sites (MERCs), causing mitochondrial dysfunction and promoting reactive oxygen species that led to activation of liver X receptor beta (NR1H2), upregulation of APOE and low-density lipoprotein receptor (LDLR), and increased cellular cholesterol and amyloid beta (Aβ)42 independent of APOE ε4. Consistently, Tomm40 KD in mice induced increased brain cholesterol, Aβ42 content, and impaired memory.

DISCUSSION: TOMM40 is a novel mediator of AD pathology through dual effects on MERCs that regulate cholesterol homeostasis and mitochondrial function.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology
Mitochondrial Precursor Protein Import Complex Proteins
*Cholesterol/metabolism
Humans
*Neurons/metabolism
*Membrane Transport Proteins/metabolism/genetics
Mice
*Brain/metabolism/pathology
Mitochondria/metabolism
Amyloid beta-Peptides/metabolism
Phenotype
Induced Pluripotent Stem Cells/metabolism
Disease Models, Animal
Male

@article {pmid41954097,
year = {2026},
author = {Swift, SK and Huang, G and Cochran, JN and D'Oliveira Albanus, R and Minaya, MA and Castruita, PA and Zhang, R and Miller, KJ and Starr, E and Galasso, G and Marsh, JA and Kao, AW and Harari, O and Yokoyama, JS and Karch, CM},
title = {Integrative genomic and functional analyses reveal NINL as a modulator of tau aggregation.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71352},
doi = {10.1002/alz.71352},
pmid = {41954097},
issn = {1552-5279},
support = {NS123985//National Institutes of Health (NIH)/ ; AG066444//National Institutes of Health (NIH)/ ; NS110890//National Institutes of Health (NIH)/ ; UL1TR002345//National Institutes of Health (NIH)/ ; T32AG058518//National Institutes of Health (NIH)/ ; AG062588//National Institutes of Health (NIH)/ ; AG057234//National Institutes of Health (NIH)/ ; AG062422//National Institutes of Health (NIH)/ ; AG019724//National Institutes of Health (NIH)/ ; AG079774//National Institutes of Health (NIH)/ ; //Rainwater Charitable Foundation/ ; //Hope Center for Neurological Disorders/ ; //Global Brain Health Institute/ ; //the Mary Oakley Foundation/ ; },
mesh = {Humans ; *tau Proteins/metabolism/genetics ; *Alzheimer Disease/genetics/metabolism ; *Frontotemporal Dementia/genetics/metabolism ; Genomics ; Proteostasis/genetics ; Brain/metabolism ; *Protein Aggregation, Pathological/genetics ; },
abstract = {INTRODUCTION: Proteostasis dysfunction is a hallmark of frontotemporal dementia (FTD) and Alzheimer's disease (AD), yet the genetic and molecular pathways that disrupt protein homeostasis remain poorly understood.

METHODS: We integrated human genetics, transcriptomics, and functional studies to identify proteostasis network components involved in tauopathy.

RESULTS: We identified 18 proteostasis network genes harboring 75 rare, damaging variants enriched in FTD and/or AD. These genes, spanning multiple proteostasis pathways, were differentially expressed in microtubule associated protein tau (MAPT) mutant neurons and dysregulated in FTD and AD brains. NINL, which encodes Nlp, emerged as the only gene consistently upregulated across all datasets. NINL overexpression reduced tau seeding and enhanced lysosomal proteolytic activity, whereas two FTD-enriched NINL frame shift variants impaired Nlp expression and abolished these protective effects.

DISCUSSION: We identified a set of proteostasis genes with genetic and transcriptional links to neurodegeneration and revealed NINL as a novel regulator of tau aggregation.},
}

Humans
*tau Proteins/metabolism/genetics
*Alzheimer Disease/genetics/metabolism
*Frontotemporal Dementia/genetics/metabolism
Genomics
Proteostasis/genetics
Brain/metabolism
*Protein Aggregation, Pathological/genetics

@article {pmid41954172,
year = {2026},
author = {Li, S and Zhang, X and Zhang, P and Wang, X and Yang, Y and Qin, D and Law, BY and Pan, Y and Tang, Y},
title = {Fruit-Derived Citri Reticulatae Semen Extract Attenuates Alzheimer's Disease Neuroinflammation and Cognitive Impairment via Modulation of the PI3K/Akt/FoxO1 Pathway.},
journal = {Molecular nutrition & food research},
volume = {70},
number = {7},
pages = {e70452},
doi = {10.1002/mnfr.70452},
pmid = {41954172},
issn = {1613-4133},
support = {2022YFS0620//the Sichuan Science and Technology Program/ ; 2024LZXNYDJ027//the Science and Technology Strategic Cooperation Programs of Luzhou Municipal People's Government and Southwest Medical University/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Plant Extracts/pharmacology ; Zebrafish ; *Citrus/chemistry ; Proto-Oncogene Proteins c-akt/metabolism ; Forkhead Box Protein O1/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Fruit/chemistry ; *Cognitive Dysfunction/drug therapy ; Mice ; Signal Transduction/drug effects ; Male ; Microglia/drug effects ; Neuroprotective Agents/pharmacology ; *Neuroinflammatory Diseases/drug therapy ; Amyloid beta-Peptides ; Mice, Inbred C57BL ; },
abstract = {Bioactive compounds from edible plants represent a promising multi-target approach for mitigating Alzheimer's disease (AD), in which neuroinflammation is a key pathological driver. Building on previous evidence that Citri Reticulatae Semen extract (CRSE) exerts neuroprotective effects, this study investigated its impact on AD related neuroinflammation and the underlying mechanisms. The major constituents of CRSE were profiled by HPLC-MS. CRSE efficacy was evaluated in Aβ1-42 stimulated BV-2 microglia, 3×Tg-AD mice, and Tg (apoeb: lynEGFP) zebrafish larvae. We found that CRSE significantly suppressed Aβ-induced microglial activation, NLRP3 inflammasome signaling, and pro-inflammatory cytokine release in BV-2 cells. In 3×Tg-AD mice, CRSE supplementation improved spatial learning and memory, reduced hippocampal glial reactivity and neuronal loss, and attenuated tau pathology and NLRP3/ASC/Caspase-1 activation. It also reduced microglial activation in zebrafish. Integrated transcriptomics and network pharmacology analyses converged on the PI3K/Akt/FoxO1 axis. Subsequent validation demonstrated that CRSE restored Aβ-impaired phosphorylation of PI3K, Akt, and FoxO1, and its anti-inflammatory effects were attenuated by the PI3K inhibitor. Collectively, these findings demonstrate that the fruit-derived CRSE ameliorates AD-related pathology by modulating the PI3K/Akt/FoxO1 pathway and suppressing NLRP3 inflammasome activation. This study provides a mechanistic basis for considering CRSE as a botanical candidate for dietary interventions aimed at neuroprotection in AD.},
}

Animals
*Alzheimer Disease/drug therapy
*Plant Extracts/pharmacology
Zebrafish
*Citrus/chemistry
Proto-Oncogene Proteins c-akt/metabolism
Forkhead Box Protein O1/metabolism
Phosphatidylinositol 3-Kinases/metabolism
Fruit/chemistry
*Cognitive Dysfunction/drug therapy
Mice
Signal Transduction/drug effects
Male
Microglia/drug effects
Neuroprotective Agents/pharmacology
*Neuroinflammatory Diseases/drug therapy
Amyloid beta-Peptides
Mice, Inbred C57BL

@article {pmid41954517,
year = {2026},
author = {Ying, M and Qi, X and Wang, A and Zhong, G and Tong, W and Yu, D and Liu, G and Guo, Y},
title = {RFWD2 Mitigates AD-Like Cognitive Impairments via the JNK-SGK1 Signaling Pathway in Mice.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {4},
pages = {e70860},
doi = {10.1002/cns.70860},
pmid = {41954517},
issn = {1755-5949},
support = {82371382//National Natural Science Foundation of China/ ; 81771381//National Natural Science Foundation of China/ ; 2308085MH256//Natural Science Foundation of Anhui Province/ ; 2021byfy002//Science Research Project of Bengbu Medical University/ ; Byycx23007//Postgraduate Innovative Training Program of Bengbu Medical University/ ; 202410367024//Undergraduate Innovative Training Program of China/ ; },
mesh = {Animals ; Mice ; *Alzheimer Disease/metabolism/genetics ; Rats ; PC12 Cells ; *Cognitive Dysfunction/metabolism/genetics ; *MAP Kinase Signaling System/physiology ; *Protein Serine-Threonine Kinases/metabolism ; *Immediate-Early Proteins/metabolism ; Male ; *Ubiquitin-Protein Ligases/metabolism/genetics ; Mice, Inbred C57BL ; Neurons/metabolism ; Signal Transduction/physiology ; Mice, Transgenic ; Disease Models, Animal ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is a degenerative disorder of the central nervous system. Its main pathological feature is the formation of neurofibrillary tangles through abnormal β-amyloid protein (Aβ) aggregation and excessive Tau protein phosphorylation. Ring finger and WD repeating domain 2 (RFWD2) is an E3 ubiquitin ligase that regulates neuronal dendrite complexity through the c-Jun N-terminal kinase (JNK) pathway. This study aimed to investigate the regulatory effect of RFWD2 on the downstream protein, serum/glucocorticoid-regulated kinase 1 (SGK1), through the JNK pathway and explore its influence on AD pathogenesis.

METHODS: Cognitive-level behavioral detection was performed in RFWD2[+/-] mice. Cultured PC12 cells and cortical neurons were also used to analyze the changes in signaling pathways caused by the decreased expression of RFWD2 in vitro and correlations between the expression of related proteins and key signaling pathways of AD at the molecular level.

RESULTS: Decreased RFWD2 expression led to cognitive deficits in AD mice, resulting in mitochondrial swelling, fragmentation of hippocampal neurons, abnormally high reactive oxygen species levels, and an imbalance between antiapoptotic and proapoptotic proteins. This effect was significantly improved by inhibiting the JNK pathway and SGK1 protein expression. Furthermore, in vitro experiments showed that in PC12 cells and cortical neurons downregulated by RFWD2, the expression levels of p-JNK, SGK1, and p-Tau increased, and those of LC3B/Beclin-1 decreased; ROS levels increased, and apoptosis was induced; inhibiting JNK or SGK1 expression reversed these changes.

CONCLUSION: RFWD2 regulates SGK1 expression through the JNK pathway, thereby regulating mitochondrial autophagy and apoptosis, altering the expression levels of p-Tau and Aβ proteins, inducing AD-like symptoms in mice, and promoting AD development. The RFWD2-JNK-SGK1 axis provides a valuable basis for studying the mechanisms of AD occurrence and developing early intervention strategies.},
}

Animals
Mice
*Alzheimer Disease/metabolism/genetics
Rats
PC12 Cells
*Cognitive Dysfunction/metabolism/genetics
*MAP Kinase Signaling System/physiology
*Protein Serine-Threonine Kinases/metabolism
*Immediate-Early Proteins/metabolism
Male
*Ubiquitin-Protein Ligases/metabolism/genetics
Mice, Inbred C57BL
Neurons/metabolism
Signal Transduction/physiology
Mice, Transgenic
Disease Models, Animal

@article {pmid41954680,
year = {2026},
author = {Youssef, B and Ibrahim, EA and Moselhy, SS and ElShebiney, S and ELabd, WK},
title = {Nano-magnolol enhances the modulatory effects of magnolol on cognitive performance and BACE1-related biochemical changes in an STZ-induced rat model of Alzheimer's disease.},
journal = {Discover nano},
volume = {21},
number = {1},
pages = {},
pmid = {41954680},
issn = {2731-9229},
abstract = {BACKGROUND: The Late-onset Alzheimer's disease (LOAD) is progressive cognitive deficits associated with different abnormalities as cholinergic dysfunction, amyloid accumulation, inflammation, and oxidative stress. Magnolol is a polyphenolic compound that abrogated the neurodegenerative disease. The application of nanoparticles in medicine showed high bioavailability and low side effects for development of novel effective therapies. This study evaluated the neuroprotective potential of magnolol nanoparticles against streptozotocin (STZ) injected in intracerebroventricularly (ICV) induced Alzheimer's disease (AD) in rats.

METHODS: In current study, six groups of male Wister rats (10 rats/ group) were injected with STZ (2 mg/kg) in ICV bilaterally for induction of pathological features similar to AD. Rats were then treated with either magnolol or nano-magnolol or donepezil (p.o). Behavioral analysis was evaluated as the Morris Water Maze (MWM), Y-Maze, Novel Object Recognition (NOR), Passive Avoidance (PA), Elevated plus Maze (EPM), and Open Field Test (OFT). In addition, biochemical markers including brain acetylcholinesterase (AChE), glutathione-S-transferase (GST), B-secretase1 (BACE1) activities and nuclear factor kappa-B (NF-κB) were analyzed in hippocampal tissue.

RESULTS: Data obtained showed that nano-magnolol significantly showed a neuroprotective effect in LOAD rat model by restoring GST activity and effectively decreased the activities of AChE, BACE1 and level of NF-κB compared to both donepezil and magnolol. Molecular docking studies indicated strengthen the affinity of magnolol to the BACE-1 active site.

CONCLUSION: Nano-magnolol is promising in developing a new agent targeting cholinergic function, amyloidogenesis, neuro-inflammation, and oxidative stress reflecting its potent neuroprotective efficacy in AD treatment.},
}

@article {pmid41954847,
year = {2026},
author = {Ma, X and Wang, M and Yang, J and Li, G and Wang, Y and Fang, H and Zhang, S},
title = {Integrated Single-Cell and System Network Analysis: Exploring Cellular Communication Network Complexity and Signal Transmission Dysregulation in Down Syndrome Brain.},
journal = {Neuroinformatics},
volume = {24},
number = {2},
pages = {},
pmid = {41954847},
issn = {1559-0089},
support = {No. 2022D03052; No. XJNUBS202419; Grant Numbers. 82270417//This research was supported by the Special Natural Science Foundation of Xinjiang Uygur Autonomous Region Special Training Programme for Ethnic Minorities (No. 2022D03052), the Doctoral (Postdoctoral) Research Start-up Fund Project of Xinjiang Normal University (No. XJNUBS202419) and the National Natural Science Foundation of China (Grant Numbers. 82270417)./ ; No. 2022D03052; No. XJNUBS202419; Grant Numbers. 82270417//This research was supported by the Special Natural Science Foundation of Xinjiang Uygur Autonomous Region Special Training Programme for Ethnic Minorities (No. 2022D03052), the Doctoral (Postdoctoral) Research Start-up Fund Project of Xinjiang Normal University (No. XJNUBS202419) and the National Natural Science Foundation of China (Grant Numbers. 82270417)./ ; },
mesh = {*Down Syndrome/metabolism/pathology/genetics ; Humans ; *Cell Communication/physiology ; Middle Aged ; Male ; Female ; Adult ; *Brain/metabolism/pathology ; *Single-Cell Analysis/methods ; Neurons/metabolism ; Young Adult ; Signal Transduction/physiology ; Aged ; },
abstract = {Down syndrome (DS) is a widespread chromosomal disorder primarily associated with cognitive impairment and progressive neurodegenerative changes. Clinically, age 50 years is considered a pivotal turning point in the health trajectory of individuals with DS. Before this age, they primarily face developmental challenges including significant cognitive deficits and difficulties in social interaction. However, as they age, they increasingly exhibit more severe neurodegenerative changes, including Alzheimer's disease (AD)-like cognitive decline and dementia symptoms. This study aimed to dissect intricate gene expression patterns in key neuronal cell types within the DS cerebral cortex and to examine how these patterns evolve with age. We conducted a detailed gene expression analysis of key neuronal cells, including inhibitory neurons, excitatory neurons, microglia, and oligodendrocyte progenitor cells, in individuals with DS. Additionally, the bioinformatics tool NeuronChat was employed to investigate the intercellular communication networks in the DS brain. Individuals with DS were divided into younger and older groups, with age 50 years as the boundary. Through comparative analysis, our findings indicated that aging in DS is associated with exacerbated neuronal dysfunction, decreased energy metabolism in microglia, and increased neurodegenerative traits in oligodendrocyte progenitor cells. Notably, compared to the control group, the DS brain showed increased complexity in cellular communication networks, reflecting an effort to maintain adaptability during syndrome progression. However, this increased complexity does not translate into effective signal transmission, suggesting significant disruptions in the function and structure of the neural network. This study provides a deeper understanding of cell function abnormalities and signal transmission irregularities in DS. By integrating single-cell and systemic network analyses, we revealed complex pathophysiological mechanisms, laying a foundational framework for developing new treatment methods. Our comprehensive analysis emphasizes the necessity for targeted strategies to address the multifaceted nature of DS pathogenesis and improve treatment outcomes.},
}

*Down Syndrome/metabolism/pathology/genetics
Humans
*Cell Communication/physiology
Middle Aged
Male
Female
Adult
*Brain/metabolism/pathology
*Single-Cell Analysis/methods
Neurons/metabolism
Young Adult
Signal Transduction/physiology
Aged

@article {pmid41955027,
year = {2026},
author = {Li, C and Wu, D and Lu, Q},
title = {Multi-marker testing based on accelerated failure time models under possible left truncation and competing risks.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {2},
pages = {},
doi = {10.1093/bib/bbag155},
pmid = {41955027},
issn = {1477-4054},
support = {R01DA043501/NH/NIH HHS/United States ; R01LM012848/NH/NIH HHS/United States ; R56AG075803/NH/NIH HHS/United States ; },
mesh = {Humans ; Alzheimer Disease/genetics/mortality ; Proportional Hazards Models ; *Models, Statistical ; *Models, Genetic ; Genetic Markers ; },
abstract = {Kernel-based multi-marker tests for survival outcomes use primarily the Cox model to adjust for covariates. The proportional hazards assumption made by the Cox model could be unrealistic, especially in the long-term follow-up. We develop a suite of novel multi-marker survival tests for genetic association and interaction based on the accelerated failure time model, which is a popular alternative to the Cox model due to its direct physical interpretation. The tests are based on the asymptotic distributions of their test statistics and are thus computationally efficient. The association tests can account for the heterogeneity of genetic effects across subpopulations/individuals to increase the power. All the new tests can deal with competing risks and left truncation. Moreover, we develop small-sample corrections to the tests to improve their accuracy under small samples. Extensive numerical experiments show that the new tests perform very well in various scenarios. An application to a genetic dataset of Alzheimer's disease illustrates the tests' practical utility.},
}

Humans
Alzheimer Disease/genetics/mortality
Proportional Hazards Models
*Models, Statistical
*Models, Genetic
Genetic Markers

@article {pmid41955054,
year = {2026},
author = {Molinare, CP and Noriega-Makarskyy, DT and Williams, JT and Oyen, E and Kim, P and Axelrod, J and Han, SD},
title = {Monetary savings and neuropsychological functioning in older adults without dementia.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001082},
pmid = {41955054},
issn = {1931-1559},
support = {//National Institutes of Health; National Institute on Aging/ ; /AG/NIA NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //Banner Alzheimer's Foundation/ ; //Flinn Foundation/ ; //Geoffrey Beene Gives Back Alzheimer's Initiative/ ; //GHR Foundation/ ; //State of Arizona (Arizona Alzheimer's Consortium)/ ; },
abstract = {OBJECTIVE: Socioeconomic status has been associated with cognitive functioning across the lifespan, but specific neuropsychological and economic components were not considered by previous studies. Here, we investigated monetary savings as a measure of socioeconomic status and its association with performance across multiple neuropsychological measures in older adults without dementia.

METHOD: Participants included 111 individuals (Mage = 68.5, SD = 7.2; M years of education = 16.7, SD = 2.2; 73% female; 75.7% White) recruited from the greater Los Angeles area. Demographic data, household income, and combined monetary savings across checking and savings accounts were self-reported through a questionnaire. Participants completed cognitive measures from the National Alzheimer's Coordinating Center Uniform Data Set, Version 3, and the National Institutes of Health Toolbox Cognitive Battery, Version 2. Multiple linear regression analyses were conducted to evaluate associations between monetary savings and each cognitive measure. All analyses controlled for age, sex, years of education, and income.

RESULTS: Greater monetary savings were associated with greater performance on a fluid cognition domain (b = 1.18, 95% CI [0.10, 2.25], p = .032), and more specifically on an inhibitory control task (b = 0.98, 95% CI [0.25, 1.70], p = .009). Post hoc analyses demonstrated that this effect was driven by individuals with above-median savings (b = 2.02, 95% CI [0.04, 3.99], p = .045).

CONCLUSIONS: Our findings suggest that greater inhibitory control is associated with greater monetary savings and that this relationship is more salient among older individuals with relatively high savings. Further research is needed to determine the underlying mechanisms of this association. (PsycInfo Database Record (c) 2026 APA, all rights reserved).},
}

@article {pmid41955088,
year = {2026},
author = {Acton, D and Jaydeokar, S and Taylor, R and Jones, S},
title = {Evaluating the feasibility of a co-produced, bespoke dementia education programme for formal caregivers of individuals with intellectual disability.},
journal = {Journal of intellectual disabilities : JOID},
volume = {},
number = {},
pages = {17446295261440431},
doi = {10.1177/17446295261440431},
pmid = {41955088},
issn = {1744-6309},
abstract = {Dementia education programmes for formal caregivers of people with intellectual disability are limited. This study was not designed or powered to evaluate effectiveness, but to assess the feasibility, acceptability, and appropriateness of outcome measures for a co-produced dementia education programme within intellectual disability services. A mixed-methods, quasi-experimental feasibility study was conducted with 40 formal caregivers recruited from supported living and residential providers across four NHS Trusts in the Northwest of England. The programme comprised interactive modules, case studies, group discussion, and practical tools to support the management of dementia-related behaviours and promote person-centred care. Feasibility outcomes included recruitment, retention, acceptability, and completion of outcome measures. The dementia education programme was feasible and acceptable with only minor modifications. Recruitment and retention were good, with 100% completion of follow-up outcome measures, supporting the suitability of the programme and study procedures for future research.},
}

@article {pmid41955089,
year = {2026},
author = {Jiang, Y and Liu, L and Xiong, M and Liu, W and Wang, H and Liu, Y and Cao, L and Zhou, J and Li, C and Yuan, C and Mao, L and Li, X},
title = {A Single-Vesicle Electroanalytical Approach Uncovers Deficits of Vesicular Acetylcholine Content in Alzheimer's Disease.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c22608},
pmid = {41955089},
issn = {1520-5126},
abstract = {The cholinergic system is essential for cognitive functions including learning, memory, and attention, with its dysfunction serving as a hallmark of neurodegenerative diseases including Alzheimer's disease (AD). However, how acetylcholine (ACh) is stored within individual synaptic vesicles, an essential compartment of cholinergic transmission, remains poorly understood, limiting insight into the nanoscale mechanisms underlying cognitive decline. Here, we present a high-throughput analytical strategy, molecular-empowered vesicle cytometry (MEVC), which employs calix[4]arene-facilitated ion transfer at the interface between two immiscible electrolyte solutions (ITIES) to quantify ACh stored in single vesicles. Validation using ACh-loaded artificial vesicles confirms its robustness and accuracy in quantifying ACh content at the single-vesicle level. Applying MEVC to brain-derived cholinergic vesicles reveals substantial depletion of vesicular ACh storage across multiple regions in an AD mouse model, including the basal forebrain, hippocampus, and cortex, alongside pronounced regional heterogeneity. These findings uncover previously inaccessible alterations in cholinergic neurotransmission and suggest that enhancing ACh synthesis and vesicular packaging may help preserve cognitive function in aging-related diseases. This approach not only paves a new path for sensitive quantification of nonredox-active neurotransmitters at the single-vesicle level, but also holds promise for advancing early diagnostics and therapeutic strategies for neurodegeneration.},
}

@article {pmid41955494,
year = {2026},
author = {Lee, S and Vicedo-Cabrera, AM},
title = {Unveiling heat vulnerability of older adults: an assessment of emergency hospital admissions in Switzerland.},
journal = {International journal of epidemiology},
volume = {55},
number = {2},
pages = {},
doi = {10.1093/ije/dyag044},
pmid = {41955494},
issn = {1464-3685},
support = {//National Centre for Climate Services/ ; },
mesh = {Humans ; Female ; Male ; Switzerland/epidemiology ; Aged ; Aged, 80 and over ; *Hot Temperature/adverse effects ; *Emergency Service, Hospital/statistics & numerical data ; *Hospitalization/statistics & numerical data ; Risk Factors ; Sex Factors ; Home Care Services ; *Heat Stress Disorders/epidemiology ; },
abstract = {BACKGROUND: Older adults are highly vulnerable to heat, yet how individual characteristics modulate its effects remains unclear. We assessed heat-related emergency hospital admission (EHA) risk across subpopulations of older adults receiving home care services in Switzerland (2019-2022).

METHODS: We analysed patient-level EHA data linked to daily maximum temperature by MedStat regions of residence. We employed a case time series design with quasi-Poisson regression and distributed lag non-linear models to examine heat-related EHA risk, stratifying by individual characteristics, including sociodemographic factors, pre-existing health conditions, primary diagnosis, and levels of dependency and social interaction.

RESULTS: The overall heat-related EHA risk was 1.12 (95% confidence interval (CI): 1.04-1.20) (at 99th percentile vs minimum temperature percentile risk). Males (1.16; 1.04-1.29) generally showed higher heat-related EHA risk than females (1.09; 0.98-1.20), except among those aged ≥85 years (females 1.16; 1.00-1.34 vs males 1.06; 0.90-1.26). Regarding functional capacity, females requiring assistance with daily tasks had an increased heat-related EHA risk, whereas males showed the opposite trend, with higher risk among those who were independent. Sex-specific analyses revealed that anxiety and dementia/Alzheimer's disease were risk factors for females, whereas cancer, chronic obstructive pulmonary disease, and coronary heart disease were risk factors for males. Joint stratification by pre-existing health conditions and primary diagnosis showed that individuals with pre-existing cancer had higher risks of admission for circulatory, genitourinary, infectious, and endocrine/metabolic causes during heat exposure.

CONCLUSION: Our results show that older individuals are not equally vulnerable to heat, underscoring the need for targeted public health interventions to protect high-risk older adults.},
}

Humans
Female
Male
Switzerland/epidemiology
Aged
Aged, 80 and over
*Hot Temperature/adverse effects
*Emergency Service, Hospital/statistics & numerical data
*Hospitalization/statistics & numerical data
Risk Factors
Sex Factors
Home Care Services
*Heat Stress Disorders/epidemiology

@article {pmid41955522,
year = {2026},
author = {Li, Y and Wang, Y and Liang, X and Xu, M and Leong, DT and Ke, PC},
title = {Nanoplastics and Neurodegeneration: A Roadmap From Mechanism to Causation.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e75151},
doi = {10.1002/advs.75151},
pmid = {41955522},
issn = {2198-3844},
support = {24PJA015//Shanghai Magnolia Talent/ ; S20250114//Ministry of Science and Technology of China/ ; 110513111//Ministry of Science and Technology of China/ ; },
abstract = {Nanoplastics are ubiquitous by-products of global plastic production and have emerged as a potentially consequential yet insufficiently defined threat to health. Recent studies have revealed that these synthetic particulates can cross the blood-brain barrier, accelerate amyloid aggregation, impair microglial clearance, hijack the gut-liver-brain axis, and drive neuroinflammation-mechanisms central to neurodegeneration in Alzheimer's and Parkinson's disease. In addition, anionic nanoplastics can induce vascular endothelial leakiness, thereby harboring a paracellular route for their systemic and cerebral access. Yet causality remains unproven in implicating nanoplastics for neurodegeneration in the absence of standardized human exposure data, mechanistic specificity, and epidemiological evidence, especially considering the supra-environmental doses employed. Here, we synthesize current knowledge, examine barriers to causal understanding, and propose a roadmap to advance this emerging scientific frontier of great public concern and inform future strategies for sustainable materials innovation.},
}

@article {pmid41955600,
year = {2026},
author = {Krupa, J and Malinowski, M and Krasowski, M and Kalinowska, A and Pietras, W and Kozieł, A and Kurek, Z and Jentkiewicz, A and Obeid, EH and Ulrych, J},
title = {The role of the MIND diet in prevention and treatment of Alzheimer's disease: A literature review.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {79},
number = {2},
pages = {390-398},
doi = {10.36740/WLek/217286},
pmid = {41955600},
issn = {0043-5147},
mesh = {Humans ; *Alzheimer Disease/prevention & control/diet therapy ; *Diet ; },
abstract = {OBJECTIVE: Aim: Recent research increasingly point to modifiable risk factors, especially dietary patterns, as potential tools to prevent or delay neurodegeneration. This review evaluates the impact of the MIND diet on the prevention and progression of AD and compares it with other dietary interventions.

PATIENTS AND METHODS: Materials and Methods: A literature search was conducted using the PubMed and Google Scholar databases for articles published from January 2015 to January 2025, focusing on the influence of the MIND diet, as well as other dietary patterns, on AD progression and cognitive performance.

CONCLUSION: Conclusions: While the MIND diet shows promise as a feasible non-pharmacological strategy, current evidence is largely observational and limited by population heterogeneity and inconsistent adherence definitions. Short-term randomized controlled trials are less conclusive. Long-term clinical trials are needed to establish causality. Despite these limitations, the MIND diet remains a practical and potentially effective approach to reducing cognitive decline and delaying the onset of AD.},
}

Humans
*Alzheimer Disease/prevention & control/diet therapy
*Diet

@article {pmid41955650,
year = {2026},
author = {Perales-Puchalt, J and Vidoni, ED},
title = {Moving toward a more rigorous science of recruitment in clinical research. Commentary on "Evaluating evidence-based recruitment strategies for Alzheimer's disease and related dementias clinical trial research: a literature review".},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100561},
doi = {10.1016/j.tjpad.2026.100561},
pmid = {41955650},
issn = {2426-0266},
}

@article {pmid41955736,
year = {2026},
author = {Bercovitch, R and Tio, ES and Wickramatunga, R and Misztal, M and Gicas, K and De Jager, PL and Schneider, JA and Buchman, AS and Bennett, DA and Rajji, T and Kennedy, JL and Felsky, D},
title = {Genetic predisposition to hand grip strength predicts cognitive decline.},
journal = {Neurobiology of aging},
volume = {164},
number = {},
pages = {28-38},
doi = {10.1016/j.neurobiolaging.2026.02.008},
pmid = {41955736},
issn = {1558-1497},
abstract = {Hand grip strength (HGS) is a predictor of cognitive decline in aging. To understand the direct and indirect mechanisms underlying this association, we performed integrative analyses of genetic, cognitive, and autopsy data. A polygenic risk score for HGS (PRSHGS) was calculated in two independent studies of aging (total n = 25,227). Cross-sectional and longitudinal modeling, including mediation with physical activity, assessed the effects of PRSHGS on cognitive performance and postmortem neuropathology. In both cohorts, higher PRSHGS predicted better global cognitive performance (p = 7.77 × 10[-4] and p = 0.025) and improved the predictive performance of an Alzheimer's disease PRS (likelihood ratio test p = 2.5 × 10[-5] and p = 0.007). PRSHGS was not associated with levels of any postmortem neuropathology. PRSHGS effects on cognition were only partially and inconsistently mediated by physical activity. Genetic predisposition for greater HGS predicts better cognitive performance in late life, independent from Alzheimer's disease-related neuropathology.},
}

@article {pmid41955837,
year = {2026},
author = {Song, Y and Zhao, Z and Dai, Y and Li, C and He, X and Wang, Y and Xu, ZD and Yang, Y},
title = {The m7G modification: An emerging player in neurological diseases.},
journal = {Pathology, research and practice},
volume = {282},
number = {},
pages = {156465},
doi = {10.1016/j.prp.2026.156465},
pmid = {41955837},
issn = {1618-0631},
abstract = {With the growing researches on RNA epigenetics, the importance of 7-methylguanosine (m7G) modification is increasingly recognized. The m7G modification is known as a kind of post-transcriptional modifications of RNA and present in many types of RNAs, including mRNAs, microRNAs, ribosomal RNA, and transfer RNAs. Increasing evidence indicates that m7G modifications are involved in a variety of critical biological processes through affecting the stability of RNA, nucleoplasmic transfer and translation efficiency. In the central nervous system (CNS), m7G modification is catalyzed by three major methyltransferase complexes: METTL1/WDR4, RNMT/RAM, and WBSCR22/TRMT112. Dysregulation of this modification is tightly associated with the pathogenesis of various neurological diseases, such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), epilepsy, glioblastoma, ischemic stroke (IS), etc. Here, we review the current knowledge regarding the latest findings on the distribution, regulatory factors, detection techniques and prediction methods of m7G. We further highlight critical knowledge gaps, especially the limited understanding of m7G "readers," the absence of validated "erasers," and the scarcity of cell-type-resolved profiling in the brain. In addition, we also discuss the translational opportunities and challenges, including biomarker discovery, therapeutic targeting of m7G regulators, and specificity concerns in precision neurological medicine.},
}

@article {pmid41955844,
year = {2026},
author = {Hasan, G},
title = {A growing role for ER-Ca[2+] release and store-operated Ca[2+] entry in neuronal physiology and pathophysiology.},
journal = {Current opinion in neurobiology},
volume = {98},
number = {},
pages = {103195},
doi = {10.1016/j.conb.2026.103195},
pmid = {41955844},
issn = {1873-6882},
abstract = {Among its many functions, the endoplasmic reticulum (ER) in eukaryotes serves as a store for intracellular Ca[2+]. In metazoan cells, there are two classes of ER membrane localized channels that release intracellular Ca[2+] in response to external signals. ER-Ca[2+] release is followed by extracellular Ca[2+] entry through a process called store-operated Ca[2+] entry (SOCE), essential for cellular Ca[2+] signaling and homeostasis. Recent findings suggest that neuronal SOCE differs based on the nature of ER-Ca[2+] release channels activated and the architecture of the ER across neuronal compartments. These properties determine the amplitude and time of ER-Ca[2+] release and SOCE, which in turn determine activation of downstream effector molecules. The importance of these findings is discussed in the context of normal physiology and neurodegenerative conditions. Drugs targeting regulators of ER-Ca[2+] release and SOCE show promise in terms of reverting symptoms of neurodegenerative conditions such as Alzheimers' disease.},
}

@article {pmid41955966,
year = {2026},
author = {Shim, YM and Yoo, S and Kwon, HJ and Lee, K and Park, SH and Won, JK},
title = {Three donor-matched iPSC lines derived from human postmortem dura mater for modeling neurodegenerative diseases.},
journal = {Stem cell research},
volume = {94},
number = {},
pages = {103984},
doi = {10.1016/j.scr.2026.103984},
pmid = {41955966},
issn = {1876-7753},
abstract = {We generated three donor-matched induced pluripotent stem cell (iPSC) lines from postmortem dura-derived fibroblasts obtained from donors with neuropathologically confirmed Alzheimer's disease (AD), Parkinson's disease (PD), and primary age-related tauopathy (PART) with TDP-43 co-pathology. All lines exhibited characteristic features of the undifferentiated human pluripotent stem cell (hPSC) state and maintained donor-specific genomic identity with stable variant profiles. These well-characterized iPSC lines provide valuable resources for modeling neurodegenerative diseases and for generating isogenic neural derivatives comparable to autopsy brain tissues from the same individuals.},
}

@article {pmid41956094,
year = {2026},
author = {Weber, AJ and Ng, B and Greathouse, KM and Bennett, DA and Tasaki, S and Gaiteri, C and Herskowitz, JH},
title = {Tau seeds induce neurofibrillary tangle formation across brain regions via individual-specific connectivity.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.03.001},
pmid = {41956094},
issn = {1097-4199},
abstract = {The spread of tau pathology across the cerebral cortex is closely tied to cognitive decline in Alzheimer's disease (AD). To investigate mechanisms underlying tau spread, we measured bioactivity of tau seeds from inferior temporal gyrus (ITG) and superior frontal gyrus (SFG) synaptosomes in 128 individuals and demonstrated that tau seed bioactivity associates with tau phosphorylation, neurofibrillary tangles (NFTs), and cognitive impairment. Incorporating genotype data from the same individuals within a Mendelian randomization framework showed that tau seeds in ITG induce NFTs locally as well as drive tau seeds and NFTs in SFG. Integrating antemortem functional magnetic resonance imaging data from the same individuals showed that person-specific connectivity modulates the tau seed-NFT relationships. These findings indicate that tau seeds underlie the spread of NFTs both locally and across distal brain regions via individual-specific connectivity.},
}

@article {pmid41956134,
year = {2026},
author = {Aurooj, A and Emmanuel, S and Jabeen, M and Minhaj, D and Kirmani, SKN and Aurooj, T and Kafeel, SR},
title = {Psychological Research on Alzheimer's Disease in Pakistan: A Systematic Review of Current Trends and Research Gaps.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103132},
doi = {10.1016/j.arr.2026.103132},
pmid = {41956134},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is an escalating public health concern in low- and middle-income countries like Pakistan, with rising prevalence among the aging population. While global research has increasingly addressed the psychological dimensions of AD, Pakistan's contribution remains limited. This systematic review, conducted in accordance with PRISMA guidelines, examines the scope and focus of psychological research on AD in Pakistan. Eleven empirical studies published between 2014 and 2025 were included, revealing key themes such as caregiver burden, sociocultural influences, assessment tools, and co-morbidities. The findings highlight a nascent but growing interest in psychological research on AD in Pakistan, along with significant gaps in methodology, cultural adaptation, and long-term data. Addressing these gaps is essential for improving patient outcomes and informing context-sensitive interventions and policies. PUBLIC SIGNIFICANCE STATEMENT: This review sheds light on the emerging body of psychological research on Alzheimer's disease in Pakistan. By identifying research trends and critical gaps, it emphasizes the urgent need for culturally relevant tools, caregiver support systems, and longitudinal studies to enhance mental health outcomes for patients and their families.},
}

@article {pmid41956136,
year = {2026},
author = {More, PS and Rangari, SW and Lade, SN and Unidrwade, DS and Burle, SS and Umekar, MJ and Lohiya, RT and Zanwar, AS},
title = {Drug Repurposing in Alzheimer's Disease: Emerging Therapeutic Strategies and Promising Candidates.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103113},
doi = {10.1016/j.arr.2026.103113},
pmid = {41956136},
issn = {1872-9649},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder, and the most common cause of dementia, which causes 60 to 70 percent of the cases worldwide, and its prevalence is increasing by more than 55 million people globally, with an expected increase of 139 million cases by 2050. AD is characterized by Amyloid-β plaque deposition, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, and oxidative stress, which makes the pathophysiology multifactorial and complex in terms of the development of therapeutic treatment. Existing approved therapies, such as cholinesterase enzyme inhibitors and NMDA receptors antagonists, are merely symptomatic, whereas novel anti-amyloid monoclonal antibodies approved recently have low clinical efficacy with safety and cost issues. The dismal success rates of clinical trials highlight the necessity of alternative approaches. Repurposing of drugs has proved to be a prospective solution, which uses drugs with established safety profiles to speed up the discovery of therapeutic solutions. Repurposed agents are used targeting diverse pathologic pathways, including amyloid aggregation, tau pathology, neuroinflammation, and synaptic dysfunction, with antidiabetic agents (metformin, GLP-1 receptor agonists) and anti-hypertensives (candesartan), anti-inflammatory ones (NSAIDs, pioglitazone), and neuroprotective ones (minocycline, sildenafil). Notably, mitochondrial dysfunction is becoming a significant early and essential cause of AD development, and mitochondria-targeted therapeutics like SS-31, Mdivi-1, MitoQ, DDQ, and SkQ1 are currently considered promising disease-modifying options. The development of artificial intelligence, multi-omics, and precision medicine also improves drug repurposing plans. Overall possibility to integrate multi-target repurposed therapies with novel technologies is a promising prospect to overcome the available shortcomings and improve clinical outcomes in AD.},
}

@article {pmid41956137,
year = {2026},
author = {Zhao, X and Li, Y and Meng, Z and Xu, X and Chen, L and Yu, Q and Wang, R and Ren, Y and Chen, F and Ai, Q and Deng, Y and Yu, H and Wei, J and Liang, G},
title = {The Role and Therapeutic Potential of DNA Glycosylases in Alzheimer's Disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103129},
doi = {10.1016/j.arr.2026.103129},
pmid = {41956137},
issn = {1872-9649},
abstract = {The aging brain is highly vulnerable to oxidative genomic damage, the accumulation of which is a hallmark of Alzheimer's disease (AD). The base excision repair (BER) pathway, initiated by DNA glycosylases, serves as the primary guardian against such damage. This review synthesizes recent evidence revealing the dual and dynamic roles of key DNA glycosylases including OGG1, MUTYH, MPG, and members of the NEIL family in AD pathogenesis. Beyond canonical repair functions, these enzymes actively participate in core pathological processes including Aβ/tau toxicity, neuroinflammation, and neuronal death, with their activities modulated by the AD microenvironment. We evaluate the therapeutic strategies targeting these enzymes, highlighting emerging strategies like OGG1 agonists for early-stage repair enhancement and inhibitors for dampening maladaptive inflammation in later stages. Finally, we propose a precision medicine approach based on a deeper understanding of glycosylase biology in distinct brain cell types and disease stages, providing a theoretical foundation for DNA repair-targeted interventions in AD.},
}

@article {pmid41956168,
year = {2026},
author = {Verma, S and Paliwal, S and Dubey, P and Kaushik, S and Joshi, R and Dwivedi, J and Sharma, S},
title = {Molecular Biochemistry of Soluble Epoxide Hydrolase in Lipid Mediator Pathways and Neuroinflammatory Responses.},
journal = {The Journal of steroid biochemistry and molecular biology},
volume = {},
number = {},
pages = {107021},
doi = {10.1016/j.jsbmb.2026.107021},
pmid = {41956168},
issn = {1879-1220},
abstract = {Soluble epoxide hydrolase (sEH) is a key enzyme in epoxy fatty acid (EpFA) metabolism, significantly affecting the balance of lipid mediators and the health of the central nervous system (CNS). This review explains the molecular biology, enzymatic activity, and clinical importance of sEH, emphasizing its role in converting anti-inflammatory epoxygenase metabolites into less active diols. Blocking sEH increases EpFA availability, leading to protective effects in experimental models of neuroinflammation, oxidative stress, and vascular failure linked to Alzheimer's, Parkinson's, and traumatic brain injury. The pharmacokinetics and chemistry of urea- and amide-based sEH inhibitors are also reviewed to highlight their development as potential CNS-targeted treatments. Recent preclinical and early clinical studies indicate that sEH inhibition may slow neurodegeneration and improve synaptic plasticity, thereby enhancing cognitive and behavioral functions. Overall, this review combines biochemical and pharmacological insights to support sEH as a promising target for treating neuroinflammation and neurodegenerative diseases characterized by disrupted lipid mediator signaling.},
}

@article {pmid41956206,
year = {2026},
author = {Puri, C and Rubinsztein, DC},
title = {Where and how do mammalian cells shape autophagosomes?.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {111428},
doi = {10.1016/j.jbc.2026.111428},
pmid = {41956206},
issn = {1083-351X},
abstract = {Autophagy is a fundamental cellular process responsible for degrading and recycling cytoplasmic components and regulates homeostasis, development, and survival under stress. Autophagy plays critical roles in diseases including neurodegeneration, cancers, and various infectious and inflammatory conditions. While the molecular machinery of autophagy has been well studied, increasing evidence highlights a complex interplay between autophagy and endocytosis. Traditionally, mammalian autophagosomes were believed to originate from compartments closely associated with the endoplasmic reticulum (ER), or the ER itself. However, more recent research has demonstrated that the recycling endosome serves as the main platform for autophagosome formation. The recruitment of WIPI2, an essential autophagy protein, to autophagosome initiation sites depends on its coincident detection of phosphatidylinositol 3-phosphate (PI(3)P) and RAB11A, a recycling endosome marker. This enables conjugation of LC3 (microtubule-associated protein light-chain 3) family members to the recycling endosome membranes to become nascent autophagosomes. These findings underscore the critical role of RAB11- compartment in autophagosome biogenesis. Contrary to the conventional model that has inferred that autophagosomes derive from spherical precursors with single apertures, structured illumination microscopy reveals these precursors are finger-like structures - much like a hand grasping an object. We will describe the experimental path that led to an understanding of how autophagosomes form from outgrowths of the recycling endosomes, then close after engulfing their contents. This step is a prerequisite for the final step of autophagosome formation, the release of autophagosomes from the recycling endosome membranes, a process that is perturbed by a major Alzheimer's disease gene.},
}

@article {pmid41956228,
year = {2026},
author = {Yuan, M and Gu, C and Nguyen, TTT and Xu, L and Chen, X and Sun, J and Zhong, L and Zheng, Y and Zhang, L and Lu, Q and Yuan, C and Xu, H},
title = {The efficacy and safety of Yokukansan for concomitant behavioral and psychological symptoms of Alzheimer's disease: a randomized, double-blinded clinical trial.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121644},
doi = {10.1016/j.jep.2026.121644},
pmid = {41956228},
issn = {1872-7573},
abstract = {ETHNOPHARMACOLOGY RELEVANCE: Yokukansan (YKS), a traditional Japanese formula, relieves agitation, anxiety, and sleep disturbance and has demonstrated potential in alleviating behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD). However, the evidence regarding its efficacy and safety remains limited.

AIM OF THE STUDY: The paper assessed the effect of YKS on managing BPSD and cognition in AD compared to placebo.

MATERIALS AND METHODS: This was a single-center, randomized, double-blinded, placebo-controlled trial performed between July 2023 and May 2024. A total of 100 subjects with AD and BPSD were registered. The YKS group received 2.5g of YKS thrice daily for 4 weeks; the placebo group received identical granules. Evaluations were conducted at baseline and at weeks 2, 4, and 8. The primary outcome was the change in Neuropsychiatric Inventory (NPI) scores from baseline to week 4. Secondary outcomes included the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Hamilton Depression Rating Scale (HAMD-17), and Liver Qi Stagnation and Spleen Qi Deficiency (LQSSQD).

RESULTS: Of the 100 participants, 89 completed the trial. The mean reduction in NPI scores was more significant in the YKS group than in the Placebo group at week 4 (P < 0.05). YKS showed trends of improvement in ADCS-ADL and MMSE scores, but no significant cognitive or mood changes were observed at week 4.

CONCLUSION: It was more effective than a placebo in reducing BPSD in AD patients, suggesting potential as an adjunct therapy. Larger studies are needed to confirm these results.

ChiCTR2300069404.},
}

@article {pmid41956234,
year = {2026},
author = {Alves, SS and Manzine, PR and Dos Santos, FM and Migliaccio, MM and de Carvalho Alves, LV and da Silva Junior, RMP and Becerra-Hernández, LV and González-Acosta, CA and Buriticá-Ramírez, E and Cominetti, MR and Camins, A and Garcia-Cairasco, N},
title = {From comorbidity to continuum: Alzheimer's disease and epilepsy are connected-now what?.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106682},
doi = {10.1016/j.neubiorev.2026.106682},
pmid = {41956234},
issn = {1873-7528},
abstract = {Alzheimer's disease (AD) and epilepsy are increasingly recognized not merely as comorbid conditions but as disorders lying along a shared pathophysiological continuum, characterized by overlapping clinical features, network hyperexcitability, and convergent molecular mechanisms. Although bidirectional interactions between AD and epilepsy are now well established, critical questions remain regarding how this knowledge can be translated into improved risk prediction, prevention, and treatment. Classical mechanisms such as amyloid-β and tau pathology, neuroinflammation, and synaptic dysfunction, together with less explored processes including brain insulin resistance, converge on shared downstream effects that promote both neurodegeneration and epileptogenesis. However, marked mechanistic heterogeneity across individuals, limits standardized therapeutic approaches and complicates the prediction of seizure risk in AD and dementia risk in epilepsy. In this review, we synthesize evidence supporting the AD-epilepsy continuum, integrating molecular pathways, genetic and metabolic modifiers, fluid biomarkers, and neuroimaging signatures that may enable earlier identification of vulnerable trajectories. We critically examine pharmacological strategies with dual effects on neuroprotection and seizure control and discuss how targeting shared mechanisms may shift interventions from symptomatic management toward disease modification. Importantly, we highlight current gaps and emerging hypotheses that define the next steps for the field, including patient stratification, early biomarker-guided trial design, and precision-based therapeutic strategies. By moving beyond descriptive associations, this review outlines a framework for translating mechanistic insight into actionable approaches aimed at early detection, personalized intervention, and improved outcomes in individuals at risk across the AD-epilepsy spectrum.},
}

@article {pmid41956888,
year = {2026},
author = {Chen, PH and Hsu, JL},
title = {Response to "Comment on 'Alzheimer's disease diagnosis: An update and review of biomarkers, positron emission tomography, and emerging therapies.".},
journal = {Journal of the Formosan Medical Association = Taiwan yi zhi},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jfma.2026.04.014},
pmid = {41956888},
issn = {0929-6646},
}

@article {pmid41956895,
year = {2026},
author = {Gupta, KR and Thombre, KR and Umekar, MJ},
title = {From Mechanisms to Medicine: Astrocyte Dysfunction in Stress-Related Neuroinflammation and Alzheimer's Disease.},
journal = {The European journal of neuroscience},
volume = {63},
number = {7},
pages = {e70508},
doi = {10.1111/ejn.70508},
pmid = {41956895},
issn = {1460-9568},
mesh = {*Astrocytes/metabolism/pathology ; Humans ; *Alzheimer Disease/metabolism/pathology/physiopathology ; *Stress, Psychological/metabolism/complications ; Animals ; *Neuroinflammatory Diseases/metabolism ; Hypothalamo-Hypophyseal System/metabolism ; },
abstract = {Chronic stress is increasingly acknowledged as a pivotal precipitating factor in the pathogenesis of neuropsychiatric and neurodegenerative disorders, notably including depression and Alzheimer's disease (AD). Astrocytes, which constitute the predominant population of glial cells involved in the maintenance of synaptic homeostasis, the recycling of neurotransmitters, and the provision of metabolic support, display a pronounced susceptibility to sustained exposure to stress. The deleterious effects of astrocytic dysfunction instigate a series of neuroinflammatory and synaptic modifications that undermine both cognitive and emotional resilience. This review articulates the mechanistic interactions between stress-induced astrocyte dysfunction, neuroinflammatory signaling, and compromised neuroplasticity, underscoring the converging pathways that are implicated in both depression and AD. A thorough synthesis of the literature from 2020 to 2025 was conducted utilizing databases such as PubMed, Scopus, and Web of Science, with an emphasis on molecular, in vitro, in vivo, and translational studies that examine the modulation of astrocytic function under conditions of chronic stress and its pertinence to depression and AD. The chronic activation of the hypothalamic-pituitary-adrenal (HPA) axis precipitates morphological alterations, diminished expression of glutamate transporters (GLT-1/EAAT2), disrupted brain-derived neurotrophic factor (BDNF) signaling, and an augmented release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) from astrocytes. These biochemical alterations exacerbate excitotoxicity, disturb monoaminergic and glutamatergic neurotransmission, and hasten synaptic degeneration. In the context of depression, this phenomenon is manifested as impaired mood regulation and a decline in neurogenesis. In AD, it synergistically interacts with amyloid-beta and tau pathologies to facilitate progressive cognitive impairment. Both conditions exhibit a common feature of diminished neurosignaling plasticity, which limits the brain's capacity for adaptation and repair. Astrocyte dysfunction constitutes a central mechanistic nexus wherein chronic stress, neuroinflammation, and synaptic pathology intersect to promote the progression of depression and AD. The targeting of astrocytic health via the modulation of reactive astrocyte phenotypes, the restoration of glutamate homeostasis, and the enhancement of neurotrophic signaling emerges as a promising therapeutic avenue for alleviating stress-related neurodegeneration and mood disorders.},
}

*Astrocytes/metabolism/pathology
Humans
*Alzheimer Disease/metabolism/pathology/physiopathology
*Stress, Psychological/metabolism/complications
Animals
*Neuroinflammatory Diseases/metabolism
Hypothalamo-Hypophyseal System/metabolism

@article {pmid41956978,
year = {2026},
author = {Vanderlip, CR and Salim, H and Houle, A and Cortes, A and Virovka, A and Liang, Y and Luc, K and Kellogg, A and Stark, CEL},
title = {Attentional Deficits Do Not Explain Age-Related Impairments on the Mnemonic Similarity Task.},
journal = {Hippocampus},
volume = {36},
number = {3},
pages = {e70095},
doi = {10.1002/hipo.70095},
pmid = {41956978},
issn = {1098-1063},
support = {R01AG066683/AG/NIA NIH HHS/United States ; P30AG066519/AG/NIA NIH HHS/United States ; T32AG00096/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Aged ; Male ; *Aging/psychology/physiology ; *Attention/physiology ; Female ; Middle Aged ; Neuropsychological Tests ; Aged, 80 and over ; Adult ; Young Adult ; Discrimination, Psychological/physiology ; *Memory/physiology ; },
abstract = {The Mnemonic Similarity Task (MST) is increasingly used to assess mnemonic discrimination and has become a valuable tool for detecting subtle cognitive decline in aging and early Alzheimer's disease. Although designed to target hippocampal function, it is unlikely to be immune to attentional effects, leading to the possibility that age-related declines in the MST stem from attention rather than mnemonic impairments. Across three experiments, we found that attentional measures or modulations did not account for a substantial portion of age-related variance in mnemonic discrimination, underscoring that age-related deficits in the MST primarily reflect declines in memory and strengthening the MST's validity as a marker of hippocampal function.},
}

Humans
Aged
Male
*Aging/psychology/physiology
*Attention/physiology
Female
Middle Aged
Neuropsychological Tests
Aged, 80 and over
Adult
Young Adult
Discrimination, Psychological/physiology
*Memory/physiology

@article {pmid41956990,
year = {2026},
author = {Futhey, NC and Vila-Rodriguez, F and Stochmanski, SJ and Gregory, E and Honer, WG and Arranz, B and Ramos, B and Escanilla, A and Vera-Montecinos, A and Cembrowski, MS and Hirsch-Reinshagen, V},
title = {Integrated clinical and postmortem profiling in schizophrenia reveals a cognitive subtype linked to cerebrovascular disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-03984-w},
pmid = {41956990},
issn = {2158-3188},
support = {480946//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; },
abstract = {Cognitive impairment is a core feature of schizophrenia with an unknown neuropathological basis. In older adults with schizophrenia, contributions of Alzheimer's pathology and cerebrovascular disease (CVD) to specific neurocognitive deficits remain largely unexplored. This study investigated the relationship between postmortem neuropathology and neuropsychological performance in 55 older adults with schizophrenia (mean age 78.2 years), providing the most detailed clinicopathologic correlation study in schizophrenia to date. Overall, 70% of the sample met criteria for cognitive impairment, but remarkably nearly half of this cognitively impaired group lacked neuropathological autopsy findings that could explain their symptoms. While the prevalence of postmortem Alzheimer's pathology (35.1%) was similar to rates in the general population, CVD pathology was more frequent (84.2%) and associated with lower Mini-Mental State Examination (MMSE) scores (p < 0.001). No other pathology-cognition relationships were observed. Clustering analysis based upon cognitive testing scores alone identified three subgroups (NCOG_1, NCOG_2, and NCOG_3) with distinct cognitive profiles despite similar postmortem neuropathology findings. NCOG_2 exhibited relatively spared cognition (mean MMSE = 26/30) and a significantly younger age at death. Interestingly, at our level of sample depth, the MMSE-CVD association was specific to only the NCOG_3 cluster, which exhibited more selective impairments, implicating vascular pathology in at least one distinct cognitive phenotype of schizophrenia. Our data suggest a novel clinicopathologic association between CVD pathology and cognitive impairment in schizophrenia and that targeted interventions to reduce cardiovascular risk may offer meaningful cognitive benefits in a specific schizophrenia patient subgroup.},
}

@article {pmid41956992,
year = {2026},
author = {Papapanagiotou, O and Cotton, K and Edwards, C and Michod, D and Crompton, L and Craig, T and Niklison-Chirou, MV},
title = {Lipid droplets in neurodegenerative diseases: pathological drivers and therapeutic vulnerabilities.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03096-w},
pmid = {41956992},
issn = {2058-7716},
abstract = {Lipid droplets (LDs) are dynamic intracellular organelles traditionally associated with energy storage, which have become increasingly recognised for their versatile roles in cellular metabolism and signalling. In the brain, LDs have emerged as critical regulators in neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Hereditary Spastic Paraplegia (HSP). LDs contribute to neurodegeneration by influencing lipid metabolism, oxidative stress, and inflammatory responses. For instance, in AD, dysregulated lipid metabolism and impaired Apolipoprotein E 4 (ApoE4) function lead to LD accumulation associated with neuroinflammation and amyloid plaque formation. In PD, interactions between LDs and α-synuclein suggest a potential link between lipid dysregulation and neurotoxicity. Mutations in LD-associated proteins, such as spastin and DDH2 in HSP, highlight the importance of proper LD regulation for neuronal health. While LD accumulation can be protective by mitigating lipotoxicity, prolonged dysregulation can exacerbate NDD pathology. Targeting LD metabolism, through enhancing lipophagy or modulating LD-associated proteins, represents a promising therapeutic avenue. This review highlights the dual roles of LDs in the brain, acting both neuroprotectively and neurotoxically, and the therapeutic potential of targeting LD dynamics for NDD treatment.},
}

@article {pmid41957047,
year = {2026},
author = {Flo, BK and Skouras, S and Matziorinis, AM and Bashevkin, T and Gaser, C and Koelsch, S},
title = {Stages of objective memory impairment are associated with accelerated brain aging.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41957047},
issn = {2045-2322},
}

@article {pmid41957096,
year = {2026},
author = {Treccarichi, S and Papa, C and Vinci, M and Cosentino, FII and Scalia, G and Mostile, G and Zappia, M and Nicoletti, A and Pennisi, M and Musumeci, A and Chiavetta, V and Di Stefano, V and Piccoli, T and Blandino, V and Tripodi, M and Lanuzza, B and Morreale, M and Cupidi, C and Ferri, R and Lanza, G and Cali, F},
title = {Dissecting genetic variant contributions to neurodegenerative disorders through targeted gene sequencing in a Sicilian population.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-47948-y},
pmid = {41957096},
issn = {2045-2322},
abstract = {Despite the technological advancements in modern genetic diagnosis, customized genetic panels are still frequently employed for diagnostic purposes due to their rapid, efficient, and cost-effective ability to detect genetic variants. In this study, we utilized a customized genetic panel designed to identify genetic variants associated with neurodegenerative disorders. The panel consisted of 61 genes and was applied to a cohort of 186 unrelated individuals diagnosed with different degenerative cognitive and movement disorders. The identified variants were filtered for a minor allele frequency of less than 1% and classified according to the American College of Medical Genetics (ACMG) guidelines. Our results showed that 20.97% of individuals carried at least one likely pathogenic or pathogenic variant, with 35% of those individuals diagnosed with Alzheimer's disease (AD). The positive diagnostic yield of the panel was 16.67%, calculated based on variant zygosity, inheritance pattern, and concordance with the clinical phenotype. Furthermore, 34.41% of the individuals carried variants of uncertain significance (VUS), and 44.62% carried benign variants. Variants have been found only in 58 genes. Among these, 24.14% showed benign variants, 48.28% had VUS, and 27.59% carried pathogenic or likely pathogenic variants. Principal component analysis analysis based on the variables "age at onset" in addition to the phenotypic scores "MMSE" (global cognitive screening test), "IADL" (instrumental activities of daily living), and "ADL" (basic activities of daily living) distributed the individuals associated with the specific disease and variant in the plot. Notably, the individuals showed AD exhibited an average age at onset of 68 ± 12.5 years and were differentiated in the plot. GBA gene exhibited the highest number of pathogenic variants (9) linked to AD, Parkinson's disease, early onset parkinsonism with epilepsy, fronto-temporal dementia, and mild cognitive impairment. The results highlighted a broad phenotypic heterogeneity associated with genes previously linked to only a limited number of neurodegenerative conditions, underscoring the value of the genetic testing performed. Translationally, although clinical exome sequencing has enabled novel gene discovery in neurodegenerative disorders, targeted genetic panels remain a cost-effective and clinically valuable approach for routine diagnostics. In this context, our study highlights the "real-world" utility and clinical impact of a focused panel-based strategy.},
}

@article {pmid41957314,
year = {2026},
author = {Park, Y and Chae, H and Yoon, E and Kim, Y and Han, JW and Woo, SJ and Yoo, S and Kim, KW},
title = {Restoration of gamma center frequency via personalized entrainment marks cognitive preservation in early Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41957314},
issn = {2509-2723},
support = {NRF-2017R1A5A1014708//National Research Foundation of Korea/ ; RS-2025-02223212//Korea Health Industry Development Institute/Republic of Korea ; },
abstract = {Gamma entrainment shows promise for Alzheimer's disease (AD) treatment in preclinical models, but human trials have yielded heterogeneous results. We hypothesized that the clinical efficacy of gamma entrainment depends on individual neurophysiological receptivity, specifically the capacity for neural circuit plasticity. In this open-label pilot study, we screened 37 individuals and enrolled 16 participants with early AD (CDR 0.5-1.0, amyloid-positive) who completed 12 weeks of home-based flickering light stimulation at individually optimized gamma frequencies (32-40 Hz). Pre- and post-intervention assessments included 64-channel EEG recordings and MMSE. Participants demonstrated dichotomous neurophysiological responses: 43.8% showed center frequency (CF) increase (increased CF [ICF+]) while 56.3% showed no change/decrease (non-increased CF [ICF-]). CF restoration was significantly associated with cognitive preservation (r = 0.52, p = 0.039). Notably, future responders exhibited distinct baseline signatures of "neural reserve," characterized by higher temporal gamma power (Cohen's d = 0.70-0.92) and stronger frontotemporal connectivity (Cohen's d = 1.11-1.47). Almost 30% of screened candidates failed to show baseline entrainment, highlighting a distinct "non-responsive" biological subtype. CF restoration following personalized gamma entrainment identifies a neurophysiological subtype capable of meaningful plasticity. Rather than a universal remedy, gamma entrainment appears to act on specific neural substrates preserved in a subset of patients. These findings suggest that baseline electrophysiological profiling could unlock gamma entrainment's therapeutic potential by stratifying likely responders for precision neuromodulation.},
}

@article {pmid41946900,
year = {2026},
author = {Wunderlin, M and Wicki, K and Teunissen, CE and Züst, MA},
title = {Deep sleep slow wave-spindle coupling is selectively linked to plasma amyloid-β levels in older adults in clinical trials.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41946900},
issn = {2045-2322},
support = {215333/WT_/Wellcome Trust/United Kingdom ; 2018-PI02 & 2021-CDA03//Stiftung Synapsis - Alzheimer Forschung Schweiz AFS/ ; 215333/WT_/Wellcome Trust/United Kingdom ; 215333/WT_/Wellcome Trust/United Kingdom ; 215333/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Humans ; *Amyloid beta-Peptides/blood ; Aged ; Male ; Female ; *Sleep, Slow-Wave/physiology ; Biomarkers/blood ; Cognition/physiology ; Aged, 80 and over ; Peptide Fragments/blood ; Alzheimer Disease/blood/physiopathology ; },
abstract = {Slow wave activity, the signature of deep/slow wave sleep, has consistently been linked to amyloid-beta (Aβ), a biomarker of neurodegeneration. Less is known about how Aβ relates to specific microstructural processes within slow wave sleep, such as the coupling of slow waves and spindles, where better functioning reflects younger age, increased memory, and less brain atrophy. Here, we pooled and re-analyzed data from three clinical trials where participants underwent an adaptation night, a baseline night and a three-night acoustic stimulation intervention to boost slow wave activity. The baseline analysis included 47 older adults (agemean = 70.5 (0.68)) with varying cognitive functioning, whereas the intervention analysis was conducted on a subsample of 39 older adults (agemean = 70.5 (0.74)) with varying cognitive functioning. Blood samples post-baseline and post-intervention were analyzed for Aβ 1-42/1-40-ratio. Irrespective of cognitive functioning, slow wave-spindle coupling was the best predictor for baseline Aβ, better than slow wave activity, age or cognitive functioning. Specifically, better Aβ-levels were linked to a coupling physiology resembling a younger brain. While intervention-induced increases in slow wave activity were linked to a beneficial Aβ-response across all cognitive levels, increases in slow wave-spindle coupling benefited Aβ-response exclusively in cognitively impaired individuals. Our results suggest a link between SW-spindle coupling and Aβ going beyond slow wave activity. This hints towards a potential specific function of SW-spindle coupling related to the early pathophysiology of Alzheimer's disease.},
}

Humans
*Amyloid beta-Peptides/blood
Aged
Male
Female
*Sleep, Slow-Wave/physiology
Biomarkers/blood
Cognition/physiology
Aged, 80 and over
Peptide Fragments/blood
Alzheimer Disease/blood/physiopathology

@article {pmid41946975,
year = {2026},
author = {Evans, TE and Harper, J and Salehi, A and Webb, AG and Cole, JH and Correa, A and Adams, HHH and Cash, DM and Jones, DK},
title = {The potential of low-field MRI for global dementia care.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {41946975},
issn = {1759-4766},
abstract = {With elderly populations increasing in many countries, rates of Alzheimer disease and related dementias (ADRD) are expected to rise worldwide in the coming years. Low-income and middle-income countries, where barriers to health care are most pronounced and research representation is limited, are predicted to experience the greatest increases in ADRD prevalence. Access to advanced diagnostic and research tools, such as neuroimaging, is severely restricted in these regions, but low-field MRI is emerging as a promising, accessible alternative to conventional imaging. By reducing infrastructure, cost and siting requirements, low-field MRI offers a potential pathway to expand access to dementia-relevant imaging beyond specialized centres. In this article, we summarize key structural imaging biomarkers in ADRD and review the current literature supporting the use of low-field MRI in the ADRD field. We highlight the utility of low-field MRI for the assessment of regional atrophy and cerebrovascular lesion burden and discuss emerging diffusion-based markers. We also consider challenges and future directions, offering insights to advance equitable access to diagnostic imaging, guide research priorities and support global implementation of low-field MRI in ADRD care and investigation.},
}

@article {pmid41946988,
year = {2026},
author = {Zhang, J and Liu, Z},
title = {Don't rush use of lymphatic surgery in Alzheimer's disease.},
journal = {Nature},
volume = {652},
number = {8109},
pages = {534},
doi = {10.1038/d41586-026-01093-8},
pmid = {41946988},
issn = {1476-4687},
}

@article {pmid41947394,
year = {2026},
author = {Li, H and Zhao, Y and Luo, Y and Bao, B and Hao, J and Duan, S and Liu, Z},
title = {Goat Milk Fat Globule Membrane Supplementation Ameliorates Alzheimer Disease Cognitive Impairment by Modulating the Gut Microbiota.},
journal = {Journal of agricultural and food chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jafc.5c11966},
pmid = {41947394},
issn = {1520-5118},
abstract = {Research has found Alzheimer disease (AD) is accompanied by cognitive dysfunction and gut microbiota imbalance. Goat milk fat globule membrane (GMFGM) derived from goat milk, is a membrane primarily composed of proteins and polar lipids that regulates the gut microbiota. However, its role in AD remains unclear. Therefore, we examined the neuroprotective effects of GMFGM in 5xFAD mice. Supplementation with GMFGM (400 mg/kg bw, 8 weeks) improved cognitive performance, reduced brain Aβ deposition, alleviated neuroinflammation, and upregulated neurotrophic factors. Moreover, GMFGM preserved gut barrier integrity, lowered serum LPS levels, and reshaped gut microbiota composition, decreasing Alistipes, Dorea formicigenerans, and Duncaniella dubosii while increasing Stenotrophomonas. Further fecal microbiota transplantation validated the mechanism by which GMFGM ameliorates AD cognitive impairment by modulating the gut microbiota. These results indicate that GMFGM may rescue cognition by modulating the gut microbiota, alleviating gut damage, reducing LPS levels, and consequently inhibiting neuroinflammatory.},
}

@article {pmid41947612,
year = {2026},
author = {Kim, AR and Yoo, YJ and Bak, EJ},
title = {Alteration in oral and non-oral tissues in ligature-induced periodontitis mice with the Alzheimer's disease risk factor APOE4.},
journal = {European journal of oral sciences},
volume = {},
number = {},
pages = {e70091},
doi = {10.1111/eos.70091},
pmid = {41947612},
issn = {1600-0722},
support = {//National Research Foundation of Korea/ ; NRF-2021R1I1A1A01044714//Korea government (MSIT)/ ; },
abstract = {The APOE4 gene, particularly the ε4 allele, is linked to susceptibility to Alzheimer's disease, and periodontitis can cause pathological changes in multiple organs, but combined effects of these conditions and the impact of tumor necrosis factor (TNF)-α regulation on the combined effects remain unclear. We examined the alterations in oral and non-oral tissues in APOE4-knockin mice with periodontitis and evaluated the effects of infliximab, a TNF-α inhibitor. Mice were grouped as control, periodontitis, APOE4-knockin, APOE4-knockin with periodontitis, infliximab-treated periodontitis, and infliximab-treated APOE4-knockin with periodontitis. There were no differences in alveolar bone volume and periodontal inflammatory cells among all periodontitis-induced groups. The APOE4-knockin with periodontitis group showed a decrease in hippocampal Cornu Ammonis 1 neurons (p < 0.05) and increased renal and hepatic fibrosis (p < 0.05) compared to control group. The infliximab-treated APOE4-knockin with periodontitis group had even greater neuronal loss (p < 0.001) and renal fibrosis (p < 0.01). Glial fibrillary acidic protein mRNA expression, a marker of astrocyte activation, was higher in the infliximab-treated APOE4-knockin with periodontitis group than in the control group. These suggest that APOE4 with periodontitis worsens neuronal loss and renal and hepatic fibrosis, and TNF-α inhibition in this coexistence may have harmful effects on both the brain and kidney.},
}

@article {pmid41947717,
year = {2026},
author = {Guo, ZX and He, XY and Ge, YJ and Zhao, B and Huang, LY and Chen, SD and Fu, Y and Gao, PY and Sheng, ZH and Huang, YM and Li, QY and Tan, L},
title = {Gene-Environment Interactions for Alzheimer's Disease Pathology in Cognitively Normal Adults: The CABLE Study.},
journal = {European journal of neurology},
volume = {33},
number = {4},
pages = {e70558},
doi = {10.1111/ene.70558},
pmid = {41947717},
issn = {1468-1331},
support = {82271475//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/cerebrospinal fluid/epidemiology ; Male ; Female ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; *Gene-Environment Interaction ; tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Middle Aged ; Risk Factors ; Peptide Fragments/cerebrospinal fluid ; Life Style ; Amyloidosis/genetics/cerebrospinal fluid/pathology ; Aged, 80 and over ; },
abstract = {BACKGROUND: Characterizing the gene-environment interactions with early pathological changes in Alzheimer's disease (AD) is critical to precision medicine.

METHODS: We recruited 1007 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Multiple linear regression models were applied to explore the associations between polygenic risk scores (PRSs) and cerebrospinal fluid (CSF) biomarkers of AD, the interactions between PRSs and potentially modifiable risk factors, and the relationships between lifestyle categories and CSF AD biomarkers.

RESULTS: A higher AD-PRS was associated with more severe amyloidosis, as indicated by pTau/Aβ42 (β = 0.091, p = 0.005) and tTau/Aβ42 (β = 0.092, p = 0.004). There were significant interactions between AD-PRS and three modifiable risk factors (anemia, gingivitis, and anxiety) in AD biomarker ratios. Stratified analyses by AD-PRS indicated that anemia was associated with higher pTau/Aβ42 and tTau/Aβ42 in the first and second quartiles, while gingivitis and anxiety correlated with amyloidosis in the fourth quartile (all p < 0.05). Additionally, a favorable lifestyle was associated with milder amyloidosis in the high genetic risk group.

CONCLUSIONS: AD-PRS was associated with amyloidosis severity. The associations between modified risk factors (anemia, gingivitis, and anxiety) and biomarker ratios differed by genetic risk strata. Moreover, a healthy lifestyle was associated with less amyloid burden in individuals with high genetic risk. These findings can be used to generate hypotheses for future longitudinal studies to investigate whether targeted management of these factors influences AD pathological progression.},
}

Humans
*Alzheimer Disease/genetics/pathology/cerebrospinal fluid/epidemiology
Male
Female
Aged
Amyloid beta-Peptides/cerebrospinal fluid
*Gene-Environment Interaction
tau Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Middle Aged
Risk Factors
Peptide Fragments/cerebrospinal fluid
Life Style
Amyloidosis/genetics/cerebrospinal fluid/pathology
Aged, 80 and over

@article {pmid41947851,
year = {2026},
author = {Li, Z and Fu, J and Pu, J and Qian, Y and Gai, X and Li, L},
title = {The cerebro-pelvic axis: a unified framework linking higher brain function, pelvic floor control, and lower urinary tract dysfunction.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1773086},
pmid = {41947851},
issn = {1662-4548},
abstract = {Clinical practice often treats higher brain disorders (e.g., Alzheimer's disease and prolonged disorders of consciousness) and pelvic floor dysfunction (e.g., stress urinary incontinence and overactive bladder) as unrelated problems, despite frequent co-occurrence and overlapping vulnerability contexts (e.g., aging, frailty, medications). Here, "axis" denotes a control-architecture mapping and phenotyping heuristic for LUT control and pelvic-floor outlet coordination, rather than a claim of new anatomy or shared etiology. Accordingly, we use a hypothesis-generating control-loop framing that links descending executive control with ascending interoceptive signaling to account for this clinicobiological mismatch. Within this framework, two provisional working failure-mode categories: top-down disintegration, in which impaired supraspinal control weakens volitional inhibition and shifts continence toward reflex-dominant regulation; and bottom-up disturbance, in which persistent peripheral salience-like signals may up-weight interoceptive processing and contribute to maladaptive central network adaptations. These categories are LUT-focused working categories and are not intended as a comprehensive taxonomy of all LUT phenotypes. We further introduce Coordinated Axis Neuromodulation (CAN) as a hypothesis-driven intervention concept that temporally couples cortical, spinal, and peripheral stimulation and may facilitate control-loop-level rebalancing compared with single-node modulation; this proposal requires direct empirical validation. This framework yields testable predictions, including directionally specific coupling between cortical biomarkers (e.g., executive/salience network metrics) and peripheral readouts (e.g., pelvic-floor EMG timing indices and/or diary-defined urgency/UUI burden; urodynamics as supportive phenotyping/secondary mechanistic data when included), and differential response profiles of CAN protocols across failure-mode-stratified cohorts. We outline a validation route spanning synchronized neurophysiology-pelvic physiology paradigms (e.g., EMG timing and diary endpoints; urodynamics as supportive phenotyping/secondary mechanistic data when included), proof-of-mechanism studies, and safety-monitored, mechanism-oriented RCTs designed to falsify or refine the CPA/CAN hypothesis.},
}

@article {pmid41947859,
year = {2026},
author = {Licatini, LM and Licatini, LM and Haddadin, FA and Conklin, GC and Badhwar, A and Sarsoza, FM and Sukreet, S and Winston, CN},
title = {Pre-analytical characterization of CNS-derived extracellular vesicles from human saliva: effect of room temperature and cellular origin.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1765229},
pmid = {41947859},
issn = {1662-4548},
abstract = {INTRODUCTION: Blood-derived extracellular vesicles (EVs) from neurons and astrocytes carrying Alzheimer's disease (AD) biomarkers can predict progression from mild cognitive impairment (MCI) to AD; however, their potential in saliva remains largely unexplored. Saliva-derived extracellular vesicles (sEVs) represent a promising non-invasive biomarker source for AD and other age-related dementias (ADRD), but progress has been limited by a lack of standardized protocols for saliva collection, storage, and central nervous system (CNS)-derived EV isolation.

METHODS: This study had two primary objectives: (1) to optimize enrichment of CNS cell-specific sEVs from the same individuals, and (2) to evaluate the impact of cellular origin and storage temperature (room temperature, 4°C, -20°C) on the stability and quantification of AD-related biomarkers and inflammatory cytokines. Saliva was collected via passive drool from participants in the Nathan Shock Healthy Aging Study (mean age 71.3 years; n = 15). EVs of neuronal, astrocytic, microglial, and oligodendrocyte origin were isolated using ExoQuick-TC precipitation followed by magnetic bead immunocapture. Executive function and attention were assessed using the NIH Toolbox Cognition Battery. Biomarkers were quantified using high-sensitivity immunoassays (MSD, SIMOA Qunaterix).

RESULTS: Astrocyte-derived EVs demonstrated significant enrichment of key AD biomarkers, including Aβ40, Aβ42, and total tau. Phosphorylated tau (p-tau217) was largely undetectable across all fractions. TDP-43 was most abundant in EV-depleted saliva, while inflammatory cytokines were broadly distributed across all fractions. Storage temperature did not consistently alter biomarker levels; however, -20°C storage yielded optimal biomarker quantification. Importantly, lower levels of inflammatory cytokines (IFN-γ, IL-10, and IL-6) in EV-depleted saliva were associated with better working memory performance.

DISCUSSION: This study provides proof-of-concept validation for the characterization and comparison of multiple CNS-derived salivary EV fractions within the same individuals. The findings support saliva as a feasible, non-invasive matrix for assessing neurodegenerative and neuroinflammatory biomarkers. Establishing a standardized methodology for salivary EV isolation and storage lays the groundwork for future longitudinal studies aimed at diagnosing and predicting AD progression using saliva-based biomarkers.},
}

@article {pmid41947888,
year = {2026},
author = {McKinstry, D and Shi, Z and Ramos-Rolón, AP and Phillips, J and Das, S and Li, X and Hager, NM and Pond, T and Volkow, ND and Kranzler, HR and Dubroff, JG and Nasrallah, IM and Wiers, CE},
title = {Hippocampal Volume and Brain Tau Pathology in Opioid Use Disorder: Associations with Non-Fatal Opioid Overdose.},
journal = {Addiction neuroscience},
volume = {19},
number = {},
pages = {},
pmid = {41947888},
issn = {2772-3925},
abstract = {Opioid use disorder (OUD) is associated with high rates of overdose (OD)-related morbidity and mortality. OD can cause hypoxic-ischemic injury to oxygen-sensitive brain regions such as the hippocampus. Post-mortem studies show Alzheimer's disease-like hyperphosphorylated tau pathology in the brains of individuals with OUD. Neurocognitive impairments in individuals with OUD may reflect incipient dementia and contribute to poor clinical outcomes. Alternatively, OUD and OD could be independent risk factors for Alzheimer's disease. To date, no study has evaluated the effects of non-fatal ODs or chronic OUD on hippocampal volume and tau deposition in the human brain in vivo. To fill this gap, we examined hippocampal volumes in OUD individuals (n=60) and healthy controls (HC, n=30) using T1-weighted magnetic resonance imaging (MRI). We found lower bilateral hippocampal volumes in OUD patients than HCs (p<0.001), but no differences between OUD individuals with a history of OD and those without (NOD) (p=0.92). We measured brain tau deposition using Positron Emission Tomography (PET) with [[18]F]PI-2620 in n=4 HC, n=4 OUD-NOD, and n=4 OUD-OD individuals, and found no difference in brain tau between groups. Functional MRI assessment of episodic memory showed no differences in memory performance or hippocampal activity between groups, although OUD-OD individuals had poorer performance than HC with a medium effect size (d=0.56). In summary, we confirm prior findings of smaller hippocampal volumes in participants with OUD than in HC. However, with a limited sample size, our findings do not show evidence of brain tau deposition in OUD participants with or without OD histories.},
}

@article {pmid41947971,
year = {2026},
author = {Arreguín-Cano, JA and Santana-Delgado, SA and Villegas-Mercado, CE and Orozco-Molina, GG and González-Acosta, A and Bermúdez, M},
title = {Linking inflammation, metabolic dysfunction, and neurodegeneration: a comprehensive review of TLR2 pathways in type 2 diabetes.},
journal = {Frontiers in clinical diabetes and healthcare},
volume = {7},
number = {},
pages = {1791782},
pmid = {41947971},
issn = {2673-6616},
abstract = {Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder increasingly recognized as a systemic inflammatory condition with significant neurological effects. Growing evidence shows that chronic low-grade inflammation (CLGI), insulin resistance, and metabolic imbalance contribute to cognitive decline and the development of neurodegenerative diseases like Alzheimer's and Parkinson's. Toll-like receptor 2 (TLR2), a critical pattern-recognition receptor of the innate immune system, has emerged as an essential molecular link between metabolic dysfunction and neuroinflammation and neuronal damage. This review summarizes current experimental, clinical, and translational evidence on the role of TLR2 in T2DM-related inflammation, mitochondrial dysfunction, lipid imbalance, insulin resistance, and blood-brain barrier (BBB) issues. We explore how ongoing TLR2 activation by internal danger signals and metabolic stressors maintains systemic inflammation and fuels neuroimmune responses via microglial activation and cytokine release, thereby accelerating neurodegenerative processes. Additionally, we discuss new therapeutic strategies targeting TLR2 signaling, including drugs, dietary supplements, and the repurposing of antidiabetic medications with neuroprotective effects. By combining immunometabolic and neurodegenerative pathways, this review highlights TLR2 as a promising target for preventing or reducing diabetes-related cognitive decline neurodegeneration.},
}

@article {pmid41948063,
year = {2026},
author = {Yang, SO and Ahn, J and Jung, YH and Jang, H and Na, DL and Kim, H and Kim, JP and Seo, SW and Kwak, K},
title = {Deep learning-based detection of cerebral microbleeds on 2D T2*-weighted GRE MRI: toward ARIA-H risk assessment in Alzheimer's treatment.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1729422},
pmid = {41948063},
issn = {1663-4365},
abstract = {BACKGROUND: Amyloid-related imaging abnormalities with hemorrhage (ARIA-H) are a key safety concern in anti-amyloid therapies for Alzheimer's disease, as they are radiologically indistinguishable from cerebral microbleeds (CMBs). Accurate detection of CMBs is therefore essential for both treatment eligibility assessment and post-treatment safety monitoring. However, manual identification on 2D T2*-weighted gradient-recalled echo (GRE) MRI is labor-intensive and subject to variability.

OBJECTIVE: To develop and validate an artificial intelligence (AI)-based model for automated CMB detection using only 2D T2*-weighted GRE MRI, which is widely used in clinical settings.

METHODS: We implemented a YOLOv11-based deep learning model, preceded by a novel multi-channel preprocessing pipeline that enhances CMB visibility. The model was trained and tested using a dataset of 758 participants, with expert consensus used as the reference standard.

RESULTS: Using the optimized basic preprocessing with super-resolution (BP + SR) pipeline, the model achieved a lesion-level sensitivity of 0.694, precision of 0.705, and F1-score of 0.699. In patient-level analysis for detecting elevated CMB burden (≥4), the system demonstrated sensitivity of 0.933 and specificity of 0.935, supporting reliable stratification of CMB severity. Regional analysis showed sensitivity of 0.625 for lobar CMBs and 0.627 for deep structures.

CONCLUSION: This study demonstrates the feasibility of robust CMB detection using only 2D T2*-weighted GRE MRI. Based on current performance, we position this system as a decision-support tool for GRE-based CMB screening, in which lesion-level detections may be aggregated to inform patient-level CMB burden relevant to ARIA-H risk stratification, while final ARIA grading and clinical decisions require expert neuroradiological confirmation.},
}

@article {pmid41948064,
year = {2026},
author = {Xu, R and Song, W and Zhang, X},
title = {Interleukin-6, CD8[+] T cells, and Alzheimer's disease: unraveling neuroimmune crosstalk via genetic and mechanistic insights.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1767927},
pmid = {41948064},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with complex interplay between neuroinflammation and immune dysfunction. Interleukin-6 (IL-6), a pleiotropic cytokine, has emerged as a controversial player in AD pathogenesis, with conflicting roles reported in inflammation and neuroprotection. This review synthesizes genetic and mechanistic evidence linking IL-6 to AD, focusing on the mediating role of peripheral immune cells-particularly CD8[+] T cell subsets like CD28[+] CD45RA[-] CD8br absolute counts (AC). We discuss how Mendelian randomization (MR) studies, including our recent work, have clarified causal relationships between IL-6, immune cell phenotypes, and AD risk. Additionally, we explore underlying mechanisms, such as IL-6-driven T cell activation, blood-brain barrier (BBB) modulation, and neuroinflammation resolution. Current controversies, including ethnic heterogeneity in genetic effects and the dual nature of IL-6 in systemic vs. central immunity, are highlighted. Finally, we address translational implications, such as immune cell-based biomarkers and targeted anti-inflammatory therapies, offering perspectives for future research.},
}

@article {pmid41948065,
year = {2026},
author = {Oh, H and Kim, H and Kang, H and Kwon, D and French, L and Park, YH and Youn, YC and An, SS and Kim, S and Kang, S},
title = {Systemic proteomic and organ aging signatures associated with plasma Aβ oligomerization in a Korean cohort: a cross-sectional study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1620991},
pmid = {41948065},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) in the brain, which begins decades before the appearance of clinical symptoms. Blood from AD patients, when spiked with synthetic Aβ, exhibited a higher Aβ oligomerization tendency (OAβT) than the non-AD subjects. OAβT reflected early pathological changes of AD and is considered as a promising blood-based biomarker. However, the mechanism underlying OAβT remained elusive. This study aimed to identify proteomic signatures associated with OAβT and explore its role in AD diagnosis.

METHODS: Forty AD and non-AD subjects from a Korean cohort were divided into four groups based on the disease diagnosis, OAβT values (thresholded at 0.78 ng/mL), and amyloid PET status (A-PET): A-PET-positive AD patients with high or low OAβT values, A-PET-negative non-AD subjects with high or low OAβT values. Using aptamer-based proteomics, 7,288 proteins from plasma samples were quantified, and the group differences were assessed in protein levels and the enrichment of gene sets associated with annotations from the Gene Ontology database. Further, we assessed whether OAβT-PET mismatched cases (A-PET-positive but OAβT-low or A-PET-negative but OAβT-high) exhibited distinct blood proteome signatures in comparison to typical AD cases. Aging signatures for 11 organs were analyzed to explore systemic factors linked to OAβT-PET discrepancies. Additionally, the pharmacological influences on the OAβT-related proteome were investigated by comparing OAβT-correlated proteins with a database of drug-induced proteomic changes.

RESULTS: Elevated OAβT values, regardless of AD diagnosis, correlated with increased immune response and decreased cellular metabolism. Dementia-predicting proteins were enriched in non-AD individuals with high OAβT. Accelerated muscle aging was associated with high OAβT values and worse cognitive function. Furthermore, several potential pharmacological modulators of OAβT, including Minocycline and Anamorelin, were identified.

CONCLUSION: Our findings demonstrated OAβT as a reflection of systemic changes linked to early AD pathology. Moreover, the influence of medications and systemic aging on OAβT values pointed to the potential avenues for intervention and emphasized the importance of considering systemic factors in AD pathogenesis and treatment.},
}

@article {pmid41948329,
year = {2026},
author = {Hu, Q and Wang, J and Cao, R and Liu, W and Wang, L},
title = {Therapeutic potential of vagus nerve stimulation in neurodegenerative diseases: research progress and mechanisms.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1811107},
pmid = {41948329},
issn = {1664-3224},
mesh = {Humans ; *Vagus Nerve Stimulation/methods ; *Neurodegenerative Diseases/therapy/etiology ; Animals ; Vagus Nerve ; },
abstract = {Neurodegenerative diseases are a group of chronic, progressive neurological disorders caused by the degeneration and functional loss of neurons and glial cells, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD). Although numerous treatments are available for these diseases, therapeutic outcomes remain unsatisfactory because of their poorly understood pathogeneses of these diseases. Vagus nerve stimulation (VNS), a noninvasive or minimally invasive neuromodulation technique, has shown significant potential in mitigating neurodegenerative conditions. This review explores the mechanisms of action and clinical applications of VNS in neurodegenerative diseases, providing novel insights for the development of novel treatments.},
}

Humans
*Vagus Nerve Stimulation/methods
*Neurodegenerative Diseases/therapy/etiology
Animals
Vagus Nerve

@article {pmid41948388,
year = {2026},
author = {Park, CK and Kang, G and Choi, SJ and Lee, YS and Shin, EC and Kim, HI and Park, J and Oh, NS and Cho, HT and Kim, TG and Pan, JH and Shin, DH and Kim, YJ and Kim, JK},
title = {Sparassis crispa and a Bioactive Compound Therein, Ergosterol, Were Effective in Preventing Acetylcholinesterase Inhibition In Vitro and In Vivo.},
journal = {Food science & nutrition},
volume = {14},
number = {4},
pages = {e71653},
pmid = {41948388},
issn = {2048-7177},
abstract = {Alzheimer's disease (AD) is characterized by multifactorial pathological processes, including cholinergic dysfunction and oxidative stress, highlighting the need for safer, multi-target interventions beyond current synthetic acetylcholinesterase (AChE) inhibitors. In the present study, we screened ethanolic extracts from various edible and medicinal plants to identify natural sources with cholinesterase-modulating activity and found that Sparassis crispa (S. crispa) extract exhibited robust AChE inhibitory activity. The extract also demonstrated significant antioxidant capacity and protected rat pheochromocytoma cells against oxidative stress-induced cytotoxicity. Chemical characterization using gas chromatography-mass spectrometry identified ergosterol as a major bioactive constituent of S. crispa extract. Ergosterol directly inhibited AChE activity in vitro and was subsequently evaluated in vivo using a trimethyltin chloride (TMT)-induced mouse model of cognitive impairment. Dietary supplementation with S. crispa extract significantly improved spatial working memory and attenuated TMT-induced elevation of brain AChE activity. Notably, ergosterol supplementation produced dose-dependent improvements in both spatial working memory and aversive learning, accompanied by restoration of cholinergic function and reduction of lipid peroxidation in brain tissues. No signs of hepatic toxicity were observed following ergosterol administration. Collectively, these findings demonstrate that S. crispa extract exerts cognitive benefits through combined modulation of cholinergic dysfunction and oxidative stress, and identify ergosterol as a key bioactive contributor to these effects. This study provides mechanistic insight into the neuroprotective potential of S. crispa and supports its development, together with ergosterol, as functional food-derived candidates for the prevention or mitigation of cognitive decline.},
}

@article {pmid41948424,
year = {2026},
author = {Liu, Y and Wang, XP},
title = {Potential correlation between chronic pain and amyloid beta in Alzheimer's disease.},
journal = {Frontiers in pain research (Lausanne, Switzerland)},
volume = {7},
number = {},
pages = {1799860},
pmid = {41948424},
issn = {2673-561X},
abstract = {Pain refers to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Chronic pain is a common symptom among Alzheimer's disease (AD) patients. Due to the cognitive impairment characteristic of mid-to-late-stage AD, many AD patients fail to receive timely pain relief, leading to worsening of the disease. Understanding the relationship between chronic pain and the pathological progression of AD is crucial. Previous studies have confirmed a close correlation between pain occurrence and the metabolism of amyloid beta (Aβ) protein, one of the hallmark pathological features of AD. This article provides an overview of recent research progress on the interaction between pain and Aβ, analyzes its molecular mechanisms, and offers new research insights for effectively alleviating pain in AD patients and preventing or treating AD.},
}

@article {pmid41948483,
year = {2024},
author = {Suresh, PN and Kazemivash, B and Jensen, DM and Calhoun, V and Liu, J},
title = {Integrating Neuroimaging and Genetics via Contrastive Learning for Working Memory.},
journal = {... IEEE-EMBS International Conference on Biomedical and Health Informatics. IEEE-EMBS International Conference on Biomedical and Health Informatics},
volume = {2024},
number = {},
pages = {},
pmid = {41948483},
issn = {2641-3590},
abstract = {Understanding working memory's genetic and neural bases is crucial for advancing cognitive neuroscience and identifying biomarkers for cognitive impairments, particularly in the older population. This study integrates SNP and neuroimaging data from the UK biobank to improve the classification of high vs. low working memory capacity and reveal genetic factors associated with brain structure. 1060 SNPs belonging to Protein-Protein Interaction networks of amyloid precursor protein and A β of Alzheimer's disease were integrated with latent features of whole brain gray matter density, extracted by a pre-trained CNN, via supervised contrastive learning. Our model effectively extracts latent representations of both modalities through enhancing genetic-imaging relation within individuals and within working memory groups, in contrast to across individuals and groups. Features derived from contrastive learning outperformed other baseline models in terms of classification. Sparse canonical correlation analysis was applied to the latent representations and uncovered significantly related genetic variants and brain regions. Genetic components highlight SNPs in genes FYN, RPL28, MAPT, enriched in the pathways of dendrite and synapse, among others. The linked brain regions support the cerebellum and striatum's role in cognitive functions. These findings provide new insights into the genetic and neural mechanisms underlying working memory, potentially guiding future research and therapeutic strategies for cognitive impairment.},
}

@article {pmid41948539,
year = {2026},
author = {Luckett, PH and Petersen, M and O'Bryant, S and Mapstone, M and Christian, BT and Handen, B and Head, E and Ances, BM and , },
title = {Application of machine learning to blood-based biomarkers of Alzheimer's disease in Down syndrome.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70325},
pmid = {41948539},
issn = {2352-8729},
abstract = {INTRODUCTION: Blood-based biomarkers can improve Alzheimer's disease (AD) characterization in Down syndrome (DS). This study applied hierarchical clustering and machine learning-based feature selection to identify biomarkers associated with disease progression.

METHODS: Cross-sectional blood-based biomarkers were analyzed from 211 DS participants (n = 79 cognitively stable [CS]; n = 72 mild cognitive impairment [MCI]; n = 60 AD dementia [DS-AD]). These included markers of amyloid, tau, neurodegeneration, and inflammation. Clustering grouped biomarkers. Decision trees classified disease stage, and Shapley values identified the strongest predictors of disease stage.

RESULTS: The strongest predictors overall were neurofilament light chain (NfL), tau/amyloid beta (Aβ)40, Aβ42/Aβ40, alpha-2-macroglobulin (A2M), and interleukin (IL)-10. Within the CS group, NfL, tau/Aβ40, A2M, and IL-10 were strong predictors. In MCI, Aβ42/Aβ40, NfL, A2M, and IL-10 were strong predictors. In DS-AD, Aβ42/Aβ40, NfL, and tau/Aβ40 were the top predictors. Cluster membership varied based on disease stage.

DISCUSSION: These findings reveal evolving biomarker signatures and clustering patterns across cognitive stages, underscoring their potential for disease monitoring.},
}

@article {pmid41948540,
year = {2026},
author = {Khorsand, B and Ghanbarian, E and Rabin, LA and Sajjadi, SA and Ezzati, A},
title = {Incremental value of plasma biomarkers in predicting clinical decline among cognitively unimpaired older adults: Results from the A4 trial.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70321},
pmid = {41948540},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) heterogeneity complicates early detection and trial design. Scalable predictors may aid risk stratification. We assessed whether scalable baseline plasma biomarkers and neuropsychological measures predict 5‑year cognitive and functional decline in cognitively unimpaired older adults.

METHODS: We analyzed 866 amyloid-positive participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and 343 amyloid-negative individuals from the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. Decline was defined as a ≥0.5 increase in Clinical Dementia Rating-Global Score over 240 weeks. The separate and joint value of demographics, apolipoprotein E (APOE) ε4, amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR), plasma phosphorylated tau-217 (p-tau217), and Preclinical Alzheimer's Cognitive Composite (PACC) were assessed. A sub-study of 656 participants evaluated added value of plasma amyloid beta (Aβ)42/Aβ40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).

RESULTS: The p-tau217 and PACC significantly improved prediction. Full models achieved areas under the curve (AUCs) of 0.78-0.80 across cohorts. Additional plasma biomarkers offered modest AUC gains (1%-3%).

DISCUSSION: The p-tau217 and PACC enhanced prediction of preclinical decline, supporting their utility in early identification and trial enrichment in AD.},
}

@article {pmid41948549,
year = {2026},
author = {Rodríguez-Rosas, AM and Baldenebro-Félix, DL and Peréz-Villarreal, JM and García-Mena, J and Kawano-Soto, CA and Camberos-Barraza, J and Valdéz-Flores, MA and Calderón-Zamora, L and Angulo-Rojo, CE and Magaña-Gómez, JA and Guadrón-Llanos, AM},
title = {Gut Microbiota Diversity and Function in Adults With Type 2 Diabetes, Alzheimer's Disease, and Both Conditions.},
journal = {International journal of microbiology},
volume = {2026},
number = {},
pages = {5247744},
pmid = {41948549},
issn = {1687-918X},
abstract = {INTRODUCTION: Type 2 diabetes mellitus (T2DM) is known to increase the risk of Alzheimer's disease (AD), but the role of the gut microbiota in this relationship is not fully understood. This study investigated the gut microbiota profiles of adults with T2DM, adults with AD, both conditions (AD-T2DM), and healthy controls to identify patterns associated with metabolic and neurodegenerative conditions.

METHODS: A cross-sectional study was conducted with 148 participants divided into six groups: CTRL < 60 years, CTRL ≥ 60 years, T2DM < 60 years, T2DM ≥ 60 years, AD, and AD-T2DM. Clinical assessments and 16S rRNA gene sequencing of fecal samples were performed to analyze microbial diversity and composition.

RESULTS: Compared with controls, older adults with T2DM, AD, and AD-T2DM presented reduced microbial diversity and distinct microbial compositions. Notably, SCFA-producing genera (Veillonella and Dialister) decreased in T2DM patients ≥ 60 years, whereas Roseburia and Blautia were more abundant in AD patients and those with AD-T2DM. GDP-mannose biosynthesis was downregulated in AD-T2DM patients.

CONCLUSION: This study highlights changes in the microbiota in T2DM and AD-T2DM patients, suggesting that targeting these microbial alterations could offer new prevention strategies for metabolic-neurodegenerative comorbidities.

SIGNIFICANCE STATEMENT: T2DM and AD share metabolic and inflammatory pathways, yet their combined impact on the gut microbiota remains unexplored. By profiling 148 adults, healthy individuals, those with T2DM, AD, and co-occurring AD-T2DM, using 16S rRNA gene V4 region sequencing, we identified specific dysbiosis in AD-T2DM. Rather than examining T2DM and AD as independent conditions, the present study conceptualizes their coexistence as a metabolic-neurodegenerative interaction state and assesses whether this comorbidity is associated with a distinct gut microbiota composition and predicted functional profile. Therefore, we examine the gut microbiota of adults with AD-T2DM using an age-stratified design in an underrepresented Mexican population, integrating clinical, metabolic, cognitive, taxonomic, and functional data to explore potential mechanisms underlying metabolic-neurodegenerative crosstalk. These findings identify microbial genera that may mediate the "diabeto-neuro" crosstalk, offering novel targets for early intervention and precision microbiota-based therapies to mitigate metabolic-neurodegenerative comorbidity.},
}

@article {pmid41948553,
year = {2026},
author = {Sólyomvári, C and Makkai, G and Capelo-Carrasco, N and Strac, DS and Zelena, D and Farkas, S},
title = {Time-dependent histological characterization of amyloid-β induced cholinergic and glial alterations and their modulation by dehydroepiandrosterone sulfate (DHEAS).},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1764298},
pmid = {41948553},
issn = {1664-2392},
mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; Male ; *Neuroglia/drug effects/pathology/metabolism ; Mice ; *Cholinergic Neurons/drug effects/pathology/metabolism ; Mice, Inbred C57BL ; *Dehydroepiandrosterone Sulfate/pharmacology ; *Alzheimer Disease/pathology/metabolism/drug therapy ; *Peptide Fragments/toxicity ; Microglia/drug effects/pathology/metabolism ; Time Factors ; *Basal Nucleus of Meynert/drug effects/pathology/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by predominant - but not exclusive - pathological accumulation of amyloid-β (Aβ) in the brain. This process affects not only neurons (particularly cholinergic) but also glial cells, contributing to progressive neuronal loss and neuroinflammation. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are endogenous steroids that are hypothesized to exert neuroprotective and anti-inflammatory effects. This study aims to histologically characterize the in vivo temporal progression of Aβ-induced alterations in cholinergic neurons and glial morphology. Our secondary aim was to evaluate whether DHEAS protects cholinergic integrity and, if so, whether this effect is mediated through glial activation.

METHODS: Aβ1-42 was injected into the cholinergic nucleus basalis magnocellularis (NBM) region of C57BL6/J male mice and one hour later 10 mg/kg DHEAS or vehicle (0.9% saline) was applied intraperitoneally. After 3, 12 or 33 days, the mice were transcardially perfused and immunohistochemical staining was used to investigate cholinergic cell (ChAT) and fiber (AChE) loss, as well as microglia (IBA1) and astrocyte (GFAP) morphology.

RESULTS: Our findings confirmed that Aβ peptide exerted neurotoxic effects on the cholinergic system and triggered time-dependent activation in both glia cell types. Microglial cells initiated their response by day 3, adopting an amoeboid morphology, whereas delayed astrocytic reactivity was observed between days 3 and 12, demonstrated by increased ramification. DHEAS treatment preserved cholinergic fiber density, without effecting the number of cell bodies and modulated the inflammatory responses of glia cells, by decreasing the area occupied and number of microglia in a time dependent manner.

DISCUSSION: Aβ toxicity exerts time-dependent effects on both cholinergic neurons and glia cells, while DHEAS shows therapeutic promise, though its efficacy and exact mechanism require further investigation.},
}

Animals
*Amyloid beta-Peptides/toxicity
Male
*Neuroglia/drug effects/pathology/metabolism
Mice
*Cholinergic Neurons/drug effects/pathology/metabolism
Mice, Inbred C57BL
*Dehydroepiandrosterone Sulfate/pharmacology
*Alzheimer Disease/pathology/metabolism/drug therapy
*Peptide Fragments/toxicity
Microglia/drug effects/pathology/metabolism
Time Factors
*Basal Nucleus of Meynert/drug effects/pathology/metabolism

@article {pmid41948610,
year = {2026},
author = {Naim, A and Farooqui, AM and Badruddeen, and Khan, MI and Akhtar, J and Ahmad, A and Ashique, S and Islam, A},
title = {Nanoengineered phytochemicals overcome blood-brain barrier constraints in neurodegenerative disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1792829},
pmid = {41948610},
issn = {1664-2295},
abstract = {Neurodegenerative disorders represent a growing global health burden and remain largely incurable, with current therapies providing only symptomatic relief and limited disease modifications. A major obstacle to effective treatment is the inability of many neuroprotective agents to reach the brain at therapeutically relevant concentrations due to poor bioavailability and the restrictive nature of the blood-brain barrier. Plant-derived phytochemicals possess well-documented antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activities; however, their clinical translation has been hindered by physicochemical instability, rapid metabolism, and insufficient brain exposure. This review critically examines nanoengineered delivery systems as a strategy to overcome these limitations and enable the effective brain targeting of neuroprotective phytochemicals. By integrating mechanistic insights with preclinical and emerging clinical evidence, we compared lipid-based, polymeric, vesicular, and dendritic nanocarriers, highlighting how particle size, surface chemistry, and ligand functionalization govern blood-brain barrier transport and intracerebral distribution. Particular emphasis is placed on rational design principles that consistently enhance brain bioavailability and therapeutic efficacy across models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and related disorders. Beyond efficacy, we analyzed key translational challenges, including nanocarrier-associated neurotoxicity, standardization of herbal activities, and regulatory gaps unique to herbal nanomedicines. Collectively, this synthesis reframes nano-phytomedicine not as an incremental formulation upgrade but as a design-driven strategy capable of unlocking the therapeutic potential of phytochemicals for neurodegenerative disease management.},
}

@article {pmid41948713,
year = {2026},
author = {Swamy, A and Agrawal, DK},
title = {Enhancing Early Diagnosis: Multimodal AI Approaches for Neurodegenerative Diseases.},
journal = {Journal of biotechnology and biomedicine},
volume = {9},
number = {1},
pages = {67-76},
pmid = {41948713},
issn = {2642-9128},
abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's impose a staggering global burden, yet timely identification remains hindered by a fundamental mismatch between the slow unfolding of pathology and the static nature of traditional diagnostic frameworks. While conventional clinical markers often fail to identify decline until irreversible neuronal loss has occurred, artificial intelligence (AI)-driven biomarkers derived from neuroimaging, electrophysiology, and digital phenotyping offer a transformative proactive paradigm. This review evaluates how machine-learning models extract high- dimensional, subvisual patterns from MRI, PET, and EEG datasets to detect preclinical deviations that outpace traditional markers in predictive timelines. We argue that the primary value of these technologies lies in a categorical shift toward continuous, temporally informed disease modeling designed to fill the "detection gap" between early protein accumulation and overt clinical impairment. By synthesizing evidence across various modalities, we highlight the superior performance of multimodal fusion architectures in capturing the biological complexity of neurodegeneration. However, clinical translation faces significant hurdles, including data heterogeneity, the "black-box" nature of deep learning, and the necessity for global equity in dataset representation. Ultimately, by integrating explainable AI with longitudinal data streams, these biomarkers can redefine neurodegenerative care-transforming diagnosis from a reactive confirmation of damage into a precise tool for risk stratification, trial enrichment, and early therapeutic intervention.},
}

@article {pmid41948730,
year = {2026},
author = {Wang, Y and Duan, J and Zang, L and Sun, T and Lv, H and Liu, F and Ma, X},
title = {Hyaluronic acid: emerging roles and biomaterial innovations in Alzheimer's and Parkinson's disease therapy.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1772172},
pmid = {41948730},
issn = {1663-9812},
abstract = {Hyaluronic acid (HA) is a key component of the extracellular matrix (ECM). Owing to its anti-inflammatory properties, biocompatibility and ability to contribute to ECM remodeling, HA is considered a promising therapeutic candidate for neurodegenerative diseases. This review summarizes the application of HA to treat Alzheimer's disease (AD) and Parkinson's disease (PD) and outlines the current understanding of the mechanism of action and strategies for HA-based biomaterial modification. For AD, HA is involved in several mechanisms including stabilizing the perineuronal net, reducing the toxic effects of Aβ and hyperphosphorylated tau, and modulating neuroinflammation through CD44/RHAMM signaling pathways. HA-based nanoparticles and hydrogels enhance drug delivery across the blood-brain barrier, facilitate Aβ clearance, and enable sustained, controlled release of therapeutic agents. In PD, HA regulates autophagic flux, inhibits α-synuclein propagation, and remodels the ECM to protect dopaminergic neurons. Modifications such as HA hydrogels with neurotrophic factors improve cell transplantation outcomes, while conjugates enhance mitochondrial targeting and dopamine delivery. While numerous preclinical studies have shown promise, significant challenges remain, including the high variability of HA formulations, limited blood-brain barrier penetration efficiency, and a paucity of well-designed clinical trials to validate preliminary findings. Future directions include standardizing laboratory protocols, developing hybrid systems integrating vascular endothelial growth factor and gene therapy, and adopting a patient-specific approach that leverages HA's multi-targeted effects on the nervous system.},
}

@article {pmid41949026,
year = {2026},
author = {Boyd, RJ and Dong, D and Sagar, R and Iliuk, A and Ahmed, W and Androni, X and Porsteinsson, AP and Rosenberg, PB and Lyketsos, CG and Witwer, KW and Mahairaki, V},
title = {Proteomic profiling of brain organoids and extracellular vesicles identifies early Alzheimer's disease biomarkers and drug response heterogeneity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71273},
doi = {10.1002/alz.71273},
pmid = {41949026},
issn = {1552-5279},
support = {1RF1AG083801/GF/NIH HHS/United States ; AGR01054771/AG/NIA NIH HHS/United States ; AGR01050515/AG/NIA NIH HHS/United States ; AGR01046543/AG/NIA NIH HHS/United States ; AGR01071522/AG/NIA NIH HHS/United States ; //The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Extracellular Vesicles/metabolism ; *Organoids/metabolism ; *Proteomics ; *Brain/metabolism/pathology ; Biomarkers/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Male ; Female ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) exhibits high genetic and clinical heterogeneity that limits therapeutic success. Patient-derived brain organoids and their extracellular vesicles (EVs) provide physiologically relevant models to study disease mechanisms and individualized drug responses.

METHODS: We generated the largest brain organoid cohort to date, derived from 30 independent induced pluripotent stem cell (iPSC) lines from AD and control individuals. Comparative proteomic profiling was performed on both organoids and their secreted EVs to capture molecular diversity and treatment effects.

RESULTS: Organoids and EVs consistently recapitulated neuronal proteomic signatures and revealed early alterations in AD-related pathways, including synaptic and neurotransmitter dysfunction. Distinct proteomic responses mirrored individual variability in selective serotonin reuptake inhibitor sensitivity.

DISCUSSION: Integrating organoid and EV data provides a systems-level view of AD pathophysiology and treatment response, positioning this dual-platform model as a cost-effective tool for precision medicine and drug discovery.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/pathology
*Extracellular Vesicles/metabolism
*Organoids/metabolism
*Proteomics
*Brain/metabolism/pathology
Biomarkers/metabolism
Induced Pluripotent Stem Cells/metabolism
Male
Female

@article {pmid41949058,
year = {2026},
author = {Lombardo, FL and Caraglia, N and Lorenzini, P and Vanacore, N and Cappa, SF and Cotelli, M and Iodice, F and Marra, C and Miraglia, F and Pappalettera, C and Perani, D and Quaranta, D and Redolfi, A and Spadin, P and Tagliavini, F and Vecchio, F and Rossini, PM and , },
title = {Mild cognitive impairment-to-Alzheimer's dementia progression risk: the contribution of the Interceptor project.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71204},
doi = {10.1002/alz.71204},
pmid = {41949058},
issn = {1552-5279},
support = {//Italian Ministry of Health/ ; //Italian Medicines Agency/ ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/diagnosis/genetics/pathology ; *Disease Progression ; Male ; Female ; *Alzheimer Disease/diagnosis/diagnostic imaging ; Aged ; Neuropsychological Tests ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; Brain/diagnostic imaging/pathology ; Apolipoproteins E/genetics ; tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Risk Factors ; Electroencephalography ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) is an intermediate stage between normal and pathological brain aging, with 30% to 50% progressing to dementia within 3 to 5 years. Early identification of individuals at high risk of progression is crucial for public health strategies.

METHODS: The INTERCEPTOR project included 398 MCI individuals. Baseline assessment included harmonized procedures for sociodemographic, clinical, neuropsychological, genetic (apolipoprotein E), cerebrospinal fluid (amyloid beta tau), electroencephalogram (brain connectivity), magnetic resonance imaging (hippocampal volumetry), and fluorodeoxyglucose positron emission tomography. The baseline and follow-up were completed by 351 individuals with MCI with neuropsychological tests every 6 months for 3 years.

RESULTS: Dementia developed in 104 individuals (29.6%), including 85 (22.4%) who met core clinical criteria for probable and possible Alzheimer's disease dementia. A Cox model combining clinical and sociodemographic data achieved a concordance index of 72%, which increased to 82% when neuropsychology and biomarkers were added.

DISCUSSION: The INTERCEPTOR nomogram represents a tool for predicting dementia progression risk, supporting public health strategies, including screening for risk assessment and risk/benefit ratio in innovative treatments.},
}

Humans
*Cognitive Dysfunction/diagnostic imaging/diagnosis/genetics/pathology
*Disease Progression
Male
Female
*Alzheimer Disease/diagnosis/diagnostic imaging
Aged
Neuropsychological Tests
Positron-Emission Tomography
Magnetic Resonance Imaging
Amyloid beta-Peptides/cerebrospinal fluid
Aged, 80 and over
Brain/diagnostic imaging/pathology
Apolipoproteins E/genetics
tau Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Risk Factors
Electroencephalography

@article {pmid41949144,
year = {2026},
author = {Pradhan, R and Kumari, S and Singh, AK and Rao, AR and Yadav, Y and Upadhyay, AD and Mehta, PK and Dey, AB and Dey, S},
title = {Blood level of β-amyloid, Tau, and p-Tau in mild cognitive impairment and Alzheimer disease: A follow up study.},
journal = {The Indian journal of medical research},
volume = {163},
number = {2},
pages = {166-173},
doi = {10.25259/IJMR_2164_2025},
pmid = {41949144},
issn = {0971-5916},
mesh = {Humans ; *tau Proteins/blood ; *Amyloid beta-Peptides/blood ; *Alzheimer Disease/blood/pathology/genetics ; *Cognitive Dysfunction/blood/pathology ; Male ; Female ; Aged ; Biomarkers/blood ; Follow-Up Studies ; Disease Progression ; Phosphorylation ; *Peptide Fragments/blood ; Middle Aged ; Aged, 80 and over ; },
abstract = {Background and objectives Deposition of β-amyloid and phosphorylated-tau proteins are major neuropathological abnormality in brain of patients with Alzheimer disease. This study aimed to study the role of various serum protein biomarkers to aid in the diagnosis and progression of Alzheimer disease. Methods Blood samples were collected from 96 patients with Alzheimer disease, 75 patients with mild cognitive impairment, and 70 geriatric controls at baseline. The number of patients (Alzheimer disease and mild cognitive impairment) who progressed after 1 year was 12, while the number of non-progressors was 24. Serum levels of β-amyloid1-42 (Aβ1-42), Tau, and phosphorylated-Tau181 (pTau) were quantified using surface plasmon resonance and further validated by Western blot. Results Comparison of proteins between the three groups revealed significantly lower Aβ1-42, higher Tau and pTau protein expression in serum of patients with Alzheimer disease as compared to patients with mild cognitive impairment and controls. In patients who progressed after one year, the baseline concentration of Aβ1-42 protein was significantly higher than their follow-up levels. Tau and pTau levels also increased significantly over the years. In non-progressors, no significant difference was observed in Aβ1-42, Tau, and pTau concentration between the baseline and follow up. Interpretation and conclusions Aβ1-42, Tau, and pTau proteins can serve as potential blood-based biomarkers for the diagnosis and monitoring the progression of Alzheimer disease.},
}

Humans
*tau Proteins/blood
*Amyloid beta-Peptides/blood
*Alzheimer Disease/blood/pathology/genetics
*Cognitive Dysfunction/blood/pathology
Male
Female
Aged
Biomarkers/blood
Follow-Up Studies
Disease Progression
Phosphorylation
*Peptide Fragments/blood
Middle Aged
Aged, 80 and over

@article {pmid41949488,
year = {2026},
author = {Chen, Y and Zhao, S and Yang, F and Wang, Y and Han, Z and Han, F and Wang, Z and Chen, Z and Sun, K and Liang, P and Li, K},
title = {The interventional effect of acupuncture on overall cognitive function in Alzheimer's disease spectrum disorders: A meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261438495},
doi = {10.1177/13872877261438495},
pmid = {41949488},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) and mild cognitive impairment (MCI) cause progressive cognitive decline, with Western medicine only alleviating symptoms at present. Acupuncture shows potential for these disorders, but existing studies have inconsistent results.ObjectiveTo examine the effect of acupuncture on overall cognitive function in patients with AD and MCI via meta-analysis.MethodLiterature from six databases on acupuncture, AD, and MCI was searched. Meta-analyses and moderator analyses were performed using Comprehensive Meta Analysis V3.0.Results52 randomized controlled trials (RCTs) involving 3362 AD/MCI patients were included. Results showed that acupuncture alone outperformed blank or placebos (SMD=1.09, 95% CI = [0.60, 1.58], p < 0.001, I[2] = 91.39%). In addition, acupuncture alone (SMD = 0.45, 95% CI = [0.22, 0.67], p < 0.001, I[2] = 69.38%) and combined with Western medicine (SMD = 1.18, 95% CI = [0.92, 1.44], p < 0.001, I[2] = 90.73%) were superior to Western medicine alone. Moderator analysis revealed significant effect of type of patients, showing larger effect in AD than MCI in acupuncture combined with Western medicine (Q = 10.20, p = 0.001). Regarding types of acupuncture, manual acupuncture (MA) and electroacupuncture (EA) showed no significant difference between them (alone: Q = 0.38, p = 0.536; combined with Western medicine: Q = 0.57, p = 0.449) and both outperformed Western medicine alone.ConclusionsAcupuncture could improve overall cognitive function in AD and MCI, with similar effects between MA and EA. Due to the heterogeneity and variable methodological quality of the studies included, our results must be interpreted with caution. Still, these results suggest acupuncture may be an adjuvant to Western medicine for eligible patients and a potential alternative for short-term cognitive improvement when Western medicine is contraindicated.},
}

@article {pmid41949889,
year = {2026},
author = {McEvoy, LK and Zhang, B and Nguyen, S and Maihofer, AX and Nievergelt, CM and Casanova, R and Horvath, S and Lu, AT and Davatzikos, C and Erus, G and Resnick, SM and Espeland, MA and Rapp, S and Beckman, K and Ferrucci, L and LaCroix, AZ and Shadyab, AH},
title = {Association of epigenetic age acceleration with MRI biomarkers of aging and Alzheimer's disease neurodegeneration.},
journal = {Aging},
volume = {18},
number = {1},
pages = {303-326},
doi = {10.18632/aging.206369},
pmid = {41949889},
issn = {1945-4589},
abstract = {Epigenetic clocks of biological aging have been associated with cognitive impairment and dementia. Less is known about whether they are associated with an older-appearing brain or with an atrophy pattern associated with dementia. We examined associations of five epigenetic clocks measured at baseline with the Spatial Pattern of Atrophy for Recognition of Brain Aging (SPARE-BA) and the Alzheimer's Disease Pattern Similarity Score (AD-PS) derived from structural MRIs obtained an average of 8 years later among 1,196 older women. Using linear regression models adjusting for relevant covariates, we observed no associations between any epigenetic clock and accelerated brain aging based on SPARE-BA. We observed a significant association between AgeAccelGrim2 and AD-PS (β = 0.015; 95% CI 0.004 to 0.027; p = 0.01). This association appeared to be primarily driven by the association of a DNA methylation marker of smoking pack years with frontal and temporal lobe volumes. AgeAccelGrim2 was not associated with volumes in regions implicated in early AD (hippocampus and entorhinal cortex). Taken together with prior findings, these results suggest that measures of epigenetic and brain age acceleration capture different aspects of biological aging, and that AgeAccelGrim2 is predictive of neurodegenerative changes associated with smoking that increase risk of dementia.},
}

@article {pmid41949989,
year = {2026},
author = {Buchal, A and Dzialas, V and Doering, E and Giehl, K and Bischof, GN and Elmenhorst, D and van Eimeren, T and Drzezga, A and Hoenig, MC and , },
title = {Home-based sleep monitoring reveals associations between amyloid accumulation and sleep alterations in individuals with subjective and mild cognitive impairment.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71326},
doi = {10.1002/alz.71326},
pmid = {41949989},
issn = {1552-5279},
support = {DR 445/9-1//Deutsche Forschungsgemeinschaft/ ; p21059//Alzheimer Forschung Initiative/ ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/metabolism/physiopathology ; Male ; Female ; Aged ; Positron-Emission Tomography ; *Sleep Wake Disorders ; *Sleep/physiology ; Brain/metabolism/diagnostic imaging ; *Amyloid/metabolism ; Aged, 80 and over ; Middle Aged ; },
abstract = {INTRODUCTION: Sleep disturbances have been associated with Alzheimer's disease (AD), but their relevance in preclinical stages, such as subjective cognitive decline (SCD), and their relationship with brain pathology remain unclear.

METHODS: We used a portable sleep-monitoring headband over four consecutive nights to assess sleep in 19 cognitively unimpaired (CU), 15 SCD, and 20 mild cognitive impairment (MCI) participants with available amyloid positron emission tomography (PET). Linear-mixed-effects models compared sleep parameters across groups, accounting for amyloid burden, age, sex, education, and recording. Regional and voxel-wise analyses examined regional associations between sleep parameters and amyloid burden.

RESULTS: MCI patients presented reduced N3 (i.e., deep sleep), while SCD individuals showed longer N1 (i.e., light sleep) duration compared to CU. Regional amyloid burden was associated with longer light and deep sleep in amyloid-positive individuals. Higher education was linked to better sleep efficiency.

DISCUSSION: Sleep changes may serve as early indicators of cognitive dysfunction and regional amyloid accumulation.},
}

Humans
*Cognitive Dysfunction/diagnostic imaging/metabolism/physiopathology
Male
Female
Aged
Positron-Emission Tomography
*Sleep Wake Disorders
*Sleep/physiology
Brain/metabolism/diagnostic imaging
*Amyloid/metabolism
Aged, 80 and over
Middle Aged

@article {pmid41949995,
year = {2026},
author = {Borelli, PV and Machado, L and Carello-Collar, G and Ferreira, PCL and Lourenço de Lima, AMD and Bellaver, B and Pascoal, TA and Benedet, AL and Ashton, NJ and Zimmer, ER and Borelli, WV},
title = {Diagnostic performance of salivary markers of Alzheimer's disease: A systematic review.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71248},
doi = {10.1002/alz.71248},
pmid = {41949995},
issn = {1552-5279},
support = {AACSFD-22-928689/ALZ/Alzheimer's Association/United States ; AARGD-21-850670/ALZ/Alzheimer's Association/United States ; AARFD-22-974627/ALZ/Alzheimer's Association/United States ; 312410/2018-2//CNPq/ ; 435642/2018-9//CNPq/ ; 312306/2021-0//CNPq/ ; 409066/2022-2//CNPq/ ; 21/2551-0000673-0//ARD/FAPERGS/ ; 16/2551-0000475-7//ARD/FAPERGS/ ; 465671/2014-4//Brazilian National Institute of Science and Technology in Excitotoxicity and Neuroprotection/ ; Serra-1912-31365//Instituto Serrapilheira/ ; ALZ-NAN-22-928381//Alzheimer's Association and National Academy of Neuropsychology/ ; 88887.687008/2022-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 5R01AG075336/AG/NIA NIH HHS/United States ; 5R01AG073267/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; *Biomarkers/analysis/metabolism ; *Saliva/chemistry/metabolism ; *Amyloid beta-Peptides/analysis/metabolism ; Sensitivity and Specificity ; Lactoferrin/metabolism ; },
abstract = {High heterogeneity of diagnostic accuracy have been reported for salivary markers of Alzheimer's disease (AD), but the reasons remain unclear. This systematic review aims to evaluate the potential sources of heterogeneity in the diagnostic performance of salivary biomarkers for the identification of AD. We systematically reviewed four databases for studies from inception to 2025. We evaluated biomarker sensitivity, specificity, and area under the curve (AUC). This study was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Of 3118 studies, 18 met the inclusion criteria. AUC data were available only for amyloid beta (Aβ)42 and lactoferrin. Pre-analytical properties were a major source of heterogeneity, comprehending prior orientation, time of collection, recipient material, and centrifugation methods. The main source of variability likely stems from substantial differences in pre-analytical procedures across studies. Further studies on salivary biomarkers in AD implementing standardized protocols are warranted.},
}

Humans
*Alzheimer Disease/diagnosis/metabolism
*Biomarkers/analysis/metabolism
*Saliva/chemistry/metabolism
*Amyloid beta-Peptides/analysis/metabolism
Sensitivity and Specificity
Lactoferrin/metabolism

@article {pmid41950003,
year = {2026},
author = {Scheidemantel, LP and de Paiva Lopes, K and Gaiteri, C and Menon, V and De Jager, PL and Schneider, JA and Buchman, AS and Wang, Y and Tasaki, S and Raittz, RT and Bennett, DA and Vialle, RA},
title = {Integration of aged brain multi-omics reveals cross-system mechanisms underlying Alzheimer's disease heterogeneity.},
journal = {Cell reports},
volume = {45},
number = {4},
pages = {117235},
doi = {10.1016/j.celrep.2026.117235},
pmid = {41950003},
issn = {2211-1247},
abstract = {The molecular correlates of Alzheimer's disease (AD) are increasingly being defined by multi-omics. However, findings from different data types are often difficult to reconcile. Here, we apply a data-driven multi-omics framework integrating seven omics layers from up to 1,358 aged human brain samples from the Religious Orders Study and Rush Memory and Aging Project. We demonstrate sprawling cross-omics biological factors relating to AD phenotypes. The strongest AD-associated factor (factor 8) is characterized by elevated immune activity at the epigenetic level, decreased heat shock gene expression in the transcriptome, and disrupted energy metabolism and cytoskeletal dynamics in the proteome. Unsupervised clustering reveals 11 molecular subtypes, including three AD-associated clusters displaying distinct molecular signatures and phenotypic characteristics. Our findings provide a comprehensive map of molecular mechanisms underlying AD heterogeneity, highlighting neuroinflammatory processes and yielding potential biomarkers and therapeutic targets for precision medicine approaches.},
}

@article {pmid41950014,
year = {2026},
author = {},
title = {Correction to "Effectiveness, safety, and biomarker dynamics of lecanemab in Chinese Alzheimer's disease population: A multicenter real-world study".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71347},
doi = {10.1002/alz.71347},
pmid = {41950014},
issn = {1552-5279},
}

@article {pmid41950049,
year = {2026},
author = {Robb, WH and Kaur, G and Huang, S and Martinez, F and Nguyen, B and Shin, CH and Yang, M and Conyers, CT and Grilli, CB and Upjohn, DP and Ortega, VE and Hohman, TJ and Keegan, RM and Parent, EE and Cogswell, PM and Graff-Radford, J and Johnson, DR and Ramanan, VK and Koran, ME},
title = {Health system patterns of imaging and fluid biomarker testing in the era of anti-amyloid therapies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71343},
doi = {10.1002/alz.71343},
pmid = {41950049},
issn = {1552-5279},
support = {//Alzheimer's Association Clinician Scientist Fellowship (MEK)/ ; K76AG088554/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; Female ; *Alzheimer Disease/drug therapy/diagnostic imaging/cerebrospinal fluid/diagnosis ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid/antagonists & inhibitors ; Retrospective Studies ; Aged ; Positron-Emission Tomography ; Apolipoproteins E/genetics ; Brain/diagnostic imaging ; Middle Aged ; tau Proteins/cerebrospinal fluid/blood ; Aged, 80 and over ; Electronic Health Records ; },
abstract = {INTRODUCTION: Anti-amyloid-β (Aβ) therapies are reshaping Alzheimer's disease (AD) management. Understanding changes in real-world patterns of diagnostic testing and infusion chair usage is essential for optimizing access to care.

METHODS: Retrospective analysis of Mayo Clinic enterprise electronic health records (Jan 2019-Mar 2025) assessed trends in AD-relevant brain imaging, fluid biomarkers, apolipoprotein E (APOE) testing, and lecanemab infusions. Rates of amyloid-beta (Aβ) positivity by sex and age, APOE genotype frequencies, and lecanemab treatment initiation and discontinuation were evaluated.

RESULTS: Following national insurance coverage changes, lecanemab infusions grew by 110 infusions per quarter to 605 in Q1 2025. Aβ positron emission tomography scans increased (+22/quarter), cerebrospinal fluid biomarker orders declined (-25/quarter), and plasma p-tau217 orders rapidly increased (+238/quarter). Females were more likely to be Aβ positive (p < 0.006). APOE-ε4 homozygotes were less likely to initiate lecanemab (HR = 0.11, p < 0.001).

DISCUSSION: The adoption of anti-Aβ therapies coincided with a rapid shift in diagnostic workflows.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
Female
*Alzheimer Disease/drug therapy/diagnostic imaging/cerebrospinal fluid/diagnosis
Male
*Amyloid beta-Peptides/cerebrospinal fluid/antagonists & inhibitors
Retrospective Studies
Aged
Positron-Emission Tomography
Apolipoproteins E/genetics
Brain/diagnostic imaging
Middle Aged
tau Proteins/cerebrospinal fluid/blood
Aged, 80 and over
Electronic Health Records

@article {pmid41950067,
year = {2026},
author = {Kanwal, A and Kerman, BE and Wang, S and Camey, K and Li, B and Flores-Aguilar, L and Ali, N and McIntire, LB and Shu, CA and Louie, SG and Head, E and Arvanitakis, Z and Yassine, HN},
title = {A perspective: PLA2G4A as drug target for vascular inflammation in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71320},
doi = {10.1002/alz.71320},
pmid = {41950067},
issn = {1552-5279},
support = {RF1AG076124/AG/NIA NIH HHS/United States ; R01AG055770/AG/NIA NIH HHS/United States ; R01AG067063/AG/NIA NIH HHS/United States ; R01AG054434/AG/NIA NIH HHS/United States ; R21AG056518/AG/NIA NIH HHS/United States ; P30AG066530/AG/NIA NIH HHS/United States ; R01AG082362/AG/NIA NIH HHS/United States ; P30AG10161/AG/NIA NIH HHS/United States ; P30AG72975/AG/NIA NIH HHS/United States ; R01AG15819/AG/NIA NIH HHS/United States ; R01AG078800/AG/NIA NIH HHS/United States ; R01AG072794/AG/NIA NIH HHS/United States ; GC-201711-2014197//Alzheimer's Drug Discovery Foundation (ADDF;/ ; //Vranos and Tiny Foundations/ ; P50AG05142/NH/NIH HHS/United States ; R01AG074549/NH/NIH HHS/United States ; RF1 AG059621/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Group IV Phospholipases A2/metabolism/antagonists & inhibitors ; *Cerebral Amyloid Angiopathy/drug therapy/metabolism ; *Inflammation/drug therapy/metabolism ; Animals ; },
abstract = {Anti-amyloid therapies for Alzheimer's disease (AD) modestly slow cognitive decline but carry significant risk of amyloid-related imaging abnormalities (ARIAs), brain swelling, and hemorrhage, particularly in apolipoprotein E ε4 carriers. Cerebral amyloid angiopathy (CAA) and vascular inflammation drive this vulnerability, highlighting the need for complementary strategies targeting upstream mechanisms of vascular injury. Cytosolic phospholipase A2 (cPLA2) regulates arachidonic acid and lysophosphatidylcholine-derived lipid signaling at the intersection of amyloid burden, oxylipin dysregulation, blood-brain barrier disruption, and neurovascular inflammation. By depleting protective membrane plasmalogens while amplifying inflammatory lipid mediators, cPLA2 creates a state of vascular vulnerability predisposing to ARIAs. This Perspective article synthesizes evidence from human, preclinical, and translational studies positioning cPLA2 as an upstream driver of CAA-related inflammation and vascular vulnerability in AD. We discuss biomarker and imaging approaches to assess cPLA2 activity in vivo and outline how targeting this pathway may enhance anti-amyloid therapy safety by mitigating ARIA risk.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Group IV Phospholipases A2/metabolism/antagonists & inhibitors
*Cerebral Amyloid Angiopathy/drug therapy/metabolism
*Inflammation/drug therapy/metabolism
Animals

@article {pmid41950270,
year = {2026},
author = {Gonzales, M and Kang, X and Cort, C and Adamson, MM and Chao, SZ and Yoon, BC and , },
title = {White matter microstructure disruption associated with PET and cognitive impairment in Alzheimer's disease.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0346661},
doi = {10.1371/journal.pone.0346661},
pmid = {41950270},
issn = {1932-6203},
mesh = {Humans ; *White Matter/pathology/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging/pathology ; Male ; Female ; *Positron-Emission Tomography ; Aged ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Diffusion Tensor Imaging ; Aged, 80 and over ; Retrospective Studies ; Aniline Compounds ; Ethylene Glycols ; Middle Aged ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is associated with regional brain atrophy as well as elevated positron emission tomography (PET) markers of amyloid-beta (e.g., [[18]F]florbetapir (FBP)) and tau protein (e.g., [[18]F]flortaucipir (FTP). White matter microstructures have also been shown to be disrupted in AD, but there is limited understanding of their specific associations with FBP, FTP, and cognitive impairment. Herein, we used both voxel-based and fixel-based analyses of diffusion tensor imaging (DTI) to characterize microstructural white matter changes associated with PET and cognitive changes in AD. A retrospective study was performed using the data from 381 ADNI-3 participants (F:M = 200:181). FBP and FTP results were correlated with DTI metrics, including the apparent fiber density (AFD), complexity (CX), functional anisotropy (FA), fixel number (FN), and mean diffusivity (MD). Linear regression analysis was performed, adjusted for age, sex, education, and cognitive impairment. Greatest negative correlations were observed between FN and FBP standardized uptake value ratio (SUVR) in 15 out of 18 white matter tracts examined (beta coefficients of -0.3991 to -0.2877). No significant correlation was observed between DTI measures and FTP SUVR, independently. However, combined PET positivity (FBP + /FTP+) generally showed the greatest reductions in CX, FN, and FA of various tracts, compared to single PET-positive or PET-negative groups. Widespread changes in FA were positively associated with cognitive impairment, with stronger associations seen with the Montreal Cognitive Assessment (MoCA) than the Mini-Mental State Examination (MMSE). Only females showed significant correlations between MD and FBP/FTP levels and showed more widespread correlations between FA and MD changes and cognitive impairment. Taken together, these findings suggest specific patterns of white matter microstructure disruption in AD with underlying sex differences and support their potential role as early biomarkers.},
}

Humans
*White Matter/pathology/diagnostic imaging
*Alzheimer Disease/diagnostic imaging/pathology
Male
Female
*Positron-Emission Tomography
Aged
*Cognitive Dysfunction/diagnostic imaging/pathology
Diffusion Tensor Imaging
Aged, 80 and over
Retrospective Studies
Aniline Compounds
Ethylene Glycols
Middle Aged
Amyloid beta-Peptides/metabolism

@article {pmid41950299,
year = {2026},
author = {VanderGiessen, M and Harris, E and Yin, L and Heath, B and Carney, SK and Woodson, CM and Wu, X and Johnson, E and Xie, H and Theus, M and Kehn-Hall, K},
title = {Venezuelan equine encephalitis virus infection causes chronic neurobehavioral outcomes, cellular remodeling, and hippocampal single-cell transcriptomic changes.},
journal = {PLoS pathogens},
volume = {22},
number = {4},
pages = {e1014115},
doi = {10.1371/journal.ppat.1014115},
pmid = {41950299},
issn = {1553-7374},
abstract = {Venezuelan equine encephalitis virus (VEEV), a neuroinvasive alphavirus, can cause significant neurological deficits in humans. Viral infections, including VEEV, have been linked to neurological diseases such as Parkinson's and Alzheimer's, though mechanisms remain unclear. Currently, not only are there no therapeutic options for VEEV available, but there is also limited information on the host responses following infection that contribute to neurological sequelae. To fill this gap in knowledge, longitudinal neuropathological, behavioral, and single-cell transcriptomic changes were examined in C57BL/6 mice intranasally infected with VEEV TC-83. Acute infection significantly altered inflammatory and innate immune single-cell signaling, induced astrocyte and microglia activation, and resulted in the loss of neurons in the hippocampus. Persistent motor dysfunction, memory impairment, and reduced anxiety-like behavior were observed up to 106 days post-infection (DPI) and more significantly in animals that displayed neurological symptoms during acute infection. These changes correlated with alterations in synaptogenic signaling single-cell gene expression, neuron loss, and persistent glia cell activation at 106 DPI. Collectively, this study demonstrates that infection with VEEV induces chronic alterations in the hippocampus that correlate with neurological sequalae observed in human patients.},
}

@article {pmid41950304,
year = {2026},
author = {Dannert, A and Schulz, N and Klimmt, J and Knez, L and Groschup, B and Gonçalves, CC and Carraro, C and Schifferer, M and Brendel, M and Paquet, D},
title = {A human iPSC model of tauopathies engineered for 4R tau isoform expression endogenously develops late-stage neuronal tau pathology.},
journal = {Science translational medicine},
volume = {18},
number = {844},
pages = {eadu9845},
doi = {10.1126/scitranslmed.adu9845},
pmid = {41950304},
issn = {1946-6242},
mesh = {Humans ; *tau Proteins/metabolism/genetics ; *Tauopathies/pathology/metabolism/genetics ; *Induced Pluripotent Stem Cells/metabolism/pathology ; *Neurons/metabolism/pathology ; Protein Isoforms/metabolism ; Phosphorylation ; *Models, Biological ; Mutation/genetics ; },
abstract = {Tauopathies, such as Alzheimer's disease and frontotemporal dementia, are common neurodegenerative diseases characterized by misfolding, hyperphosphorylation, and aggregation of tau. Molecular mechanisms underlying tauopathies are still poorly understood, which is in part due to a lack of human models autonomously developing major disease hallmarks. The formation of late-stage disease phenotypes may require adult tau isoform expression, which contributes to tau pathogenesis but is challenging to replicate in human stem cell-derived systems, thus impeding research on underlying mechanisms and drug development. Here, we show that induction of adult human brain-like 4R tau isoform expression enables cell-intrinsic formation of late-stage tauopathy hallmarks in induced pluripotent stem cell-derived neurons engineered to contain synergistic tau mutations without exogenous sources of tau pathology. Neurons accumulated seeding-competent and hyperphosphorylated tau in tangle-like structures. Furthermore, exclusive expression of mutant 4R in the absence of the 3R tau isoform disproportionately intensified pathology, resulting in abundant tau misfolding and aggregation. Last, we provide proof of principle that our model can be translationally applied both to test chemical disease modulators and evaluate human tau PET tracers. Collectively, our model corroborates the central role of 4R tau isoform expression for pathogenesis in human neurons and enables investigations to elucidate mechanisms underlying human tauopathy formation. Moreover, it may serve as a platform supporting urgently needed development of disease-modifying drugs.},
}

Humans
*tau Proteins/metabolism/genetics
*Tauopathies/pathology/metabolism/genetics
*Induced Pluripotent Stem Cells/metabolism/pathology
*Neurons/metabolism/pathology
Protein Isoforms/metabolism
Phosphorylation
*Models, Biological
Mutation/genetics

@article {pmid41950393,
year = {2026},
author = {Sun, H and Perry, B},
title = {Factors related to cognitive reserve: A comparative analysis of education, occupation, lifestyle, and social network factors based on brain measures.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbag059},
pmid = {41950393},
issn = {1758-5368},
abstract = {OBJECTIVES: Cognitive reserve (CR) refers to the ability to sustain cognitive performance despite age- and disease-related brain changes, which supports prolonged independent living. Prior research suggests that education, occupational complexity, participation in cognitively engaging and social activities, lifestyle factors, and social connectedness may enhance CR. However, few studies directly compare the relative significance of these factors within the same sample, using magnetic resonance imaging (MRI) based brain markers to measure CR. We also examine whether, and to what extent, relatively proximal factors serve as downstream effects of education within a cumulative (dis)advantage framework.

METHODS: We analyzed data from 279 MRI visits from 201 older adults enrolled in the Social Networks and Alzheimer's Disease (SNAD) study, diagnosed as cognitively normal or with mild cognitive impairment. CR was assessed as residual global cognition based on MRI-derived brain measures and demographic covariates. Multivariate models estimated standardized effect sizes for each factor, followed by mediation analyses to assess whether they are downstream of education.

RESULTS: As expected, higher educational attainment was significantly associated with greater CR. Among occupational measures, only complexity with people showed a significant relationship, but this association diminished in fully adjusted models. Cognitive-oriented activities and social network bridging capital were independently associated with CR, while only bridging capital remained significant in fully adjusted models and mediated approximately 11% of the association between education and CR.

DISCUSSION: While early-life education appears fundamental to CR, broader and more diverse social networks are beneficial, partly reflecting downstream effects of education, and may represent a modifiable pathway to promote CR.},
}

@article {pmid41950435,
year = {2026},
author = {Park, SY and Setiawan, VW and Crimmins, EM and White, LR and Haiman, CA and Wilkens, LR and Le Marchand, L and Lim, U},
title = {Plant-Based Dietary Patterns and Risk of Alzheimer Disease and Related Dementias in the Multiethnic Cohort Study.},
journal = {Neurology},
volume = {106},
number = {9},
pages = {e214916},
doi = {10.1212/WNL.0000000000214916},
pmid = {41950435},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/epidemiology/ethnology ; Middle Aged ; *Dementia/epidemiology/ethnology ; Prospective Studies ; Longitudinal Studies ; Cohort Studies ; *Diet, Vegetarian ; Hawaii/epidemiology ; Ethnicity ; Risk Factors ; California/epidemiology ; },
abstract = {BACKGROUND AND OBJECTIVES: Plant-based diets have been linked to slower cognitive decline, but data on long-term dietary changes and from diverse populations are limited. The primary aim of this study was to examine plant-based dietary patterns and their change over time in relation to Alzheimer disease and related dementias (ADRDs).

METHODS: This prospective longitudinal analysis of the Multiethnic Cohort Study, based in Hawaii and California (primarily Los Angeles County), included data on African American, Japanese American, Latino, Native Hawaiian, and White participants who completed food frequency questionnaires at baseline (1993-1996; age 45-75 years) and at 10-year follow-up (2003-2008) and whose Medicare claims were linked to identify incident ADRDs. A priori indices for the overall plant-based diet index (PDI), the healthful plant-based diet index (hPDI), and the unhealthful plant-based diet index (uPDI) were analyzed in Cox regression models for ADRD.

RESULTS: The analysis included 92,849 participants (mean age 59.2 years, 55.1% female, 21,478 with ADRDs) for the baseline diet and 45,065 participants (8,360 with ADRDs) for the 10-year dietary change. For the baseline diet, comparing the highest vs lowest quintile, PDI and hPDI were associated with 12% (hazard ratio [HR] 0.88; 95% CI 0.85-0.92) and 7% (HR 0.93; 95% CI 0.89-0.97) lower risks of ADRD, respectively, whereas uPDI was related to a 6% higher risk (HR 1.06; 95% CI 1.01-1.10). For the dietary change over time, the strongest association with ADRD was observed for uPDI rather than for PDI or hPDI. Compared with those with a stable score (<0.5 SD change), participants with a large increase in uPDI (≥1 SD) showed a 25% higher risk (HR 1.25; 95% CI 1.15-1.36) and those with a large decrease in uPDI showed an 11% lower risk (HR 0.89; 95% CI 0.84-0.94). The associations between the plant-based diet indices and ADRD were generally similar by age group (<60 vs ≥60 years at baseline), race and ethnicity, or APOE ℇ4 carrier status.

DISCUSSION: These findings suggest that adopting plant-based diets, specifically refraining from low-quality plant-based diets, even at an older age, is associated with a lower risk of ADRDs.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/epidemiology/ethnology
Middle Aged
*Dementia/epidemiology/ethnology
Prospective Studies
Longitudinal Studies
Cohort Studies
*Diet, Vegetarian
Hawaii/epidemiology
Ethnicity
Risk Factors
California/epidemiology

@article {pmid41950468,
year = {2026},
author = {Llibre-Guerra, JJ and Lu, R and Clarens, MF and Liu, I and Renton, A and Ryan, NS and Goate, AM and Aguillón, D and Allegri, RF and Benzinger, TLS and Berman, S and Chhatwal, JP and Chrem Mendez, P and Vigo, G and Cruchaga, C and Day, GS and Farlow, MR and Fox, NC and Gordon, BA and Hassenstab, J and Huey, ED and Ibanez, L and Ikeuchi, T and Jucker, M and Lee, JH and Levey, AI and Levin, J and Niimi, Y and Perrin, RJ and Rosa-Neto, P and Sánchez-Valle, R and Schofield, PR and Wang, G and Li, Y and Xiong, C and Morris, JC and Karch, C and Daniels, AJ and McDade, E and Bateman, RJ},
title = {Effect of Cognitive Reserve on Age at Symptom Onset and Cognitive Decline in Individuals With Dominantly Inherited Alzheimer Disease.},
journal = {Neurology},
volume = {106},
number = {8},
pages = {e214804},
doi = {10.1212/WNL.0000000000214804},
pmid = {41950468},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/genetics/psychology ; Male ; *Cognitive Reserve/physiology ; Female ; *Cognitive Dysfunction/genetics/psychology ; Age of Onset ; Middle Aged ; Aged ; Disease Progression ; Longitudinal Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: Cognitive reserve has been shown to modulate the onset and progression of Alzheimer disease (AD) symptoms. Although its role in sporadic AD is well-studied, how cognitive reserve influences the timing and progression of symptoms in dominantly inherited AD (DIAD) remains unclear. This study aimed to quantify cognitive reserve in DIAD carriers and test whether higher cognitive reserve is associated with later symptom onset and slower functional decline.

METHODS: We analyzed data from the Dominantly Inherited Alzheimer's Network study. Cognitive reserve was modeled using a residual-based latent variable approach, decomposing cognitive performance into demographic (CogD), biomarker (CogB), and reserve or residual (CogR) components. Primary outcomes were age at clinical symptom onset (CDR >0) and longitudinal change in the Clinical Dementia Rating-Sum of Boxes (CDR-SBs). Data were analyzed using Cox proportional hazards models and linear mixed-effects models, adjusting for estimated years from onset (EYO).

RESULT: A total of 710 Dominantly Inherited Alzheimer Network (DIAN) participants were included in the analysis, comprising 271 non-DIAD carriers (nMC), 284 asymptomatic DIAD carriers (aMC), and 155 symptomatic DIAD carriers. In asymptomatic carriers, using a zero-inflation model adjusted for EYO showed that a 1 SD increase in the reserve component (CogR) was associated with a 4.06-fold increase in the odds of being clinically unimpaired (CDR-SB = 0; 95% CI 1.84-8.95). Similarly, a 1 SD increase in the demographic (CogD) and biomarker (CogB) components increased the odds of being CDR-SB = 0 by 2.60 (95% CI 1.10-6.16) and 5.16 (95% CI 2.00-13.33), respectively. Among symptomatic carriers, only the reserve and the biomarker components were significant. A 1 SD increase in CogR was associated with a 0.81-fold reduction in baseline CDR-SB score (95% CI 0.72-0.92), and a 1 SD increase in CogB was associated with a 0.60-fold reduction in CDR-SB (95% CI 0.50-0.71).

DISCUSSION: Our findings indicate that higher cognitive reserve values are associated with delayed conversion to mild cognitive impairment and slower progression on clinical dementia rating scales. These findings suggest that cognitive reserve plays a protective role in modifying the clinical trajectory of genetically determined AD.},
}

Humans
*Alzheimer Disease/genetics/psychology
Male
*Cognitive Reserve/physiology
Female
*Cognitive Dysfunction/genetics/psychology
Age of Onset
Middle Aged
Aged
Disease Progression
Longitudinal Studies