@article {pmid42103698,
year = {2026},
author = {Gerónimo-Olvera, C and Scheeler, SM and Aguirre, CG and Vega-Hormazabal, G and Garcia, D and Wu, L and Murad, N and Schneider, K and Wilson, KA and Markov, NT and Song, S and Simons, J and Gerencser, AA and Parlan, E and Mooney, SD and Verdin, E and Campisi, J and Tracy, TE and Furman, D and Melov, S and Ellerby, LM},
title = {Exceptional Longevity Modifying Allele APOE2 Promotes DNA Signaling Pathways Resisting Cellular Senescence in Human Neurons.},
journal = {Aging cell},
volume = {25},
number = {5},
pages = {e70494},
pmid = {42103698},
issn = {1474-9726},
support = {1RO1AG061879/AG/NIA NIH HHS/United States ; 5P01AG066591/AG/NIA NIH HHS/United States ; T32 AG000266/AG/NIA NIH HHS/United States ; //Paul F. Glenn Center for Biology of Aging/ ; //CatalystX award from Alex and Bob Griswood/ ; },
mesh = {Humans ; *Apolipoprotein E2/genetics/metabolism ; *Cellular Senescence/genetics ; *Signal Transduction/genetics ; *Longevity/genetics ; *Neurons/metabolism ; Alleles ; Animals ; DNA Damage ; Mice ; Induced Pluripotent Stem Cells/metabolism ; Apolipoprotein E4/genetics ; DNA Repair ; Alzheimer Disease/genetics ; },
abstract = {Genome-wide association studies (GWAS) have identified APOE2 allele as linked to exceptional longevity, with carriers exhibiting a reduced risk of Alzheimer's disease (AD). Apolipoprotein E (APOE), a glycoprotein involved in lipid transport, has three major alleles. However, alterations in lipid metabolism alone do not fully explain APOE2's protective effects. In contrast, APOE4 is the strongest genetic risk factor for AD. To investigate how APOE2 promotes neuronal longevity and confers neuroprotection, we generated human isogenic APOE iPSC-derived models of both inhibitory GABAergic and excitatory neurons. In GABAergic neurons, APOE alleles differentially influenced endogenous DNA damage, DNA repair, and neuronal motility. Single-cell RNA sequencing revealed APOE4-specific gene expression signatures associated with AD, whereas APOE2 GABAergic neurons were enriched for DNA repair and signaling pathways. Consistent with this, APOE2 neurons exhibited significantly lower levels of DNA damage. APOE4 GABAergic neurons exhibit increased expression of repetitive ribosomal RNA, which is associated with DNA damage and cellular senescence. To determine whether the effects extended to excitatory neurons, we used a separate human model of Ngn2-induced glutamatergic neurons, and found that APOE2 excitatory neurons were more resistant to cellular senescence and DNA damage than isogenic APOE3 and APOE4 neurons. Similarly, we found human APOE2-targeted replacement mice exhibited less nucleolar enlargement and increased nuclear Lamin A/C, Hmgb1, and H3K9me3 compared to APOE4 counterparts. Together, our findings identify DNA repair and suppression of senescence-associated processes as key mechanisms by which APOE2 is associated with neuronal resilience, providing mechanistic insight into its association with exceptional longevity and protection against AD.},
}

Humans
*Apolipoprotein E2/genetics/metabolism
*Cellular Senescence/genetics
*Signal Transduction/genetics
*Longevity/genetics
*Neurons/metabolism
Alleles
Animals
DNA Damage
Mice
Induced Pluripotent Stem Cells/metabolism
Apolipoprotein E4/genetics
DNA Repair
Alzheimer Disease/genetics

@article {pmid42104415,
year = {2026},
author = {Malorny, N and Chausse, B and Khodaie, B and Elgez, A and Söder, L and Lewen, A and Egorov, AV and Kann, O},
title = {TNF-α and IFN-γ impair neural oscillations and induce neurodegeneration by microglial nitric oxide, metabolic and oxidative stress.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03835-x},
pmid = {42104415},
issn = {1742-2094},
abstract = {BACKGROUND: The cytokine tumor necrosis factor-alpha (TNF-α) regulates inflammatory responses in infectious and neurodegenerative diseases and also affects neuronal function. The role of TNF-α in the activation of microglial cells (resident central nervous system macrophages), including the impact on neuronal survival, excitability, and synaptic transmission is incompletely defined, however. We explored the effects of chronic TNF-α exposure (72 h) on microglia and neurons in organotypic hippocampal slice cultures from male and female rats, i.e., postnatal cortex tissue lacking leukocyte invasion and adaptive immunity.

METHODS: We applied gene expression analysis, biochemical assays, immunohistochemistry, electrophysiology by extracellular (local field potential) and intracellular (intrinsic membrane properties) recordings, and pharmacological ablation of the microglial cell population. We mainly focused on carbachol-induced neural network oscillations (brain waves) in the gamma frequency band (30-70 Hz) that underlie higher cognitive functions such as perception, attention, and memory.

RESULTS: TNF-α induced microglial proliferation and upregulation of genes related to inflammation and oxidative stress such as Il6 (interleukin-6), Nos2 [inducible nitric oxide (NO) synthase, iNOS] and Sod2 (superoxide dismutase 2), which was accompanied by a decreased number of slices showing gamma oscillations in extracellular recordings. Notably, a fraction of slices presented neural bursting reflecting hyperexcitability in the tissue. Neuronal dysfunction was absent during acute TNF-α exposure (30 min). When paired with the lymphocyte cytokine interferon-gamma (IFN-γ), TNF-α induced an amplified neuroinflammation response dominated by bursting or loss of electrical activity. In intracellular recordings, neurons showed a brief burst of action potentials followed by slowing of spiking with pronounced afterhyperpolarization (switch from regular to burst firing behavior) during depolarizing current injection. Notably, the impairments could be attenuated by inhibition of iNOS and NADPH oxidase, glucose supplementation, microglial depletion or blockade of TNF receptor 1 (TNFR1) signaling with small molecule drugs, RIPA-56 and ICCB-19.

CONCLUSIONS: Our data provide mechanistic insight into TNF-α- and IFN-γ-induced neuronal impairments mediated by microglial NO, metabolic and oxidative stress, and demonstrate functional neuroprotection by pharmacology. Our study extends the pathophysiological understanding of diseases such as sepsis, multiple sclerosis, Alzheimer's disease, depression and schizophrenia featuring activated microglia, infiltrating monocytes and T cells, and/or blood-brain barrier leakage.},
}

@article {pmid42104459,
year = {2026},
author = {Comas-Albertí, A and Lladó, A and Esteller-Gauxax, D and Borrego-Écija, S and Falgàs, N and Dakterzada, F and Pérez-Millan, A and Puey, R and Collet-Romà, T and Guillén, N and Massons, M and Tort-Merino, A and Augé, JM and Fernandez-Villullas, G and Bosch, B and Ruiz-García, R and Naranjo, L and Balasa, M and Piñol-Ripoll, G and Antonell, A and Sánchez-Valle, R},
title = {Proteomic analysis in Alzheimer's disease and other dementias: a focus on sex-specific differences.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02068-7},
pmid = {42104459},
issn = {1758-9193},
support = {PI23/00173//Instituto de Salud Carlos III/ ; JR22/00014//Instituto de Salud Carlos III/ ; Joan Rodés-Josep Baselga grant//Fundación BBVA/ ; polAris project//Fundació Rosa Maria Vivar/ ; polAris project//Fundació Rosa Maria Vivar/ ; SGR 2021-01126//Generalitat de Catalunya/ ; },
abstract = {BACKGROUND: Fluid protein studies in cerebrospinal fluid (CSF) and plasma have provided important insights into neurodegenerative dementias; however, there is a limited investigation of sex-related differences and cross-biofluid relationships. In Alzheimer's disease (AD), Lewy body dementia (LBD), and frontotemporal dementia (FTD), large-scale, sex-stratified analyses of paired CSF and plasma samples remain scarce. Using the multiplex and ultrasensitive capabilities of NULISAseq™ technology, this study aims to characterize sex- and disease-specific proteomic alterations associated with Central Nervous System (CNS) pathology to explore underlying mechanisms.

METHODS: CSF and plasma samples from 359 individuals with AD, LBD, FTD, and cognitively healthy controls were analyzed using the NULISAseq™ CNS Disease Panel 120. Differential protein expression analyses were conducted across diagnoses and stratified by sex, adjusting for relevant covariates. Spearman's correlation analyses were performed to assess concordance between CSF and plasma protein levels. All statistical analyses were conducted in R v4.4.3.

RESULTS: Differential protein expression analyses across diagnoses revealed two potential transdiagnostic biomarkers: ICAM1 in CSF and ANXA5 in plasma, showing consistent increases across AD, LBD, and FTD. Sex-stratified analyses in CSF showed modest changes, including higher CCL26, ANXA5, and IL10 in females with AD, and higher IL9, PRDX6, and CX3CL1 in males with AD. In LBD, females exhibited upregulation of ACHE, SFRP1, POSTN in both CSF and plasma. NPTX1 was identified as a potential CSF biomarker for FTD, showing downregulation particularly in males. In contrast, analyses stratified by sex in plasma displayed a larger number of proteins across all dementias, with females showing a higher number of upregulated inflammation-related proteins predominantly involved in cytokine signaling. Overall cross-fluid correlations were restricted to a small subset of proteins, indicating compartment-specific regulation.

CONCLUSIONS: This study represents a large-scale, sex-stratified proteomic analysis of CSF and plasma across major neurodegenerative dementias using NULISAseq™ technology. The findings highlight sex-dependent biomarker patterns, particularly in plasma, and underscore the importance of incorporating sex as a biological variable in dementia research. Future studies should validate candidate proteins in independent cohorts, investigate their functional and mechanistic roles, and assess their utility for biomarker development and sex-tailored therapeutic strategies.},
}

@article {pmid42104633,
year = {2026},
author = {Martínez-Tazo, P and Mejias-Ortega, M and López-López, V and Bhojwani-Cabrera, AM and Saxton, E and Canals, S and Hardingham, G and Gutierrez, A and Lopez-Atalaya, JP and De Santis, S},
title = {Multiscale Approximations to Understand the Complex Role of Microglia in Alzheimer's Disease.},
journal = {The European journal of neuroscience},
volume = {63},
number = {9},
pages = {e70536},
pmid = {42104633},
issn = {1460-9568},
support = {2023-1296//Fundacion Pasqual Maragall/ ; PI24/00274//Instituto de Salud Carlos III/ ; PROMETEO 2020/007//Generalitat Valenciana/ ; CIESGT/2025/06//Generalitat Valenciana/ ; CIDEGENT/2021/015//Generalitat Valenciana/ ; CIPROM/2022/15//Generalitat Valenciana/ ; PID2021-129053OB-I00//Ministerio de Ciencia e Innovación/ ; PID2021-128909NA-I00//Ministerio de Ciencia e Innovación/ ; CNS2023-144883//Ministerio de Ciencia e Innovación/ ; RTI2018-102260-B-I00//Ministerio de Ciencia e Innovación/ ; PID2021-128158NB-C21//Ministerio de Ciencia e Innovación/ ; PID2024-162400OB-C21//Ministerio de Ciencia e Innovación/ ; PCI2024-153491//Ministerio de Ciencia e Innovación/ ; //UK Dementia Research Institute/ ; CTS950-G-FEDER//Junta de Andalucía/ ; CEX2021-001165-S//Programa para Centros de Excelencia en I+D Severo Ochoa/ ; FPU20/05737//Spanish Ministry/ ; },
mesh = {*Microglia/pathology/metabolism/immunology/physiology ; *Alzheimer Disease/pathology/immunology/metabolism ; Humans ; Animals ; *Brain/pathology/immunology ; },
abstract = {Microglia, the resident innate immune cells of the central nervous system, play a pivotal role in the pathogenesis of Alzheimer's disease (AD). Microglia are now recognized as a highly dynamic and heterogeneous population whose molecular and functional states vary with spatial context, disease stage, and genetic background. Recent discoveries across multiple scales from genetics, molecular and cellular biology, to systems-level imaging and epidemiology have underscored the complex and context-dependent contributions of microglia to the AD cascade. Together, these findings highlight the need for integrative, multiscale approaches that bridge molecular, cellular, and systemic perspectives to elucidate the diverse roles of microglia and their impact on disease progression. This mini-review discusses recent advances in understanding microglial biology across these dimensions and outlines current challenges toward achieving a more unified and therapeutically oriented framework for studying microglia in AD.},
}

*Microglia/pathology/metabolism/immunology/physiology
*Alzheimer Disease/pathology/immunology/metabolism
Humans
Animals
*Brain/pathology/immunology

@article {pmid42104655,
year = {2026},
author = {Sharmin, T and Doecke, JD and Chatterjee, P and Pedrini, S and Sohrabi, HR and Ashton, NJ and Zetterberg, H and Garg, ML and Blennow, K and Martins, RN},
title = {Circulating Sphingomyelins Correlate With Plasma T-Tau in Cognitively Unimpaired Older Adults at Risk of Developing Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {5},
pages = {e70436},
pmid = {42104655},
issn = {1471-4159},
support = {2018-02532//MQ Research Seeding Grant, Macquarie University/ ; 681712//MQ Research Seeding Grant, Macquarie University/ ; 201809-2016862//MQ Research Seeding Grant, Macquarie University/ ; 2017-00915//MQ Research Seeding Grant, Macquarie University/ ; FO2017-0243//MQ Research Seeding Grant, Macquarie University/ ; JPND2019-466-236//MQ Research Seeding Grant, Macquarie University/ ; //Macquarie University HDR Fund, Macquarie University/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; 2019-02397//Swedish Research Council/ ; },
mesh = {Humans ; Female ; Aged ; *tau Proteins/blood ; Male ; *Alzheimer Disease/blood/diagnostic imaging/psychology ; *Sphingomyelins/blood ; Cross-Sectional Studies ; Positron-Emission Tomography ; Aged, 80 and over ; Biomarkers/blood ; Amyloid beta-Peptides/metabolism ; Cognition/physiology ; Cohort Studies ; },
abstract = {Alterations in plasma sphingomyelin (SM) levels have been reported in Alzheimer's disease (AD), pointing to disturbances in lipid metabolism that may contribute to disease pathogenesis. Neuronal damage in early AD triggers tau release into central and peripheral systems. Despite influence from peripheral contributions, alterations in plasma total-tau (T-tau) remain valuable in indicating AD-related neurodegeneration. Investigating relationships between SM metabolism and tau release during preclinical AD may uncover important biochemical processes and support advancing early non-invasive detection and treatment approaches. This cross-sectional study investigated cognitively unimpaired (CU) older adults from the KARVIAH cohort, grouped by cortical amyloid-β (Aβ) status through positron emission tomography (PET) imaging (CU Aβ- and CU Aβ+) and utilised a Biocrates-targeted metabolomic platform and Single-molecule array (Simoa) technology to quantify plasma levels of SMs and T-tau, respectively. Associations between circulating SMs and T-tau were examined within each group, with T-tau-associated SMs further evaluated for their association with cognitive performance and cortical Aβ burden and their potential to discriminate CU Aβ+ from CU Aβ- individuals. Significant positive correlations were observed between SMs and T-tau levels exclusively in CU Aβ+ individuals, suggesting connections between SM-mediated biochemical pathways and tau release from early neurodegeneration in preclinical AD. Lower SM levels were associated with weaker working memory and executive function, as well as poorer global cognition, indicating their potential predictive value for weaker cognitive performance. Moreover, SMs were also inversely associated with cortical Aβ load in CU Aβ+ individuals, possibly reflecting early SM-mediated neuroprotective responses against AD pathogenesis. Receiver operating characteristic analysis further revealed the significant potential of the SM panel in distinguishing cortical PET-Aβ status and enhancing the predictive performance of plasma T-tau in CU individuals. Therefore, circulating T-tau-associated SMs may serve as promising early biomarkers of lipid-mediated processes in CU older adults with cortical amyloid pathology and tau-related neurodegeneration.},
}

Humans
Female
Aged
*tau Proteins/blood
Male
*Alzheimer Disease/blood/diagnostic imaging/psychology
*Sphingomyelins/blood
Cross-Sectional Studies
Positron-Emission Tomography
Aged, 80 and over
Biomarkers/blood
Amyloid beta-Peptides/metabolism
Cognition/physiology
Cohort Studies

@article {pmid42104711,
year = {2026},
author = {Hao, X and Jiao, B and Wang, Y and Xu, T and Yang, Q and Zhu, Y and Liu, Y and Zhang, C and Liang, X and Zhou, Y and Liao, X and Luo, S and Tang, B and Li, J and Xiao, X and Shen, L},
title = {Association of mitochondrial genome variants with Alzheimer's disease in a Chinese population.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261442231},
doi = {10.1177/13872877261442231},
pmid = {42104711},
issn = {1875-8908},
abstract = {BackgroundResearch on the mitochondrial genome variants of Alzheimer's disease (AD) in Chinese populations is lacking.ObjectiveThe study aimed to identify mitochondrial DNA (mtDNA) variants associated with AD risk and explore the relationship between mtDNA variants and plasma biomarkers in AD patients.MethodsWhole genome sequencing was performed in 1509 AD patients and 2010 controls from the Chinese population. mtDNA variants were called according to GATK's best practice mitochondrial pipeline. We evaluated the association of AD risk with mtDNA variants and mitochondrial haplogroup. Common variant (MAF≥0.01) based association analysis and gene-based tests of rare variants (MAF<0.01) were carried out with PLINK 1.9 and SKAT-O, respectively. Spearman correlation analysis was performed to assess the association between the burden of mtDNA variants and plasma biomarker levels.ResultsThe frequency of mitochondrial haplogroup G in AD group was nominally higher than control group (p = 0.019, OR = 1.48). Rare variants of MT-CYB gene were significantly enriched in controls compared to AD patients (p = 2.81 × 10[-4], OR = 0.886). Besides, the control group exhibited considerably lower mRNA expression of MT-CYB in brain regions compared to AD patients in GEO database. Furthermore, the number of mtDNA indel variants per individual correlated positively with plasma Aβ42 levels.ConclusionsMitochondrial haplogroup G may serve as a risk factor for AD, while rare variants of MT-CYB gene acted as protective factor against AD in mainland China. Moreover, mtDNA variants were related to AD plasma biomarker levels. Our findings highlighted the role of mitochondrial genome variants in the pathogenesis of AD.},
}

@article {pmid42104715,
year = {2026},
author = {Tang, Q and Liu, J and Fan, C and Zhang, X and Zhang, C and Qi, H},
title = {Early diagnosis of Alzheimer's disease through handwriting analysis and deep learning: A review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261446573},
doi = {10.1177/13872877261446573},
pmid = {42104715},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders worldwide, requiring early identification for timely intervention and to slow disease progression. However, existing diagnostic approaches, while effective at later stages, remain limited in detecting early-stage AD. Handwriting analysis has recently emerged as a non-invasive, cost-effective, and ecologically valid digital behavioral biomarker that reflects neurocognitive impairment. This review examines the role of handwriting as a neurocognitive marker for AD, focusing on integrating deep learning methodologies to enhance early diagnostic accuracy. It also elucidates the neurocognitive mechanisms linking handwriting behavior and AD, addressing current methodological and translational challenges. We performed a PRISMA-informed structured literature search and narrative synthesis of handwriting- and drawing-based studies for detecting AD/mild cognitive impairment (MCI), including offline handwriting images and online pen-stroke kinematics captured by digital devices. Task paradigms, data dimensions, preprocessing pipelines, modeling strategies (traditional machine learning and deep learning), evaluation practices, and translational considerations were summarized, and studies were organized by detection purpose and analytic approach. Our findings show that handwriting-based models generally discriminate AD/MCI from healthy controls with accuracy exceeding 80%, while deep learning models (e.g., convolutional neural network and multimodal Transformer fusion) approach 90% in structured tasks like clock drawing and figure copying. Online kinematic markers (e.g., reduced velocity, prolonged in-air time, increased pausing, and pressure instability) recur across studies, and multimodal integration with speech, gait, or facial signals can further improve sensitivity and ecological validity, although most studies are small and single-center.},
}

@article {pmid42104723,
year = {2026},
author = {Keret, O and Xia, T and Wilkins, S and Ncube, LNL and Smaw, B and Xiong, Y and Gandy, S and Pereira, A and Georges, N and Elahi, FM},
title = {Real-world clinical profile of individuals with cerebrospinal fluid Aβ[-]/pTau181.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261445561},
doi = {10.1177/13872877261445561},
pmid = {42104723},
issn = {1875-8908},
abstract = {BackgroundCerebrospinal fluid (CSF) pTau181 is used to support Alzheimer's disease (AD) diagnosis but can also rise in amyloid-negative individuals. This CSF profile (Aβ[-]/pTau181[+]) lies outside the AD continuum and complicates real-world etiologic diagnosis of neurocognitive disorders.ObjectiveTo determine the prevalence and clinical phenotype associated with the Aβ[-]/pTau181[+] CSF biomarker profile in a real-world memory clinic population.MethodsWe screened the Mount Sinai Hospital database (2015-2024) for patients who underwent ADmark CSF biomarker testing. An Aβ[-]/pTau181[+] group was classified using assay cutoffs (Amyloid-Total-Tau Index>1.2, pTau181 > 54 pg/mL) and compared to an Aβ[+] group (Amyloid-Total-Tau Index<0.8) matched for pTau181 and total-Tau. Clinical variables were extracted via chart review, limited to notes preceding CSF and blinded to CSF results.ResultsThe Aβ[-]/pTau181[+] group included 25 individuals (10.1% of the cohort) and had equally impaired cognition but fewer episodic memory complaints. Diagnosis was more often Lewy body or frontotemporal dementia. On neuroimaging, Aβ[-]/pTau181[+] exhibited less white matter hyperintensity burden and temporoparietal atrophy.ConclusionsCSF Aβ[-]/pTau181[+] is frequent in real-world evaluations of cognitive impairment and presents with fewer AD phenotypic features. Further research is required to clarify Aβ[-]/pTau181[+] underlying biology and clinical trajectory.},
}

@article {pmid42104729,
year = {2026},
author = {Si, K and Sun, C and Guo, H and Shi, C and Wang, Y},
title = {Association between the Dietary Index for Gut Microbiota and cognitive function among older adults in the United States.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449420},
doi = {10.1177/13872877261449420},
pmid = {42104729},
issn = {1875-8908},
abstract = {BackgroundThe Dietary Index for Gut Microbiota (DI-GM) is a novel index reflecting diet quality relative to gut microbiota health.ObjectiveThe study aims to investigate the relationship between DI-GM and cognitive function in older adults.MethodsData were obtained from 2629 participants aged ≥60 years in the National Health and Nutrition Examination Surveys (NHANES) (2011-2014). Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), the Animal Fluency Test (AFT), the Digit Symbol Substitution Test (DSST), and a global z score. Multivariable linear regression, restricted cubic splines (RCS), and subgroup analysis were performed. Predictive utility of DI-GM was assessed via the receiver operating characteristic (ROC) analysis against a baseline model. Mediation analysis examined relationships among DI-GM, the Dietary Inflammatory Index (DII), and cognitive outcomes.ResultsHigher DI-GM was associated with higher AFT, DSST, and the global z scores (p < 0.001). After full adjustment, participants with DI-GM (≥ 6) showed higher AFT score (β = 1.11, 95% CI 0.46∼1.75), DSST score (β = 4.95, 95% CI 3.05∼6.86) and z score (β = 0.19, 95% CI 0.10∼0.28), compared to those with DI-GM (0-3). No significant direct association was observed with CERAD (β = 0.45, 95% CI -0.29∼1.18, p = 0.233). RCS indicated linear relationships between DI-GM and cognitive function scores. DI-GM had excellent predictive performances based on the ROC. No significant interactions were detected by subgroup analysis. Furthermore, DII partly mediated the relationship between DI-GM and cognitive function.ConclusionsThe DI-GM showed a linear positive correlation with cognitive function in older adults.},
}

@article {pmid42104730,
year = {2026},
author = {Panigrahi, B},
title = {A novel synaptic compartmentalization failure framework for neurodegeneration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449379},
doi = {10.1177/13872877261449379},
pmid = {42104730},
issn = {1875-8908},
abstract = {Synaptic plasticity relies on precise spatial and temporal compartmentalization of signaling within dendritic spines, presynaptic terminals, and axonal domains. This compartmentalization is usually reinforced through activity-dependent remodeling of spine geometry, cytoskeletal scaffolds, calcium handling, and local protein synthesis, allowing plasticity signals to remain localized and terminate appropriately. Here, a unifying framework is proposed in which neurodegenerative diseases emerge when the capacity to maintain and renew these compartments declines. Ageing and glial dysregulation may act as major biological drivers of this process by altering dendritic spine structure, calcium homeostasis, metabolic support, neurotransmitter clearance, and activity-dependent synaptic remodeling. In this state, plasticity induction remains largely preserved, but signaling becomes spatially diffuse and temporally prolonged, imposing chronic structural and energetic stress on synapses and axons. Proteins such as tau and alpha synuclein, which normally support cytoskeletal organization and dynamic phase separated assemblies, may become destabilized under these conditions leading to pathological aggregation. This framework provides an explanation for early synaptic dysfunction, selective neuronal vulnerability, long presymptomatic phases, network-level disease propagation, the protective effects of education and cognitive engagement, and the limited efficacy of proteinopathy centric therapeutic strategies. Neurodegeneration may be conceptualized as a failure of synaptic compartmentalization, with protein aggregation arising downstream of this primary vulnerability.},
}

@article {pmid42104731,
year = {2026},
author = {Tsotsoros, CE and Centeno Román, CA and Clark, AL and De Anda-Duran, I and Ajrouch, KJ and Vega, IE},
title = {Cognitive function in immigrants from Mexico and Latin America: The role of age at migration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261446976},
doi = {10.1177/13872877261446976},
pmid = {42104731},
issn = {1875-8908},
abstract = {BackgroundLatino immigrants in the United States represent diverse national origins, with Mexicans comprising the largest group. Cognitive health disparities among Latino immigrants may reflect differences in migration experiences, including age at migration, socioeconomic differences, and acculturation. Whether Mexican immigrants differ from Latin American immigrants in cognitive outcomes remains unclear.ObjectiveThis study examined the independent and interactive effects of Mexican origin and age at migration on cognitive levels and decline compared to other Latin American immigrants. We also test whether socioeconomic and acculturation factors help explain differences in cognitive outcomes.MethodsData came from 2077 Latino immigrants in the Health and Retirement Study (2014-2020). Cognition was assessed using the Telephone Interview for Cognitive Status. Mixed-effects models evaluated the main and interaction effects of origins and age at migration on age-related decline, controlling for demographic, health-related, socioeconomic, and acculturation covariates.ResultsMexican immigrants had significantly lower cognitive levels than Latin American immigrants. However, after adjusting for socioeconomic indicators and language acculturation, Mexican immigrants demonstrated higher cognitive scores. Among Mexicans, late-life migration was associated with significantly poorer cognitive levels, which persisted after accounting for socioeconomic and acculturation factors. No significant differences were observed in rates of cognitive decline by origin or age at migration.ConclusionsLate-life migration is associated with poorer cognitive outcomes among Mexican immigrants. Findings indicate that socioeconomic and acculturation factors mask underlying differences in cognitive performance between Mexican and Latin American immigrants, underscoring the need to consider both migration experiences and social context when evaluating cognitive disparities.},
}

@article {pmid42104858,
year = {2026},
author = {He, Y and Xue, H and Bi, S and Wang, Y and Liu, X and Li, Y and Chen, Z and Rong, D and Cui, B and Ma, J and Yan, S and Lu, J},
title = {Correspondence of Basal Forebrain Resting-State Functional Connectivity and Cerebral Glucose Metabolism Alterations With Neurotransmitter Maps in Alzheimer's Disease.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {5},
pages = {e70901},
doi = {10.1002/cns.70901},
pmid = {42104858},
issn = {1755-5949},
support = {82394434//National Natural Science Foundation of China/ ; 62333002//National Natural Science Foundation of China/ ; HZ2025PYDTR006//Xuanwu Hospital Talent Convergence Program/ ; },
mesh = {Humans ; Male ; *Alzheimer Disease/metabolism/diagnostic imaging ; Female ; Aged ; *Glucose/metabolism ; *Neurotransmitter Agents/metabolism ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; *Basal Forebrain/metabolism/diagnostic imaging ; Middle Aged ; Rest ; Aged, 80 and over ; },
abstract = {AIMS: To investigate alterations in basal forebrain (BF) subregional functional connectivity (FC), cerebral glucose metabolism, and their spatial correspondence with atlas-based neurotransmitter distributions in Alzheimer's disease (AD).

METHODS: Forty-two Aβ-PET-positive AD patients and forty-one matched healthy controls (HC) underwent simultaneous PET/MRI. We analyzed resting-state FC of BF subregions (Ch1-3, Ch4) and measured cerebral glucose metabolism using [18]F-FDG PET standardized uptake value ratio (SUVR). Spatial correlations with neurotransmitter maps were assessed using the JuSpace toolbox.

RESULTS: Compared with HC, AD patients showed decreased FC between the left Ch4 and hippocampus/posterior cingulate gyrus, and increased FC between the right Ch4 and precentral/postcentral gyrus. Additionally, AD patients showed increased FC between the left Ch1-3 and superior temporal gyrus/insula, decreased FC between the right Ch1-3 and the orbitofrontal gyrus, and increased FC between the right Ch1-3 and the left temporal lobe (voxel-level p < 0.001, cluster-level p < 0.05, GRF correction). These FC changes were spatially correlated with serotonergic (5HT1a, 5HT4, SERT) and dopaminergic (D1, D2, DAT) receptor distributions (p < 0.05, FDR corrected). Widespread cerebral hypometabolism in temporoparietal and frontal regions was spatially correlated with serotonin, dopamine, GABA, glutamate, and kappa-opioid systems (p < 0.05, FDR corrected).

CONCLUSION: The FC of BF and cerebral metabolic changes in AD show distinct spatial correspondence with specific neurotransmitter systems, highlighting the crucial involvement of serotonin and dopamine in AD pathophysiology.},
}

Humans
Male
*Alzheimer Disease/metabolism/diagnostic imaging
Female
Aged
*Glucose/metabolism
*Neurotransmitter Agents/metabolism
Positron-Emission Tomography
Magnetic Resonance Imaging
*Basal Forebrain/metabolism/diagnostic imaging
Middle Aged
Rest
Aged, 80 and over

@article {pmid42104909,
year = {2026},
author = {Kramarczyk, D and Ballard, C and Corbett, A and Da Silva, MV and Mcleish, KI and Cummings, J and Khan, Z},
title = {Racial and Ethnic Representation in Dementia Clinical Trials Registered on ClinicalTrials.gov in the United States, United Kingdom, and Canada.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {5},
pages = {e70211},
doi = {10.1002/gps.70211},
pmid = {42104909},
issn = {1099-1166},
support = {//National Institute for Health and Care Research HealthTech Research Center in Brain Health./ ; },
mesh = {Humans ; United Kingdom ; United States ; Canada ; *Dementia/ethnology/therapy ; Male ; Female ; *Ethnicity/statistics & numerical data ; Aged ; *Clinical Trials as Topic/statistics & numerical data ; Patient Selection ; Aged, 80 and over ; *Racial Groups/statistics & numerical data ; Alzheimer Disease/therapy/ethnology ; Middle Aged ; },
abstract = {OBJECTIVE: To evaluate racial and ethnic representation and temporal trends in phase II-IV dementia clinical trials conducted in the United States, United Kingdom, and Canada.

METHODS: We interrogated ClinicalTrials.gov for interventional dementia and Alzheimer's disease (AD) trials completed since 2000. Data on age, gender, and ethnicity were extracted from 163 eligible trials. Representation was compared across two time periods (2000-2015 and 2016-2019) to assess progress in diversity.

RESULTS: Of the 163 trials, 58.9% (n = 96) reported ethnicity data. Among the 12,900 participant records in these trials, 80.6% were Caucasian. Since 2016, despite improved reporting standards (100% of recent trials reported ethnicity), actual diversity declined: Asian participant representation dropped from 4.9% to 1.2%, and Hispanic/Latino representation fell from 2.2% to 0.7%. No ethnic minority group showed an increase in participation over the study period.

CONCLUSIONS: Diverse ethnic groups remain significantly underrepresented in dementia clinical trials, with diversity metrics stagnating or declining over the last decade. Greater inclusivity in trial design and recruitment is urgently required to ensure that emerging dementia treatments are safe and effective for all populations.},
}

Humans
United Kingdom
United States
Canada
*Dementia/ethnology/therapy
Male
Female
*Ethnicity/statistics & numerical data
Aged
*Clinical Trials as Topic/statistics & numerical data
Patient Selection
Aged, 80 and over
*Racial Groups/statistics & numerical data
Alzheimer Disease/therapy/ethnology
Middle Aged

@article {pmid42105113,
year = {2026},
author = {Kaya, M and Konukoglu, O and Genç, H and Cindemir, E and Onay, M},
title = {Differentiation of normal pressure hydrocephalus from alzheimer's and Parkinson's Diseases using the splenial angle measured on brain CT: diagnostic performance and reliability study.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42105113},
issn = {1432-1920},
abstract = {BACKGROUND: Although MRI and diffusion tensor imaging (DTI) based studies have evaluated the Splenial Angle (SA) in distinguishing normal pressure hydrocephalus (NPH), its reproducibility and diagnostic utility on CT remain untested.

OBJECTIVE: To assess the diagnostic performance and intra/inter-observer repeatability of CT-derived SA measurements for differentiating NPH from Alzheimer's and Parkinson's diseases.

MATERIALS AND METHODS: This retrospective study included 325 individuals: 87 with NPH, 71 with Alzheimer's disease, 66 with Parkinson's disease, and 101 healthy controls. Evans Index (EI), Callosal Angle (CA), and SA were measured on brain CT images. Two radiologists assessed intra- and inter-observer repeatability. Continuous variables were analyzed using ANOVA, categorical variables using Chi-square tests, and Receiver Operating Characteristic (ROC) analysis determined diagnostic performance.

RESULTS: EI, CA, and SA differed significantly between the NPH group and the other groups (p < 0.001). The SA showed the highest diagnostic accuracy for NPH (AUC = 0.999; cut-off = 49.5°; sensitivity = 0.996; specificity = 0.989; LR + = 86.63; LR- = 0.004). The CA also demonstrated strong performance (AUC = 0.993; cut-off = 87.5°). The EI achieved high accuracy (AUC = 0.928) but was less specific. In the Alzheimer's and Parkinson's groups, these measurements had limited discriminatory ability. Intra- and inter-observer agreement was high for all three parameters, with the SA showing the greatest repeatability.

CONCLUSION: The SA can be used as a reliable CT-based marker to help distinguish NPH from neurodegenerative diseases, serving as a supportive imaging parameter in clinical assessment.},
}

@article {pmid42105174,
year = {2026},
author = {Lai, L and Tang, Y and Song, G and Long, Y and Chen, C and Chen, C and Li, W},
title = {Lipid metabolism, neuroinflammation, and oxidative stress in Alzheimer disease: an integrated mechanistic review.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42105174},
issn = {2240-2993},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by the accumulation of amyloid-β plaques, tau tangles, and extensive synaptic and neuronal loss. Increasing evidence suggests that the condition develops through the combined effects of protein misfolding, lipid dysregulation, oxidative stress, and chronic neuroinflammation. Among these processes, the APOE ε4 allele has a central role by linking disrupted lipid metabolism to impaired amyloid clearance, abnormal tau phosphorylation, and heightened neuronal vulnerability. This relationship highlights lipidopathy as a potential upstream driver of disease progression rather than a secondary feature. Advances in biomarker research, including cerebrospinal fluid and plasma assays, molecular imaging, and microRNA profiles, now enable detection of AD pathology years before clinical symptoms become evident and allow patient stratification based on molecular signatures. Despite these advances, currently available symptomatic and disease-modifying therapies remain limited in their ability to halt or reverse cognitive decline. This review synthesises recent findings across amyloid, tau, and lipid-driven mechanisms, while providing a comparative analysis of therapeutic strategies and their limitations. A lipid-focused, multi-target framework is proposed in which correcting metabolic imbalance enhances the effectiveness of amyloid- and tau-directed interventions. Such an approach may strengthen precision medicine and offer a realistic path toward improved outcomes in AD.},
}

@article {pmid42105291,
year = {2026},
author = {Sandhu, JK and Tanha, J and Arbabi-Ghahroudi, M},
title = {Targeting the NLRP3 inflammasome with antibody-based Therapeutics for chronic neurodegenerative diseases.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2671675},
pmid = {42105291},
issn = {1744-7631},
abstract = {INTRODUCTION: The NLRP3 inflammasome is a central regulator of innate immunity that becomes aberrantly activated by amyloid-β, hyperphosphorylated tau, and α-synuclein aggregates in chronic neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). Sustained activation drives neuroinflammation, synaptic dysfunction, and neuronal loss, making NLRP3 a compelling therapeutic target in chronic neurodegeneration.

TOPICS COVERED: This review summarizes current insights into NLRP3 inflammasome biology in AD and PD, with emphasis on antibody-based interventions. Emerging delivery approaches, such as receptor-mediated transcytosis, nanoparticles, adeno-associated viral vectors, and magnetic resonance-guided focused ultrasound are also examined for their potential to enhance central nervous system (CNS) delivery of NLRP3-targeting antibodies.

EXPERT OPINION: Antibody-based inhibitors of the NLRP3 inflammasome offer high specificity and favorable safety profile compared with small-molecular-weight inhibitors; however, limited blood-brain barrier (BBB) penetration remains a major challenge. Advances in antibody engineering, modular bi-/multi-specific designs, and targeted CNS delivery platforms may soon enable the development of first-in-class antibodies capable of directly modulating neuroinflammation. To realize this potential, the field should prioritize: (1) developing BBB-penetrant antibody constructs; (2) integrating delivery technologies with target biology; and (3) accelerating translation toward first-in-human studies. Successful implementation could transform therapeutic strategies for AD and PD and extend antibody-based interventions across a broader spectrum of neuroinflammatory disorders.},
}

@article {pmid42105317,
year = {2026},
author = {Balwant Patil, K and Sugunan, S and Padiyar, A and Mishra, AK and Jain, S},
title = {Neuroprotective role of phenolic acids: mechanistic insights into cognitive decline and neurodegenerative disorder.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/1028415X.2026.2669234},
pmid = {42105317},
issn = {1476-8305},
abstract = {BACKGROUND: Age-associated cognitive deterioration and neurodegenerative conditions, including Alzheimer's disease (AD) and Parkinson's disease (PD), are predominantly influenced by oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation. Dietary phenolic acids, prevalent in plant-based foods, have demonstrated potential neuroprotective and cognitive-enhancing effects in recent studies.

PURPOSE: This review seeks to thoroughly assess the neuroprotective mechanisms of phenolic acids and to consolidate existing evidence from human and preclinical studies concerning their potential efficacy in alleviating cognitive impairment and neurodegeneration.

STUDY DESIGN: Narrative and evidence-based literature review.

METHODS: Recent experimental, clinical, and epidemiological studies examining significant phenolic acids - such as caffeic, chlorogenic, ferulic, gallic, rosmarinic, sinapic, ellagic, protocatechuic, p-coumaric, and tannic acids - in relation to AD, PD, and cognitive functions were retrieved from electronic databases. We put together the most important information about molecular mechanisms and treatment.

RESULTS: Preclinical studies show that phenolic acids have antioxidant, anti-inflammatory, anti-apoptotic, and anti-aggregation effects by changing important signaling pathways like Nrf2/HO-1, NF-κB, and PI3 K/Akt. These actions protect dopaminergic neurons, lower the toxicity of amyloid-beta and α-synuclein, and make behavior better in disease models. Human studies suggest that increased dietary consumption of phenolic acids, especially hydroxycinnamic acids such as caffeic and chlorogenic acid, is associated with enhanced cognitive performance and a diminished risk of cognitive decline, although results are not uniform.

CONCLUSION: Phenolic acids are secure, readily accessible neuroprotective compounds that can alter various pathological pathways associated with cognitive decline and the progression of neurodegenerative diseases.},
}

@article {pmid42105452,
year = {2026},
author = {Uehara, MA and Bretecher, CA and Teschuk, JM and Verot, A and Saha, C and Fitzgerald, PB and Koski, L and Millikin, C and Moussavi, Z},
title = {Examining adverse effects in a large clinical trial of rTMS application as a treatment for Alzheimer's disease.},
journal = {Psychiatry research},
volume = {362},
number = {},
pages = {117212},
doi = {10.1016/j.psychres.2026.117212},
pmid = {42105452},
issn = {1872-7123},
abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has several advantages compared to other interventions for neurological and psychological disorders. However, various adverse effects have been reported in rTMS research, and little is known about who is most susceptible to rTMS adverse effects, or how they can be minimized.

AIMS: We aimed to identify risk factors for adverse effects reported in a recent clinical trial examining rTMS as a treatment for Alzheimer's disease (AD). We hypothesized that higher stimulation intensity would be associated with experiencing unspecified pain/discomfort, dental pain, headache, jaw pain, and muscle contractions, but not be associated with other adverse effects.

METHODS: Using detailed notes from treatment sessions, 10 adverse effects were identified. Spearman correlations were conducted to assess relationships between the highest applied stimulation intensity and normalized frequency of each adverse effect amongst those who experienced that adverse effect. Demographic information, cognitive scores, and withdrawal status were compared between the binarized groups of participants who experienced adverse effects versus those who did not. Spearman correlations were also conducted on the binarized adverse effects and the highest applied stimulation intensity. Logistic regressions were conducted to identify potential risk factors.

RESULTS: In both the sham and active treatment groups, unspecified pain/discomfort was the most common adverse effect, followed by muscle contractions and dizziness. In both the active and sham treatment groups, stimulation intensity was positively associated with muscle contractions, but was not significantly related to any other adverse effect. In evaluating groups with/without adverse effects, we found there was a significantly higher proportion of males reporting adverse effects in both the active treatment group and the sham treatment group compared to females.

CONCLUSION: The findings of this study are a step toward understanding how researchers can minimize such adverse effects, and thereby, create a less aversive experience for rTMS participants.},
}

@article {pmid42105723,
year = {2026},
author = {Sambuco, N and Scaramuzzi, GF and Gasparre, D and Cornacchia, E and Bonvino, A and Antonucci, LA and Pergola, G and Taurisano, P},
title = {Baseline brain volumes predict cognitive decline more robustly than atrophy rates: Evidence for brain reserve.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {200},
number = {},
pages = {200-215},
doi = {10.1016/j.cortex.2026.03.022},
pmid = {42105723},
issn = {1973-8102},
abstract = {The concept of brain reserve offers a framework for understanding the mechanisms of cognitive resilience in later life. This study investigated whether a static measure of brain structure, a proxy for accumulated reserve, or a dynamic measure of atrophy is a more powerful predictor of future cognitive changes. Using Alzheimer's disease (AD) as a model of accelerated cognitive aging, we investigated this question across the neurocognitive continuum. We analyzed longitudinal structural MRI and neuropsychological data from 75 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (Healthy, MCI, Dementia) using LASSO regularization and logistic regression to identify associations with cognitive change and model MCI conversion. Baseline brain volumes were robust predictors of cognitive decline, significantly outperforming short-term volumetric changes (atrophy rate). Specifically, larger lateral ventricles and smaller hippocampal and thalamic volumes, particularly in the anterior and medial thalamic nuclei, were associated with greater impairment in memory and executive function. Importantly, while APOE ϵ4 carrier status was high across the MCI group (∼56%), it did not differentiate converters from non-converters, indicating that genetic risk alone does not account for divergent clinical trajectories. Our model, based on these baseline volumes, predicted MCI conversion with good accuracy (AUC = .82). These findings highlight the importance of structural brain reserve, as a proxy for the resilience of integrated neural networks against neurodegeneration. Our results underscore the clinical utility of a single baseline MRI scan for identifying individuals at risk and advancing a network-based understanding of neurodegeneration.},
}

@article {pmid42105724,
year = {2026},
author = {Karalı, FS and Tosun, S and Çınar, N and Gerwien, J},
title = {Macro-event processing in Alzheimer's disease, mild cognitive impairment, and healthy aging: Evidence from a Turkish sample.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {200},
number = {},
pages = {216-236},
doi = {10.1016/j.cortex.2026.04.016},
pmid = {42105724},
issn = {1973-8102},
abstract = {Understanding everyday events requires integrating individual event units (micro-events) into coherent higher-level representations (macro-events). Cognitive decline may disrupt this ability, contributing to difficulties in comprehension, prediction, and goal inference. We investigated macro-event processing in Turkish-speaking healthy older adults, individuals with mild cognitive impairment (MCI), and individuals with Alzheimer's disease (AD) across two experiments. Participants recognized and labeled macro-events from sets of component micro-events. In Experiment 1, participants arranged micro-events into the correct temporal order. In half of the trials, the macro-event name was provided to test whether verbal cueing improved ordering performance; in the other half, participants named the macro-event after uncued ordering. A subsample completed a second administration to assess response stability. In Experiment 2, participants identified macro-events from incrementally presented micro-events, allowing assessment of how much information was required before recognition. Across experiments, we observed graded impairment with increasing cognitive decline. Naming accuracy reliably distinguished AD from the other groups, whereas differences between MCI and healthy controls were less consistent. Non-verbal measures, including temporal ordering, response stability, and the amount of information sampled before responding, revealed more robust group differences. These findings support macro-event processing as a core mechanism of event cognition that is progressively disrupted in MCI and AD, and indicate that non-verbal measures may provide sensitive markers of impairment beyond naming accuracy.},
}

@article {pmid42105801,
year = {2026},
author = {Hoyer-Kimura, C and Hay, M},
title = {Neurovascular unit dysfunction in vascular cognitive impairment: Mechanisms, biomarkers, and translational strategies.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115815},
doi = {10.1016/j.expneurol.2026.115815},
pmid = {42105801},
issn = {1090-2430},
abstract = {Vascular cognitive impairment and dementia (VCID) encompasses a heterogeneous spectrum of cognitive disorders driven by cerebrovascular pathology and represents a major contributor to late-life cognitive decline. VCID is highly prevalent and frequently coexists with Alzheimer's disease pathology. Despite this, it remains poorly defined in clinical practice and lacks approved disease-modifying therapies. Therapeutic development has been hindered by biological heterogeneity, challenges in patient stratification, and a historical emphasis on neurodegenerative targets that inadequately address vascular mechanisms. Increasing evidence implicates dysfunction of the neurovascular unit-including small vessel disease, chronic hypoperfusion, blood-brain barrier disruption, and neuroinflammation-as a central driver of vascular-mediated cognitive impairment and a unifying therapeutic target across diverse VCID phenotypes. In this review, we synthesize current understanding of VCID pathobiology with a focus on neurovascular unit dysfunction and emerging mechanism-based strategies aimed at restoring vascular and neurovascular homeostasis. We further examine translational considerations for targeting neurovascular signaling pathways, including endothelial stabilization, modulation of vascular inflammation, and preservation of blood-brain barrier integrity. As an illustrative example, we discuss preclinical evidence supporting Mas receptor agonism, including the glycosylated angiotensin-(1-7) analogue PNA5, as a potential approach to address vascular-mediated cognitive impairment. Finally, we explore implications for biomarker selection, patient enrichment, and early clinical trial design. Together, this framework highlights neurovascular dysfunction as a tractable therapeutic target in VCID and underscores the need for mechanism-driven approaches to address a substantial unmet clinical need.},
}

@article {pmid42105904,
year = {2026},
author = {Guo, M and Zou, Y and Wang, T and Wu, H and Ji, Y and Liu, S and Xu, G and Wang, P},
title = {Spatiotemporal reconfiguration of functional networks by transcranial magnetic stimulation in Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.05.002},
pmid = {42105904},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is associated with impaired connectivity in critical functional networks. This study investigated the effects of 20 Hz transcranial magnetic stimulation (TMS) on brain network mechanisms in 25 patients with AD, including 17 in the TMS group and 8 in the sham group. We analyzed resting-state functional magnetic resonance imaging data, using the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) to quantify neural activity and identify regions of interest. Subsequently, changes in static and dynamic functional connectivity were analyzed based on these regions. The results showed that: (1)In the TMS group, significant increases in ALFF/fALFF were observed specifically in the right dorsolateral superior frontal gyrus (SFGdor.R) and the left anterior cingulate gyrus (ACG.L); (2)Enhanced static functional connectivity between the SFGdor.R and the right middle temporal gyrus was positively correlated with improvements in Montreal Cognitive Assessment scores, while reduced static functional connectivity between the ACG.L and the left inferior temporal gyrus was associated with gains in Boston Naming Test scores; (3)Improvements in both Montreal Cognitive Assessment scores and Mini Mental State Examination scores were linked to decreased dynamic functional connectivity variability between the ACG.L and the middle occipital gyrus. These findings suggest that TMS improves cognitive and behavioral performance in patients with AD through multiscale regulatory effects, and that this improvement may be associated with alterations in functional integration among brain regions as well as reduced variability of abnormal network dynamics, providing new insights into the mechanism of action of TMS in AD.},
}

@article {pmid42105919,
year = {2026},
author = {Barough, SS and Ohno, S and Bilgel, M and Moghekar, A and Sair, HI and Luciano, MG and Moghekar, A},
title = {Disproportionately Elevated Sulcal Index (DESI): An automatically driven index representing disproportionate subarachnoid space enlargement in brain MRI scans.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111928},
doi = {10.1016/j.brainresbull.2026.111928},
pmid = {42105919},
issn = {1873-2747},
abstract = {INTRODUCTION: Idiopathic normal pressure hydrocephalus (iNPH) is frequently underdiagnosed due to non-specific symptoms and the risks of invasive testing. While disproportionately enlarged subarachnoid space hydrocephalus (DESH) is a hallmark imaging feature, manual assessment is subjective and qualitative. We developed the Disproportionately Elevated Sulcal Index (DESI), a fully automated deep learning-based volumetric biomarker, to objectively quantify these morphological changes.

METHODS: We trained a U-Net model with an EfficientNet-B0 encoder on T1-weighted MRI scans from the Baltimore Longitudinal Study of Aging and Johns Hopkins Clinic (n=1,248) to segment Sylvian fissures and superior sulcal spaces. DESI was defined as the volumetric ratio of the Sylvian fissure to superior sulci within an AC-PC aligned wedge. The model was externally validated on the multi-site PENS trial dataset (n=94), comparing NPH patients against healthy controls and participants with Alzheimer's disease and vascular dementia.

RESULTS: In external validation, DESI demonstrated high diagnostic accuracy. The index distinguished NPH patients with DESH features from non-DESH NPH cases with an Area Under the Curve (AUC) of 0.97. When differentiating NPH with DESH from a pooled group of healthy controls and neurodegenerative mimics, DESI achieved an AUC of 0.99 (sensitivity 98%, specificity 100%). In a broad comparison of all NPH cases versus all non-NPH groups, DESI maintained an AUC of 0.94.

CONCLUSIONS: DESI provides a robust, fully automated quantification of sulcal disproportion that effectively differentiates iNPH from normal aging and neurodegenerative mimics. This continuous, non-invasive metric offers a scalable tool for accurate iNPH screening and patient stratification in clinical settings.},
}

@article {pmid42105933,
year = {2026},
author = {Pourzal, R and Agarwal, P and Leurgans, SE and McCarthy, SM and Hall, DJ and McDevitt, CA and Ganio, K and Ayton, S and Bush, AI and Grodstein, F and James, B and Agrawal, S and Hallab, NJ and Bennett, DA and Schneider, JA and Jacobs, JJ},
title = {Cobalt and titanium levels in the brain are associated with Alzheimer's disease pathology but not cognition: A study of older adults with and without total joint replacement.},
journal = {Acta biomaterialia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.actbio.2026.05.006},
pmid = {42105933},
issn = {1878-7568},
abstract = {Alzheimer's disease (AD) and total joint arthroplasty are prevalent and often concomitant in older adults, but an etiologic link is debated. Since wear particles are an inevitable side product of total joint arthroplasty (TJA), we hypothesized that older adults with TJA agglomerate higher-than-normal concentrations of implant alloy elements caused by the dissemination of debris from the implants, resulting in a pathological reaction. A cross-sectional analysis was conducted among 701 autopsied participants of an ongoing longitudinal cohort (Memory and Aging Project (MAP)) of whom postmortem neuropathologic data was available and implant-related metals (cobalt, titanium) were quantified in four brain regions by inductively coupled mass-spectrometry. MAP participants are enrolled without known dementia at baseline and followed annually for cognitive assessments using 19-test battery. In the analytical sample, 229 had TJA (total hip arthroplasty, total knee arthroplasty, and total shoulder arthroplasty) and n=472 had no total joint. Due to a higher likelihood of cobalt release in total hip arthroplasty, the TJA group was subdivided into a hip (n=146) and a knee/shoulder (n=83) group. We used regression and linear mixed-effects models, adjusted for demographics and apolipoprotein E ε4 status, to examine associations between metals, AD pathology and cognitive decline. Cobalt content of brain tissue was 8.9% higher in the total hip arthroplasty group than in the no-TJA group (p=0.003). Cobalt-containing particles were identified within brain tissue using scanning electron microscopy. In the inferior temporal cortex, cobalt was positively associated (p=0.0004) and titanium was negatively associated (p=0.038) with amyloid-beta load, but had no association with cognition. These results warrant monitoring the potential impact of metal implant debris on brain health. STATEMENT OF SIGNIFICANCE: This study is of great clinical significance because Alzheimer's disease (AD) and total joint arthroplasty (TJA)-the end-stage treatment of osteoarthritis-affect large and overlapping groups in our aging population. There is limited knowledge about the relationship between the prominent TJA implant metals cobalt and titanium and the pathogenesis of AD. This study shows that Co28Cr6Mo and Ti6Al4V implant alloy particles-most likely from a subset of total hip replacements with accelerated wear or tribocorrosion-can disseminate to the brain and be associated with increased cobalt and titanium concentrations. Cobalt was associated with greater AD pathology in the inferior-temporal cortex, even after correction for other known AD risk factors. However, there was no correlation with cognitive decline. Titanium was negatively associated with AD pathology, but titanium oxide appeared to be abundant in the brain from sources other than joint replacements.},
}

@article {pmid42105996,
year = {2026},
author = {Bashir, MA and Ullah, I and Aara, G and Khan, AU and Shah, SUA},
title = {Multitarget Pharmacological Effects of Lawsone in Mitigating Alzheimer's Disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178920},
doi = {10.1016/j.ejphar.2026.178920},
pmid = {42105996},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive neuronal loss, cognitive impairment, oxidative stress, neuroinflammation, and aggregation of abnormal proteins, including amyloid precursor protein (APP), amyloid-beta (Aβ), and hyper phosphorylated Tau (p-Tau). Developing therapies that simultaneously target multiple pathogenic pathways remains a major therapeutic challenge. Lawsone (LW), a naturally occurring naphthoquinone derived from the leaf of henna plant (Lawsonia inermis), was investigated for its therapeutic potential in AD. Computational studies were performed to evaluate binding affinities and stability of the compound against key AD-related molecular targets. Sprague-Dawley rats were randomly assigned to five groups: vehicle control, Scopolamine (SCP), donepezil (DNZ), and two groups treated with LW at doses of 2.5 and 5mg/kg. Morris water Maze and Y Maze tests were employed to validate the behavioral performance. Oxidative stress markers were measured biochemically, tissue histopathology was evaluated using hematoxylin-eosin and Congo red staining. Expression of the proinflamatory markers, nuclear factor kappa β (NF-κβ), c-Jun N terminal kinase (c-JNK), Tumor necrosis factor-α (TNF-α) and Alzheimer's associated proteins APP, Aβ1-42, and Tau were assessed through real time polymerase chain reaction (qPCR), enzyme linked immunosorbent assay (ELISA). Computational evaluation showed strong binding to NF-κβ, c-JNK, acetylcholinestrase (AChE), butyrylcholinestrase (BuChE) and TNF-α, supporting its multi-target potential. LW demonstrated neuropharmacological efficacy through preservation of neuronal structure, suppression of Aβ pathology, enhancement of cognitive function, restoration of antioxidant defenses, downregulation of proinflamatory, amyloidogenic, and tauopathic markers. These findings featured its potential as a multi target therapeutic agent for the management of AD.},
}

@article {pmid42106150,
year = {2026},
author = {Xiang, J and Xu, J and Zhang, Y and Liu, X},
title = {Urolithin A: potential to enhance autophagic clearance and mitigate neuroinflammation in Alzheimer's disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103157},
doi = {10.1016/j.arr.2026.103157},
pmid = {42106150},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and the leading cause of dementia in older adults. The presence of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) constitutes the two principal neuropathological features of AD. However, current therapies targeting only Aβ or tau remain suboptimal, likely due to intrinsic neuronal and glial dysfunction in affected brain regions. Urolithin A (UroA) is a widely recognized mitophagy activator with potent antioxidant and anti-inflammatory properties. Current clinical studies confirm UroA's safety in humans and its broad benefits for mitochondrial health. Preclinical data show enhanced lysosomal and mitochondrial quality in neurons and glia during AD progression. Given current AD pathology insights, UroA shows significant therapeutic promise. The AMPK/SIRT/mTOR signaling axis regulates cellular adaptation to metabolic stress and energy balance, and is significantly dysregulated in AD progression. This review comprehensively evaluates the structural and biological characteristics of UroA, with a focus on its role in enhancing mitophagy, promoting lysophagy, and mitigating neuroinflammation in the context of AD. However, current research has not clarified how UroA enhances mitochondrial and lysosomal function while suppressing neuroinflammation. This report further investigates the potential interplay between UroA and the AMPK/SIRT/mTOR signaling pathway, elucidating a plausible mechanism through which UroA regulates the autophagic-lysosomal system and mitigates neuroinflammation via modulation of this axis.},
}

@article {pmid42106151,
year = {2026},
author = {Sharma, P and Kaur, N and Vasal, N and Solanki, K and Sunkaria, A},
title = {The Mitochondria-Synapse Axis in Alzheimer's Disease: Lost Coordination in Early Stages.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103168},
doi = {10.1016/j.arr.2026.103168},
pmid = {42106151},
issn = {1872-9649},
abstract = {Synaptic dysfunction emerges early in Alzheimer's disease, often years before the appearance of clinical symptoms, and is among the most reliable predictors of subsequent cognitive decline. Despite its importance, the cellular events that trigger this early synaptic vulnerability remain poorly defined. Growing evidence points to a critical failure at the interface between neuronal energy metabolism and synaptic signalling, commonly referred to as the mitochondria-synapse axis, suggesting that its disruption may occur well before the accumulation of classical amyloid and tau pathology. In this Review, we combine findings from human neuronal models, multi-omics analyses, and in vivo studies to show how amyloid-β oligomers (Aβ oligomers) induce subtle yet consequential defects in mitochondrial trafficking, calcium handling, redox homeostasis, and local ATP supply. Together, these changes undermine the precise coordination between mitochondrial metabolism and calcium-dependent signalling that is essential for synaptic plasticity. As a result, affected neural circuits lose the capacity to meet the energetic demands of sustained information processing. We propose that this early uncoupling of energy availability from synaptic demand represents a leading contributor to neuronal vulnerability rather than a secondary consequence of protein aggregation, based on converging evidence from iPSC-derived cortical neurons, human neuronal cultures, and transgenic mouse models, with human in vivo validation still emerging. Finally, we highlight emerging therapeutic strategies aimed at restoring mitochondrial quality control, axonal transport, and metabolic communication. By re-aligning bioenergetic support with synaptic function, such approaches may open a critical window for intervention before irreversible circuit degeneration takes hold.},
}

@article {pmid42106438,
year = {2026},
author = {Aydin, AG and Manoj, P and Ramadan, F and Rajan, S and Youssef, E and Torres, EB and Bieszczad, KM},
title = {Sound-evoked auditory neurophysiological signals are a window into prodromal functional differences in a preclinical model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-51854-8},
pmid = {42106438},
issn = {2045-2322},
support = {Career Continuation Award//Nancy Lurie Marks Family Foundation/ ; DC018561/DC/NIDCD NIH HHS/United States ; },
abstract = {Hearing is the largest modifiable mid-life risk factor for Alzheimer's disease (AD), yet its link to dementia remains unclear. We identified a neurophysiological biomarker of AD risk using the non-invasive, rapidly acquired, and clinically translatable auditory brainstem response (ABR) in normal hearing knock-in rats (Swedish familial AD risk variant to Amyloid precursor protein, App[S]; male and female). Human ABRs have been proposed as a biomarker for AD and related dementias. The novel metric reported here is derived from multidimensional parametric feature extraction on the distribution statistics of repeated single-trial ABR traces. We report accurate prediction of genetic risk for AD risk in young and aged rats: App[S] separate clearly from healthy humanized (App[H]) in sex- and age-dependent manners. Notably, auditory learning during young adulthood shifted the App[S] ABR signature towards a healthy App[H]-like state that maintained over time into older age. Altogether the findings support the utility of the ABR to track disease state, progression, and effects of intervention, and point to a central neural generator of auditory dysfunction related to AD risk. ABRs could provide a very early biomarker for detection of AD risk and used to test the synergy of auditory and cognitive functions in human dementia.},
}

@article {pmid42106468,
year = {2026},
author = {Santos, ACC and Corrêa, JL and Duarte, RMF and Malta, SM and Rodrigues, TS and de Oliveira Santos, D and de Faria, PR and do Prado Mascarenhas, FNA and Zanon, RG and Cassemiro, NS and Carollo, CA and Espindola, FS and Martins, MM and Mendes-Silva, AP and Bonetti, AM and Dos Santos, AR and Ueira-Vieira, C},
title = {Bacterial polar metabolites modulate β-amyloid toxicity and cholinergic dysfunction in models of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-52291-3},
pmid = {42106468},
issn = {2045-2322},
support = {APQ-00269-22//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 403193/2022-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; APQ-03613-17; APQ-02766-17//Fundação de Amparo à Pesquisa do Estado de Minas Gerais , Brasil/ ; },
abstract = {Alzheimer's disease is characterized by progressive neurodegeneration driven by β-amyloid (Aβ) toxicity, oxidative stress, and cholinergic dysfunction. In this study, we investigated whether polar metabolites derived from a cultivable bacterial isolate could modulate Aβ-associated neurodegenerative phenotypes in complementary experimental models. A bioactivity-guided approach identified an aqueous fraction with high antioxidant capacity in DPPH, FRAP, and ORAC assays. In a transgenic Drosophila melanogaster model expressing human Aβ, treatment with this fraction significantly reduced amyloid accumulation and attenuated neurodegenerative histopathological alterations. In human SH-SY5Y neuronal cultures, the metabolites improved cell viability under therapeutic, but not preventive, conditions following exposure to aggregated Aβ. The aqueous fraction also exhibited significant inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Whole-genome sequencing assigned the bioactive isolate to the genus Providencia, with comparative genomic analyses suggesting its placement within a distinct taxonomic lineage. Metabolomic profiling by LC-ESI-MS/MS revealed a diverse set of polar metabolites, including metabolites putatively annotated based on spectral matching, previously associated with neuroprotective and cholinesterase-modulating activities. Collectively, these findings demonstrate that bacterial polar metabolites can modulate key pathological features of Alzheimer's disease, supporting their relevance for mechanistic studies of Aβ toxicity and cholinergic dysfunction.},
}

@article {pmid42106823,
year = {2026},
author = {Yin, C and Nelen, I and Harms, A and Hartman, R and Bos, S and Nijgh-van Kooij, C and Hankemeier, T and Kindt, A and de Lange, E},
title = {Longitudinal metabolomic profiling of biogenic amines in plasma and CSF, and their correlation, reveals sex-specific and age changes in TgF344 Alzheimer's disease transgenic and wildtype rats.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00811-8},
pmid = {42106823},
issn = {2045-8118},
support = {175.2019.032//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; },
abstract = {BACKGROUND: Alterations in amine metabolism have been implicated in Alzheimer's disease (AD), but the relationships between plasma and cerebrospinal fluid (CSF) amine levels remain insufficiently understood.

AIM: To investigate longitudinal changes in amines in plasma and CSF, as well as their cross-matrix correlations, in male and female TgF344-AD transgenic rats compared with wild-type (WT) controls.

METHOD: LC-MS-based targeted metabolomics was used to quantify 60 plasma amines and 55 CSF amines in male and female TgF344-AD and WT rats at 12, 25, 50 and 85 weeks of age. Generalized linear models, Pearson correlations, and Fisher's r-to-z transformation were applied for statistical analysis.

RESULTS: In plasma, age- and sex-associated differences were observed. At 25 weeks, three amines (4-hydroxy-proline, homocitrulline, and hydroxylysine) showed significantly increased levels in male TgF344-AD rats after multiple-testing correction. Additional trend-level changes were observed at 12, 50, and 85 weeks. In CSF, no amines passed the significance threshold after multiple-testing correction, although descriptive age- and sex-associated patterns were observed, with earlier changes in males and later-stage trends in females. CSF-plasma correlations tended to be stronger in TgF344-AD rats than in WT rats, with relatively strong correlations for alpha-aminobutyric acid, citrulline, N6,N6,N6-trimethyl-lysine, and putrescine.

CONCLUSIONS: Body fluid, age- and sex-dependent amine alterations in CSF and plasma of TgF344-AD rats compared to WT controls provide important insights into AD disease processes and may aid early diagnosis and therapeutic targeting.},
}

@article {pmid42107073,
year = {2026},
author = {Xiong, L and Sun, D and Guo, HH and Lee, D and Liu, Z and Mei, L and Xiong, WC},
title = {A Skull Bone Marrow-to-Brain Axis Links Osteoblastic Activity to Myeloid Cell Trafficking, Cerebral Blood Flow, and Cognition in Alzheimer's Progression.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e75622},
doi = {10.1002/advs.75622},
pmid = {42107073},
issn = {2198-3844},
support = {AG051510/NH/NIH HHS/United States ; AG066526/NH/NIH HHS/United States ; },
abstract = {Patients with Alzheimer's disease (AD) often develop osteoporosis, but the role of bone remodeling in AD remains unclear. We previously showed that osteoblast-specific expression of APPswe induces bone loss, glial activation, and behavioral deficits, suggesting a bone-to-brain signaling axis. Here, we identify an altered skull bone marrow (SBM)-to-brain axis in AD. Early SBM changes, including reduced cellularity, increased density, and expanded vascular channels to the meninges, occur in multiple APPswe mouse models. These vascular changes facilitate migration of SBM-derived myeloid cells into the meninges and cortex, improving cerebral blood flow (CBF) and slowing cognitive decline. Notably, these effects are age-dependent, emerging at 6 months but diminishing by 12 months. Enhancing this axis via bone marrow transplantation improves CBF and cognitive function in aged mice, whereas disrupting it through osteoblastic deletion of ATP6AP2 impairs both. Together, these findings reveal a previously unrecognized SBM-to-brain axis that regulates immune, vascular, and cognitive functions, highlighting systemic contributions to AD pathogenesis.},
}

@article {pmid42107260,
year = {2026},
author = {Huang, Y and Wang, Y and Wang, Y and Cheng, H and Yang, H and Wang, C and Xu, Y},
title = {The design, synthesis and evaluation of the first carbon-11 positron emission tomography radiotracer for ASK1 imaging.},
journal = {Bioorganic chemistry},
volume = {178},
number = {},
pages = {109970},
doi = {10.1016/j.bioorg.2026.109970},
pmid = {42107260},
issn = {1090-2120},
abstract = {Apoptosis signal regulating kinase 1 (ASK1) plays a central role in the molecular pathogenesis of various neurological disorders by mediating inflammation, oxidative stress, and apoptosis. ASK1 has emerged as an important therapeutic target in a range of neurodegenerative and neuroinflammatory disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Herein, we describe the development and preclinical evaluation of [[11]C]HYF038 as the first positron emission tomography radiotracer for imaging ASK1. In vitro autoradiography, [[11]C]HYF038 performed good specific binding to the ASK1 proteins in the mice brain regions, data are expressed as the density light units per square millimeter (DLU/mm[2]) in the blocking group was reduced by 28%. In vivo PET imaging of [[11]C]HYF038 in rodent model demonstrated a certain blood-brain barrier (BBB) penetration with SUV = 0.5, the biodistribution result of [[11]C]HYF038 in different organs showed that [[11]C]HYF038 is mainly metabolized in the liver. These findings indicate that [[11]C]HYF038 can act as a promising lead for the further development of PET tracers to image ASK1 in neurodegenerative disease progression.},
}

@article {pmid42107267,
year = {2026},
author = {Wei, Y and Zhang, A and Qiu, W and Xiong, B and Song, Z and Zheng, N and Wu, Y and Zhang, C and Cao, Z and Wang, X and Xu, C and Zhao, Q and Wu, Y and Liu, Z and Chen, Y and Sun, H},
title = {Development of tacrine-based multitarget-directed ligands as dual AChE/EGFR inhibitors with neuroprotective activity.},
journal = {Bioorganic & medicinal chemistry},
volume = {139},
number = {},
pages = {118677},
doi = {10.1016/j.bmc.2026.118677},
pmid = {42107267},
issn = {1464-3391},
abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disease for which current therapies primarily rely on cholinesterase inhibitors (ChEIs). Tacrine was the first and potent ChEI, which was soon withdrawn due to hepatic side effects. Meanwhile, the epidermal growth factor receptor (EGFR) inhibitor gefitinib has shown anti-AD potential. Inspired by these findings, we designed a series of hybrid molecules by conjugating the tacrine and gefitinib pharmacophores to create dual AChE/EGFR inhibitors, aiming to ameliorate cognitive impairment. After the structure-activity relationship (SAR) studies, two lead compounds (S24-1008 and S24-1017) were identified with high target affinity. These optimized compounds exhibited moderate cytotoxicity across various neuronal cell lines. Compared to traditional EGFR inhibitors, they demonstrated superior blood-brain barrier (BBB) permeability. Furthermore, they conferred significant neuroprotection against H2O2- and glutamate-induced neuronal damage. In vivo studies confirmed that both S24-1008 and S24-1017 effectively reversed cognitive deficits and enhanced learning and memory in mice, with no significant change in body weight observed.},
}

@article {pmid42107310,
year = {2026},
author = {Xiao, P and Yu, J and Han, Y and Chen, X and Hu, Y and Huang, X},
title = {[1,3]Oxazine-based NIR molecular switches: Hydrochromic behavior, viscosity sensing, and targeted cell imaging.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {360},
number = {},
pages = {128046},
doi = {10.1016/j.saa.2026.128046},
pmid = {42107310},
issn = {1873-3557},
abstract = {Molecular switches based on [1,3] oxazine show distinctive properties between their ring-closed and ring-opened forms (RCF and ROF), differing in conjugation length, charge, hydrophilicity, and optical behavior. These features enable low background interference and organelle-selective targeting, which are highly valuable for intracellular fluorescence imaging. However, related studies remain scarce. In this work, two near-infrared (NIR) molecular switches, BOA-1 and BOA-2, were designed using [1,3] oxazine as the core scaffold. They exhibit excellent hydrochromic behavior with a 300 nm absorption red-shift, supporting applications in water-ink painting. BOA-1 shows a pKa of 8.78 and specific endoplasmic reticulum (ER) targeting in living cells. It also presents specific fluorescence activation toward viscosity, with two non-overlapping emission peaks separated by 230 nm, ensuring high anti-interference performance and quantitative ratiometric detection. Notably, BOA-1 shows great potential for Alzheimer's disease (AD) diagnosis and therapeutic monitoring. This work first reports the NIR fluorescent sensing of [1,3] oxazine derivative toward intracellular microenvironments, which provides a promising platform for disease diagnosis and further biological fluorescence sensing applications.},
}

@article {pmid42107415,
year = {2026},
author = {Stepanchuk, AA and Joseph, JT and Lashley, T and Stys, PK},
title = {Disentangling amyloid polymorphs in normal aging and Alzheimer's disease using dual-probe spectral imaging.},
journal = {Neurobiology of aging},
volume = {165},
number = {},
pages = {51-59},
doi = {10.1016/j.neurobiolaging.2026.04.009},
pmid = {42107415},
issn = {1558-1497},
abstract = {Variability in Alzheimer's disease (AD) clinical presentation complicates mechanistic studies and therapeutic outcome prediction. Brain protein aggregate load does not directly correlate with clinical symptoms; however, different subtypes of AD have been reported to exhibit structural variation (polymorphism) of aggregates. Little is known about the structural diversity of the deposits in cognitively normal aged brains. This study investigates the structural heterogeneity of amyloid aggregates in the hippocampus and their association with age- and disease-related pathology. Post-mortem hippocampal tissue from cognitively normal aged controls and AD patients was co-stained with the amyloid-sensitive dyes BSB and MCAAD-3 and imaged across various subregions using spectral fluorescence microscopy. Machine learning analysis of spectral data differentiated amyloid polymorphs between cognitively normal and Alzheimer's cases. Our analysis revealed distinct spectral features across the amyloid plaques, neurofibrillary tangles and the background tissue parenchyma associated with AD compared to those observed in cognitively normal aging, irrespective of overall aggregate load. This study underscores the importance of amyloid polymorphism in determining the clinical impact of protein pathology in AD. Our findings highlight that focusing on amyloid structure rather than total load can aid in advancing personalized approaches in the diagnosis and treatment of neurodegenerative diseases.},
}

@article {pmid42107515,
year = {2026},
author = {Verma, B and Singh, P and Goberdhan, DCI and Wilson, C},
title = {Defective Regulated Secretion: A Trigger for Alzheimer's Pathology?.},
journal = {Progress in neurobiology},
volume = {},
number = {},
pages = {102926},
doi = {10.1016/j.pneurobio.2026.102926},
pmid = {42107515},
issn = {1873-5118},
abstract = {Extracellular amyloid plaques formed from aggregated Amyloid-β (Aβ), a specific cleavage product of Amyloid Precursor Protein (APP), and intracellular tau-containing neurofibrillary tangles are the two key histopathological hallmarks of Alzheimer's Disease (AD). However, increasing evidence suggests that the trigger for neurodegeneration in AD involves intraneuronal defects in endolysosomes, which might be induced by both Aβ and tau. Recent high-resolution analysis of trafficking inside neuronal and non-neuronal cells suggests such defects may arise through aberrant compartmental maturation events during regulated secretion. These events bring together APP, secretory and endosomal compartments, and also the proteolytic secretases that generate Aβ. They may be initiated by the accumulation of Aβ and/or C-terminal fragments of APP, which interfere with endolysosomal trafficking and potentially induce tau pathology. They also lead to secretion of proteins from these Aβ-containing compartments, which can trigger endolysosomal phenotypes in other cells that endocytose them. By implicating regulated secretion in the initiation of AD, this new model highlights novel intracellular mechanisms that might drive neurodegeneration. Identifying suppressors of these pathways could suggest entry points for the development of novel therapies that target the earliest stages of AD pathology.},
}

@article {pmid42107604,
year = {2026},
author = {Shaheen, H and Melnik, R},
title = {Bayesian modelling of amyloid-beta dynamics and astrocyte influence in Alzheimer's disease.},
journal = {Journal of neuroscience methods},
volume = {},
number = {},
pages = {110785},
doi = {10.1016/j.jneumeth.2026.110785},
pmid = {42107604},
issn = {1872-678X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a complicated neurological condition defined by the deposition of amyloid-beta (Aβ) plaques. Despite extensive research, the dynamics of Aβ growth, particularly the role of astrocytes, remain poorly understood, limiting the development of effective treatments.

NEW METHOD: This study addresses this gap by introducing a Bayesian inference framework for modelling Aβ dynamics, incorporating both strong and weak astrocyte effects utilizing Alzheimer's Disease Neuroimaging Initiative (ADNI) clinical data.

RESULTS: Through a combination of stochastic growth models and approximate Bayesian computation (ABC), we evaluate how astrocyte concentrations influence Aβ accumulation in different disease stages. Our findings show that higher astrocyte levels can suppress Aβ growth, while lower levels promote it, suggesting that astrocyte-targeted interventions may alter disease progression.

This data-driven probabilistic approach not only captures the inherent biological variability but also provides a tractable method to estimate uncertain parameters.

CONCLUSIONS: The present research offers a valuable tool for therapeutic modelling and prediction in AD.},
}

@article {pmid42107617,
year = {2026},
author = {Tian, Y and Whitwell, JL},
title = {Advanced Diffusion MRI Tract Signatures in Alzheimer's Disease, Dementia with Lewy Bodies, and the FTD/PPA Spectrum.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121984},
doi = {10.1016/j.neuroimage.2026.121984},
pmid = {42107617},
issn = {1095-9572},
abstract = {Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and primary progressive aphasia (PPA) are heterogeneous neurodegenerative syndromes with overlapping clinical features and substantial societal burden. Their phenotypic diversity, including atypical AD variants and multiple PPA subtypes, poses major challenges for early diagnosis and disease monitoring. Sensitive, non-invasive imaging biomarkers remain limited. Diffusion magnetic resonance imaging (dMRI) has evolved beyond conventional diffusion tensor imaging (DTI) to include multi-shell models such as neurite orientation dispersion and density imaging (NODDI), free-water imaging (FWI), and fixel-based analysis (FBA), which offer increased microstructural specificity by probing neurite organization, extracellular water content, and fiber-specific degeneration. In this review of 54 dMRI studies spanning AD, DLB, FTD, and PPA spectrums, we identify both convergent microstructural patterns shared across techniques and disease-specific signatures revealed by advanced models. Canonical DTI findings demonstrate consistent syndrome-related alterations, including fornix and cingulum involvement in AD, widespread diffusivity increases in DLB, uncinate fasciculus degeneration in FTD, and arcuate fasciculus disruption in PPA. Advanced dMRI methods extend these observations by revealing disease-specific neurite and free-water alterations, associations with molecular imaging markers, and improved sensitivity to clinical severity, longitudinal cognitive decline, and microstructural progression. Across syndromes and subtypes, NODDI- and FBA-based metrics consistently outperform conventional DTI. Together, this review provides a comprehensive framework for interpreting advanced dMRI markers across the AD, DLB, and the FTD-PPA spectrum, and highlights their potential for refining disease characterization and tracking neurodegenerative progression.},
}

@article {pmid42107621,
year = {2026},
author = {Khattab, NA and El Kadeem, A and Goda, AE and El-Mahdy, NA and El-Shitany, N},
title = {Aluminum chloride in Alzheimer's disease: A dual focus on molecular mechanisms and rat experimental models.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115814},
doi = {10.1016/j.expneurol.2026.115814},
pmid = {42107621},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a leading cause of dementia among middle-aged and elderly individuals globally. Animal models of AD are widely used to investigate disease mechanisms and evaluate potential treatments for disease modification. Among non-genetically modified models, aluminum (Al[3+]) induced neurotoxicity has been widely employed to mimic key features of AD, including neuroinflammation and cognitive decline. This review comprehensively elucidates current evidence on the molecular and cellular mechanisms underlying Al[3+]-induced AD-like pathology, including amyloid-β accumulation, tau protein hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, cholinergic system impairment, synaptic plasticity deficits, apoptosis, metal ion dyshomeostasis, and epigenetic alterations. This review critically discusses methodological variables that significantly influence experimental outcomes in Al[3+]-based models, including dosage, route of administration, exposure duration, and animal age and gender. Moreover, this review emphasizes the translational significance, advantages, and limitations of the Al[3+]-induced model by merging mechanistic insights with experimental design considerations, offering guidelines for its optimal application in AD research and treatment development.},
}

@article {pmid42107623,
year = {2026},
author = {Martínez-Drudis, L and Sheta, R and Musiol, D and Teixeira, M and Oueslati, A},
title = {The emerging role of polo-like kinase 2 in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115806},
doi = {10.1016/j.expneurol.2026.115806},
pmid = {42107623},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated Tau tangles. Protein phosphorylation is increasingly recognized as a key modulator of AD pathology, but the specific kinases involved remain incompletely characterized. Polo-like kinase 2 (PLK2), a serine/threonine kinase previously studied in Parkinson's disease, has recently emerged as a potential contributor to AD pathogenesis. This review explores the physiological and pathological roles of PLK2, emphasizing its expression in the brain, its regulation by neuronal activity, and its involvement in synaptic homeostasis. Evidence from postmortem brain studies, in vivo models, and cell-based experiments indicates that PLK2 is associated with AD through multiple mechanisms. PLK2 has been shown to modulate the amyloidogenic processing of amyloid precursor protein (APP), is associated with increased Aβ production, and can directly phosphorylates APP at critical sites. Elevated PLK2 levels have also been associated with reduced APP surface expression and increased endocytosis, changes that are consistent with enhanced Aβ generation. Although direct phosphorylation of Tau by PLK2 has not been clearly established, recent findings suggest that PLK2 activity can modulate Tau protein levels and influence its phosphorylation state, potentially through regulation of other kinases and phosphatases. Pharmacological inhibition of PLK2 has shown promising effects in transgenic mouse models of AD, including modulation of Aβ and Tau pathology and improvement in cognitive performance, with some sex-specific responses. While these findings support a contributory role for PLK2 in AD-relevant pathways, its precise position within the causal hierarchy of disease progression remains to be fully established.},
}

@article {pmid42107748,
year = {2026},
author = {Suriyaamporn, P and Wongprayoon, P and Pannakkong, W and Pamornpathomkul, B and Ngawhirunpat, T and Rojanarata, T and Opanasopit, P},
title = {Development of AI-assisted 3D-printed degradable hydrogel microneedles for transdermal delivery of progesterone-loaded solid lipid nanoparticles: a novel approach to slowing Alzheimer's disease progression.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {126967},
doi = {10.1016/j.ijpharm.2026.126967},
pmid = {42107748},
issn = {1873-3476},
abstract = {Progesterone (PG) is used to slow the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD) in postmenopausal women. However, PG exhibits high lipophilicity, resulting in strong binding to skin tissues and plasma proteins, which may limit its systemic transport via transdermal routes. Solid lipid nanoparticles (SLNs) have been highlighted for their potential to enhance drug solubility and facilitate brain-targeted drug delivery for AD treatment. Microneedles (MNs) offer an advanced microtechnology for transdermal drug delivery, significantly improving drug permeation into the skin. However, traditional MNs fabrication methods face challenges related to shape control, dosage precision, high costs, and time consumption. Recent advancements in 3D printing technology offer a promising solution to these limitations. This study aimed to design and evaluate 3D-printed MNs-loaded with PG-SLNs for AD treatment. Biodegradable resin was utilized to fabricate MNs, aided by a Convolutional Neural Networks (CNNs) prediction model for improved accuracy. Mechanical strength, penetration efficiency, degradation, in vitro and in vivo drug delivery efficiency, cellular toxicity, and stability were evaluated. The optimized MNs, with a height of 756.98 ± 14.78 µm, effectively penetrated the skin barrier. SLNs exhibited a particle size of 308.91 ± 1.66 nm, PDI of 0.19 ± 0.08, and ZP of -30.03 ± 1.19 mV. The MNs retained sufficient mechanical strength post-drug loading, enabled efficient transdermal PG delivery, exhibited no cytotoxicity to neuronal cells, and remained physicochemically stable for up to 3 months. This study highlights the potential of 3D-printed MN patches as a novel transdermal drug delivery system, demonstrating practical feasibility for medical applications.},
}

@article {pmid41913175,
year = {2026},
author = {Ito, K and Tsuda, S and Wake, T and Hatakeyama, A and Ogisawa, F and Ono, M and Nakayama, R and Wakui, T and Nagano, N and Iwata, A},
title = {Reframing dementia care in the era of disease-modifying therapies: informational, psychosocial, and systemic insights from Japan.},
journal = {BMC health services research},
volume = {26},
number = {1},
pages = {},
pmid = {41913175},
issn = {1472-6963},
support = {25K14240//Grants-in-Aid for Scientific Research/ ; 25GB0301//Health and Labor Sciences Research Grant/ ; },
abstract = {BACKGROUND: The introduction of disease-modifying therapies (DMTs) for Alzheimer’s disease has prompted major changes in diagnostic pathways, referral processes, and service coordination in dementia care. Japan, as an early adopter of DMTs within a nationally coordinated dementia-care framework, offers an opportunity to examine how health service structures respond to these changes. This study explored health service–related support needs emerging across the DMT pathway, focusing on patient and informal caregiver experiences, with complementary perspectives from service providers.

METHODS: A qualitative study was conducted using semi-structured interviews with 48 participants, including nine patients who underwent DMT eligibility assessment, seven informal caregivers, 11 physicians, four nurses, five clinical psychologists, five social workers, and seven community-based dementia support providers. Data were analyzed using the Framework Method, an applied qualitative approach suitable for health services research. Patients’ and caregivers’ accounts were treated as the primary analytic focus, while provider perspectives were used to contextualize system-level factors influencing care delivery.

RESULTS: Three interrelated themes were identified. First, informational support needs reflected inequitable access to trustworthy information, difficulties in sustaining understanding of complex medical explanations, and a lack of structured opportunities to revisit information over time, particularly during transitions such as ineligibility, treatment discontinuation, or completion. Second, psychosocial support needs were closely shaped by service processes, including stigma-related experiences across clinical and social contexts, family-related tensions around treatment decisions, fluctuating expectations regarding treatment effects, and limited support for adjustment when DMT was no longer an option. Third, systemic and collaborative support needs highlighted fragmented roles between primary care and DMT-designated institutions, unclear referral and handover pathways, insufficient psychosocial care capacity, and weak integration between DMT delivery systems and existing dementia-care services.

CONCLUSIONS: The implementation of DMTs has amplified pre-existing gaps in dementia care systems, revealing previously underrecognized structural vulnerabilities across informational, psychosocial, and systemic domains. Findings indicate that DMTs should be embedded within coordinated care pathways that ensure continuity of information provision, access to psychosocial support, and clear allocation of follow-up responsibility regardless of treatment eligibility. Aligning pharmacological innovation with health service design is essential to support equitable, continuous, and person-centered dementia care.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12913-026-14472-8.},
}

@article {pmid41913207,
year = {2026},
author = {Che, J and Li, X and Qiu, Z and Li, R and Yu, H and Xie, J and Guo, T and Tang, Z and Xia, P and Xu, K and Li, R and Yang, K and Geng, T and Pan, A and Liu, G},
title = {Phenotypic heterogeneity of type 2 diabetes and risks of complications with a tree-like representation.},
journal = {Cardiovascular diabetology},
volume = {25},
number = {1},
pages = {},
pmid = {41913207},
issn = {1475-2840},
support = {82325043//National Natural Science Foundation of China/ ; 2023YFC3606305//National Key Research and Development Program of China/ ; 82273623//National Nature Science Foundation of China/ ; 2021GCRC076//Fundamental Research Funds for the Central Universities/ ; },
abstract = {BACKGROUND: Type 2 diabetes shows clinical heterogeneity which cannot be fully captured by glycemic metrics, highlighting the need to better define patient phenotypes and progression pathways. This study aims to elucidate the heterogeneity of type 2 diabetes and risks of major associated diseases, as well as underlying proteomic mechanism.

METHODS: We applied discriminative dimensionality reduction with trees (DDRTree) algorithm to construct a tree from seven clinical variables (body mass index, high density lipoprotein cholesterol, triglyceride, HbA1c, systolic blood pressure, diastolic blood pressure, and total cholesterol). Disease risks were assessed using competing risk models.

RESULTS: This study included 6406 individuals with newly diagnosed type 2 diabetes from the UK Biobank. All seven clinical variables formed a gradient distribution across the DDRTree-derived phenotypic structure, revealing three distinct disease risks patterns: participants with adiposity, hypertension and dyslipidemia exhibited elevated risks of macrovascular complications, diabetic kidney disease, Parkinson’s disease and non-alcohol fatty liver disease; those with hyperglycemia and dyslipidemia had higher risks of myocardial infarction, diabetic neuropathy, diabetic retinopathy, depression and chronic obstructive pulmonary disease; while elevated total cholesterol and high-density lipoprotein cholesterol were associated with increased risks of cancer and Alzheimer’s disease. Proteomic analyses identified pattern-specific pathways: metabolic dysregulation and extracellular matrix remodeling in the first pattern, inflammatory activation and lipid metabolism alterations in the second, and immune activation with chemical carcinogenesis in the third. Furthermore, sensitivity to lifestyle factors were phenotypic-specific. These patterns were similar in the Dongfeng-Tongji Diabetes cohort, though cardiovascular disease and retinopathy risks were strongly associated with hypertension. An online tool was provided for individual risk prediction.

CONCLUSIONS: Our findings reveal distinct spatial distributions of clinical features and associated disease risks in type 2 diabetes, with subgroups exhibiting unique proteomic signatures and differential lifestyle responses, underscoring the importance for personalized management for diabetes care.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-026-03147-7.},
}

@article {pmid42103118,
year = {2026},
author = {Lee, J and Lee, K and Kim, M and Kim, MW and Lim, M and Yoo, J and Lee, SH},
title = {Polyamine and tau: a chemical framework for understanding the hyperphosphorylated tau condensation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {152366},
doi = {10.1016/j.ijbiomac.2026.152366},
pmid = {42103118},
issn = {1879-0003},
abstract = {The pathological aggregation of tau proteins is a defining feature of Alzheimer's disease (AD), yet the molecular mechanisms underlying this process remain unresolved. Hyperphosphorylated tau, which detaches from microtubules and disrupts neuronal integrity, carries a high net negative charge. Despite this, most current models of tau aggregation overlook the electrostatic repulsion that should prevent condensation. Here, we investigate the potential role of polyamines, ubiquitous and multivalent cations, as mediators that help compensate for this charge imbalance, using fluorescence microscopy and molecular dynamics simulations. We show that polyamines promote liquid-liquid phase separation (LLPS) of hyperphosphorylated tau through charge-charge interactions, enabling the formation of dense protein condensates. Importantly, we further demonstrated that polyamine-dependent tau condensates also formed in cellular environments, supporting the potential physiological relevance of this mechanism. Over time, these condensates undergo a transition into filament-like structures, suggesting a possible pathway linking polyamine-mediated LLPS to tau aggregation processes. The results reveal polyamines as important modulators of tau condensation and aggregation in both in vitro and cellular contexts.},
}

@article {pmid42103119,
year = {2026},
author = {Shahab, M and Xiao, J and Wang, J and Huang, Z},
title = {Molecular basis of BACE1 modulation revealed by machine learning, molecular simulations, and experimental validation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {152409},
doi = {10.1016/j.ijbiomac.2026.152409},
pmid = {42103119},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) remains one of the most prevalent and debilitating neurodegenerative disorders worldwide, with no currently available disease-modifying treatments. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) catalyzes the rate-limiting step in amyloid-β (Aβ) production and represents a validated therapeutic target for AD intervention. In this study, we developed an integrated computational framework combining machine learning-based virtual screening, molecular docking, and molecular dynamics simulations with experimental validation using CCK-8 assays and Western blot analysis to identify novel BACE1 inhibitors from a natural product library. A curated dataset of experimentally validated BACE1 inhibitors retrieved from the ChEMBL database was used to construct 36 classification models based on three molecular fingerprint representations MACCS Keys, ECFP4, and Topological Torsion in combination with four machine learning algorithms such as Support Vector Machine (SVM), Random Forest (RF), Decision Tree (DT), and Extreme Gradient Boosting (XGBoost). Among all developed models, the SVM model using ECFP4 fingerprints achieved the best predictive performance, with an external test set accuracy of 0.91 and a Matthews Correlation Coefficient (MCC) of 0.78. The optimized models were subsequently applied to screen 4779 natural product compounds from the MedChemExpress library using a consensus prediction strategy. Promising hits were evaluated by molecular docking against the BACE1 crystal structure (PDB: 6PZ4), and top-ranked candidates were subjected to 200 ns molecular dynamics simulations followed by MM/GBSA binding free energy calculations. Among the identified candidates, HY-N7141 exhibited the most favorable docking score (-9.04 kcal/mol) and binding free energy (ΔG = -67.30 kcal/mol), driven predominantly by strong van der Waals interactions with key catalytic residues. Structural stability analysis confirmed that the majority of protein-ligand complexes maintained stable conformations throughout the simulations. Experimental validation in SH-SY5Y human neuroblastoma cells further assessed the effects of selected compounds on BACE1 protein expression. Collectively, these findings demonstrate the utility of integrating machine learning with structure-based approaches for accelerating the discovery of potent BACE1 inhibitors, and present several promising candidates warranting further preclinical investigation.},
}

@article {pmid42103123,
year = {2026},
author = {Andrade, S and Ferreira, Â and Ramalho, MJ and do Carmo Pereira, M and Loureiro, JA},
title = {Targeted liposomal epigallocatechin delivery for Alzheimer's disease: Effect on amyloid β fibrillation and neutralization of free radicals.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {152399},
doi = {10.1016/j.ijbiomac.2026.152399},
pmid = {42103123},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is a neurodegenerative condition marked by amyloid β (Aβ) plaque accumulation, contributing to cognitive decline. Epigallocatechin (EGC) has shown potential in preventing Aβ aggregation and disrupting fibrils, but its low bioavailability and poor blood-brain barrier (BBB) penetration limit its therapeutic use. To address these challenges, this study introduces the first functionalized nanosystem developed for the EGC delivery. Liposomal EGC was optimized and conjugated with transferrin (Tf), given literature evidence supporting its potential role in BBB-targeting strategies. The optimal formulation exhibited a mean diameter of 127 ± 14 nm, a polydispersity index of 0.20 ± 0.02, a zeta potential of -0.9 ± 0.3 mV, and an encapsulation efficiency of 20 ± 3%, properties that were maintained after 1 month of storage at 4 °C. Moreover, the nanosystem exhibited a controlled and sustained release, achieving 77 ± 11% release over 9 days. In terms of therapeutic activity, the nanoformulation showed an antioxidant capacity of 53 ± 6%, demonstrating its potential to neutralize free radicals, a key factor in AD progression. Furthermore, targeted liposomal EGC completely inhibited Aβ fibrillation, as demonstrated by thioflavin T assays. Data revealed a reduction in parallel β-sheet content from 44 ± 4% to 33 ± 5% and an increase in α-helices from 31 ± 5 to 45 ± 4%, suggesting inhibition of fibril formation. Additionally, Tf conjugation enhanced liposome uptake by endothelial cells without inducing cytotoxicity. These findings support the potential of this nanosystem as a promising platform for further investigation in AD.},
}

@article {pmid42103223,
year = {2026},
author = {Suresh, K and Rainvillee, C and Sterner, DE and Goldberg, MS and Butt, TR},
title = {The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113128},
doi = {10.1016/j.jbc.2026.113128},
pmid = {42103223},
issn = {1083-351X},
abstract = {Mitochondria play a major role in cellular health, yet their contribution to chronic diseases has been underestimated. Mitochondria are essential for all tissues, and a major source of ATP in high-energy-demand organs such as brain and heart being vulnerable to mitochondrial dysfunction. Failure to repair or remove damaged mitochondria contributes to aging and chronic diseases. Cells have evolved quality control mechanisms, including mitophagy to eliminate damaged mitochondria and mitobiogenesis to replenish them. The ubiquitin-proteasome system (UPS) is responsible for removing misfolded proteins, a process that is highly ATP dependent and therefore reliant on mitochondrial function. In turn, damaged mitochondria are eliminated through coordinated actions of the UPS and lysosomal degradation through mitophagy. Many neurodegenerative diseases are characterized by the presence of disease-specific protein aggregates, such as α-synuclein aggregates in Parkinson's disease and tau neurofibrillary tangles in Alzheimer's disease. These aggregates impair mitochondrial function, while dysfunctional mitochondria generate reactive oxygen species that further exacerbate proteotoxic stress, creating a pathogenic cycle. This highlights the functional interplay between mitochondria and the UPS. Recent studies have uncovered phosphorylation of ubiquitin at Serine 65 by the mitochondrial kinase PINK1 as a key signal of mitochondrial dysfunction. Phospho-Ser65-Ubiquitin (pUb) has emerged as an indicator of mitochondrial health and a potential biomarker for aging and neurodegenerative disease. However, due largely to a lack of tools, little is known about the role of pUb in cellular physiology. Here we review the current landscape of pUb biology, the phospho-ubiquitome, and its role as biomarker for mitochondrial health, and neurodegeneration.},
}

@article {pmid42103387,
year = {2026},
author = {Laugesen, K and Skjærbæk, C and Okkels, N and Møller, HJ and Borghammer, P and Gottrup, H and Parkner, T},
title = {ODIN Biobank: a Danish cohort for dementia research- cohort profile.},
journal = {BMJ open},
volume = {16},
number = {5},
pages = {e114084},
doi = {10.1136/bmjopen-2025-114084},
pmid = {42103387},
issn = {2044-6055},
mesh = {Humans ; Female ; Denmark ; Male ; Aged ; *Biological Specimen Banks ; *Dementia/cerebrospinal fluid/blood/diagnosis ; Biomarkers/cerebrospinal fluid/blood ; Aged, 80 and over ; Cohort Studies ; Middle Aged ; Alzheimer Disease/cerebrospinal fluid/blood ; Cognitive Dysfunction/cerebrospinal fluid/blood ; },
abstract = {PURPOSE: Biomarkers related to the diagnosis, prognosis and treatment of dementia will play a key role in future clinical practice. The overarching aim of the ODIN (blood and cerebrospinal fluid) Biobank is to study biomarkers for dementia and contribute to the transition from cerebrospinal fluid to blood-based biomarkers.

PARTICIPANTS: ODIN recruited 451 patients (median age 74 years, 53% females) referred to the Department of Neurology at Aarhus University Hospital, Denmark, for diagnostic assessment of dementia. Enrolment started in March 2020 and ended in July 2025. Patients referred for a lumbar puncture were eligible for inclusion. Cerebrospinal fluid and blood samples (plasma, serum and buffy coat) were stored at -80°C. Information about sociodemographic, educational level, dementia subtype, cognitive test scores, neuroimaging results, hypertension, diabetes, height, weight, alcohol consumption and smoking was collected.

FINDINGS TO DATE: The most frequent diagnoses were Alzheimer's disease (n=268, 59%), frontotemporal dementia (n=26, 5.8%) and mixed Alzheimer's and vascular disease (n=23, 5.1%). N=82 (18%) were cognitively unimpaired or had mild cognitive impairment but not dementia. The median Mini-Mental State Examination score was 23 (IQR: 20-26) and the median Addenbrooke's Cognitive Examination score was 68 (IQR: 58-77).

FUTURE PLANS: ODIN will contribute to the development, validation and implementation of new biomarkers related to diagnosis, prognosis and treatment of dementia. Furthermore, the cohort will assist the transition from cerebrospinal fluid to blood-based biomarkers.},
}

Humans
Female
Denmark
Male
Aged
*Biological Specimen Banks
*Dementia/cerebrospinal fluid/blood/diagnosis
Biomarkers/cerebrospinal fluid/blood
Aged, 80 and over
Cohort Studies
Middle Aged
Alzheimer Disease/cerebrospinal fluid/blood
Cognitive Dysfunction/cerebrospinal fluid/blood

@article {pmid42103483,
year = {2026},
author = {Nagano, W and Takahashi, J and Yamauchi, T and Yamada, D and Sano, Y and Furuichi, T and Saitoh, A},
title = {Oxytocin Neuron-Specific CAPS2 Deficiency in Mice Impairs Hippocampal Plasticity and Long-Term Memory Through Reduced ERK Phosphorylation in the Ventral hippocampus.},
journal = {The European journal of neuroscience},
volume = {63},
number = {9},
pages = {e70530},
doi = {10.1111/ejn.70530},
pmid = {42103483},
issn = {1460-9568},
support = {JP 21J20036//JSPS Fellows/ ; JP 26KJ2003//JSPS Fellows/ ; },
mesh = {Animals ; *Oxytocin/metabolism ; *Hippocampus/metabolism/physiology ; *Memory, Long-Term/physiology ; Mice ; Mice, Knockout ; *Neurons/metabolism ; Phosphorylation ; *Calcium-Binding Proteins/genetics/deficiency/metabolism ; *Nerve Tissue Proteins/genetics/deficiency/metabolism ; Male ; *Neuronal Plasticity/physiology ; Long-Term Potentiation ; *Extracellular Signal-Regulated MAP Kinases/metabolism ; Mice, Inbred C57BL ; },
abstract = {Oxytocin (OXT), a neuropeptide produced in the paraventricular nucleus (PVN) of the hypothalamus, regulates social behaviour, stress responses, and memory. Our previous studies demonstrated that intracerebroventricular administration of OXT ameliorates amyloid-β-induced cognitive deficits and that selective activation of PVN OXT neurons enhances memory performance. These findings suggest that endogenous OXT secretion is essential for normal memory processing and that its impairment may lead to cognitive dysfunction. To test this hypothesis, we generated oxytocin neuron-specific conditional knockout (cKO) mice for the Ca[2+]-dependent activator protein for secretion 2 (CAPS2) by crossing Caps2-floxed mice with oxytocin-iCre mice. In these mice, OXT exocytosis was selectively impaired in OXT neurons. Behavioural analyses revealed that Caps2 cKO mice exhibited deficits in long-term memory in the novel object recognition test (NORT) and passive avoidance tests, whereas short-term spatial memory assessed by the Y-maze test remained unaffected. Electrophysiological recordings further showed that hippocampal long-term potentiation was markedly attenuated in Caps2 cKO mice. Consistently, phosphorylated ERK levels in the ventral hippocampus were significantly reduced following the NORT. These findings demonstrate that CAPS2-dependent OXT release is critical for long-term memory formation and hippocampal synaptic plasticity. Our results provide new insight into the physiological role of endogenous OXT signalling in cognitive function and suggest its potential relevance to the pathogenesis of memory disorders such as Alzheimer's disease.},
}

Animals
*Oxytocin/metabolism
*Hippocampus/metabolism/physiology
*Memory, Long-Term/physiology
Mice
Mice, Knockout
*Neurons/metabolism
Phosphorylation
*Calcium-Binding Proteins/genetics/deficiency/metabolism
*Nerve Tissue Proteins/genetics/deficiency/metabolism
Male
*Neuronal Plasticity/physiology
Long-Term Potentiation
*Extracellular Signal-Regulated MAP Kinases/metabolism
Mice, Inbred C57BL

@article {pmid42103554,
year = {2026},
author = {Michel, CM and Bréchet, L},
title = {EEG microstates: from methodological foundations to clinical translation.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.04.003},
pmid = {42103554},
issn = {1878-108X},
abstract = {Electroencephalography (EEG) microstates represent discrete topographic configurations persisting approximately 50-120 ms before transitioning to new patterns. These transient states provide unique insights into large-scale brain organization in health and disease, capturing reference-independent, zero-lag, synchronized networks at timescales matching cortical communication constraints. This review addresses critical methodological challenges in EEG microstates, including data-driven cluster optimization, template derivation strategies for group comparisons, and interpretive frameworks based on convergent evidence rather than premature functional consensus. Future advances will require transitioning from arbitrary conventions to optimization-based approaches, characterizing higher-order temporal dynamics, establishing multimodal integration, and building validation standards that prioritize convergent evidence. With methodological rigor, microstate analysis can advance our understanding of brain dynamics and their role in cognition, consciousness, and brain disorders.},
}

@article {pmid42103686,
year = {2026},
author = {Barros, TGR and Grossi, LB and da Silva Campos, ML and Cardoso, IBN and Teixeira, AL and de Miranda, AS and de Brito Toscano, EC},
title = {Asymptomatic Versus Symptomatic Alzheimer's Disease Neuropathology: A Systematic Review of Differences Reported in Post-Mortem Studies.},
journal = {Neuropathology and applied neurobiology},
volume = {52},
number = {3},
pages = {e70077},
doi = {10.1111/nan.70077},
pmid = {42103686},
issn = {1365-2990},
support = {306078/2025-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; APQ 0158424//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism ; Humans ; *Brain/pathology/metabolism ; Autopsy ; *Asymptomatic Diseases ; },
abstract = {A subset of individuals exhibit substantial Alzheimer's disease (AD) neuropathology but remain asymptomatic (ASYMAD). The biological processes underlying this phenomenon remain poorly understood. We searched the PubMed/MEDLINE, Web of Science and CAPES databases to synthesise post-mortem brain tissue findings that differ between symptomatic and asymptomatic AD. Thirty-four studies met the predefined eligibility criteria. Multiple reports described lower levels of oligomeric Aβ and p-tau in ASYMAD, with reduced accumulation at synapses. Consistent with synaptic resilience, ASYMAD showed preserved expression of markers and proteomic signatures linked to synaptic function, homeostasis and plasticity. Further analyses supported preserved parenchymal architecture and dendritic and axonal morphology in ASYMAD. Some authors also described compensatory adaptations, including neuronal hypertrophy, increased neurogenesis and cellular antioxidant responses in ASYMAD brains. Additional findings indicated partial resistance to disruption of brain glucose, polyunsaturated fatty acid and one-carbon/polyamine metabolism. Glial and immune findings suggested a profile characterised by increased glial reactivity in specific regions and disease stages, alongside preserved glial homeostasis and lower cytokine expression in other contexts. In conclusion, although this review identified multiple processes potentially associated with the ASYMAD phenotype, the current evidence remains largely descriptive. Additionally, this synthesis is limited by substantial methodological heterogeneity and inconsistencies in data reporting. Future research should prioritise standardised clinicopathological definitions, pathology stage matching between ASYMAD and symptomatic AD groups, systematic assessment of mixed pathologies and further replication of exploratory findings to better elucidate the mechanisms underlying clinical resilience to AD neuropathology.},
}

*Alzheimer Disease/pathology/metabolism
Humans
*Brain/pathology/metabolism
Autopsy
*Asymptomatic Diseases

@article {pmid42097504,
year = {2026},
author = {Agüero, P and Gómez Tortosa, E},
title = {ADAM10 and its role in Alzheimer disease.},
journal = {Neurologia},
volume = {},
number = {},
pages = {502083},
doi = {10.1016/j.nrleng.2026.502083},
pmid = {42097504},
issn = {2173-5808},
abstract = {BACKGROUND: The amyloidogenic pathway of amyloid precursor protein (APP) processing is well known in the pathogenesis and therapeutics of Alzheimer disease (AD), whereas the non-amyloidogenic pathway has been less studied. ADAM10 is the main α-secretase responsible for this pathway in the human brain.

CONTENT: ADAM10 belongs to a family of transmembrane proteins with catalytic activity. It acts as an α-secretase on APP and many other substrates, some of which are particularly relevant in the central nervous system. The ADAM10 gene has been identified in genome-wide association studies of patients with AD; mutations have been reported in families with strong functional support but incomplete segregation; and haploinsufficiency has been reported in a family carrying a nonsense mutation. However, genetic studies of AD cohorts have not identified causal variants. ADAM10 levels in biological fluids show conflicting results, except in platelets, where patients with AD consistently exhibit reduced levels. Stimulation of ADAM10 as a therapeutic target offers new opportunities through various components and such measures as physical exercise. However, only one (positive) clinical trial has been published to date, using the retinoid acitretin.

CONCLUSIONS: ADAM10 plays a fundamental role in brain function, and sufficient studies support its involvement in AD pathogenesis. There are only isolated examples of ADAM10 mutations as a genetic cause, but these encourage continued screening in familial AD. ADAM10 levels in platelets could be considered as a biomarker. The enhancement of ADAM10 expression in AD remains a therapeutic target that requires further research.},
}

@article {pmid42097853,
year = {2026},
author = {Rohatgi, S and Omid-Fard, N and Zhu, S and Martinez Imbett, RE and Ford, JN and Dowling, TP and Kirsch, JE and Romero, JM},
title = {Relationship of Inferior Frontal Sulcal Hyperintensities with Amyloid-Related Imaging Abnormalities.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9395},
pmid = {42097853},
issn = {1936-959X},
abstract = {OBJECTIVE: Anti-amyloid immunotherapies used to treat Alzheimer's disease (AD) are often associated with amyloid-related imaging abnormalities (ARIA). We aim to indirectly assess glymphatic function by using inferior frontal sulcal hyperintensity (IFSH) as a biomarker in patients receiving anti-amyloid therapy, both with and without ARIA, as well as in healthy controls. We hypothesize that patients who develop ARIA will have higher IFSH scores than non-ARIA patients and healthy controls.

METHODS: Eligible AD patients who received anti-amyloid treatment were included in our retrospectively collected dataset. Only scans performed at 3T were used. Inter-rater reliability was evaluated and statistical analyses of IFSH scores and demographic data were performed to compare between groups. Additionally, within-subject analysis was used to compare the baseline and ARIA scans. Significance set at P < 0.05.

RESULTS: A total of 104 patients were selected based on the study criteria, of whom 60 had a clinical diagnosis of dementia. 36 patients developed ARIA, while 24 did not develop ARIA. 23 were age-matched healthy controls, and 21 were young healthy controls. Inter-rater reliability between the two readers was concordant when using quadratic weights appropriate for ordinal data (κ (w) = 0. 91, 95% CI 0.86-0.95). IFSH was significantly higher in the older age cohorts compared to young healthy controls (median 3.5 [IQR 2.5-5] versus 0 [0-1], P<0.001), with no significant difference between the dementia and healthy elderly groups (3.25 [3-4.875] versus 3.5 [2.5-5]). Among dementia patients on anti-amyloid therapy, significantly higher IFSH was observed in ARIA patients (at time of ARIA scan) compared to their non-ARIA counterparts (3.75 [3-5] versus 3 [2-4], P= 0.04). There was no significant difference in IFSH score between baseline and ARIA scans (P = 0.16).

CONCLUSION: IFSH was higher among dementia patients on anti-amyloid therapy with ARIA than among their non-ARIA counterparts. This supports its role as a potential biomarker of glymphatic dysfunction, although its utility on an individual basis is limited. Future prospective studies could benefit from incorporating IFSH as a variable, particularly if glymphatic therapies become a reality.},
}

@article {pmid42097981,
year = {2026},
author = {Tammaro, P and Hashitani, H},
title = {Calcium-activated chloride channels in pericytes and their role in regulating organ blood flow.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP287607},
pmid = {42097981},
issn = {1469-7793},
support = {MR/X010511/1/MRC_/Medical Research Council/United Kingdom ; 23K08767//Japan Society for Promotion of Sciences/ ; },
abstract = {Pericytes are mural cells of the microvasculature, characterised by a distinctive 'bump-on-a-log' morphology and elongated processes extending along the abluminal surface of capillary and pre- and post-capillary segments. They are widely distributed across organs and exhibit functional heterogeneity. Contractile pericytes directly regulate local blood flow, whereas non-contractile pericytes contribute to electrical signalling by generating depolarising or hyperpolarising events that propagate to upstream vessels and coordinate tissue perfusion. These functions are closely linked to intracellular ion homeostasis. Recent evidence highlights a role for Ca[2+]-activated Cl[-] channels (CaCCs), particularly TMEM16A (ANO1), in coupling intracellular Ca[2] [+] signals to membrane depolarisation and pericyte activity. In contractile pericytes, TMEM16A-mediated currents promote depolarisation to activate L-type voltage-gated Ca[2] [+] channels, facilitating Ca[2+] entry to support contraction. In non-contractile capillary pericytes, periodically generated TMEM16A-dependent depolarisations contribute to the initiation and propagation of spontaneous electrical activity, supporting intercellular synchrony within microvascular networks. Alternatively, asynchronous TMEM16A-dependent depolarisations could sum with each other to maintain resting membrane potentials and basal vascular tone. In this review, we summarise current understanding of CaCC channel function in pericytes across organs, and discuss emerging directions for future research and therapeutic targeting.},
}

@article {pmid42098313,
year = {2026},
author = {Shinagawa, S and Onuki, K and Shimizu, K},
title = {Physicians' perceptions and treatment practices for agitation associated with Alzheimer's dementia vary by specialty in Japan.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-51118-5},
pmid = {42098313},
issn = {2045-2322},
support = {NA//Otsuka Pharmaceutical Co., Ltd./ ; NA//Otsuka Pharmaceutical Co., Ltd./ ; NA//Otsuka Pharmaceutical Co., Ltd./ ; },
abstract = {Agitation, a behavioural and psychological symptom of dementia, is under-recognized in Japan. To describe the physician's perceptions and treatment practice for agitation in Alzheimer's dementia (AAD) in Japan, we conducted a cross-sectional web-based survey in October 2024. The survey included physicians in neurology, neurosurgery, psychiatry, or general internal medicine who were registered with the survey panel; consented to participation; affiliated with hospitals or clinics; treating ≥ 10 people with Alzheimer's dementia (AD)/month. Responses from 529 physicians showed that they treated an average of 35.0 people with AD per month, of whom 8.4 (24%) had AAD. When asked what "agitation" brought to mind, physicians most commonly selected the Japanese term for "excitability", corresponding to the "agitation/aggression" item in the Neuropsychiatric Inventory (58.6%). In general internal medicine, 24.2% were unaware of agitation. Anti-dementia drugs (91.7%) were most frequently selected as new medications for AD, whereas in psychiatry, antipsychotics were most frequently selected (95.8%), and side effects were cited more often as a key consideration than in other specialties. These results suggest that perceptions and treatment practices vary by specialty, particularly reflected in common antipsychotic prescriptions with higher safety awareness among psychiatrists and limited recognition of AAD in others, especially in general internal medicine.},
}

@article {pmid42098470,
year = {2026},
author = {Elghanam, Y and Kim, E},
title = {Evaluating the clinical effects of GLP-1 receptor agonists for Alzheimer's and Parkinson's diseases using minimal clinically important difference: systematic review and meta-analysis.},
journal = {Archives of pharmacal research},
volume = {},
number = {},
pages = {},
pmid = {42098470},
issn = {1976-3786},
support = {NRF-2021R1F1A1062044//Ministry of Science and ICT/ ; NRF-2021R1A6A1A03044296//Ministry of Education/ ; },
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are promising candidates for Alzheimer's disease (AD) and Parkinson's disease (PD). However, their effects in non-diabetic populations, independent of metabolic confounding, remain unclear. We evaluated the effects of GLP-1RAs on cognition, clinical outcomes, biomarkers, and safety in non-diabetic individuals with PD, AD, and mild cognitive impairment. We assessed the clinical meaningfulness of these effects using minimal clinically important difference thresholds. Relevant studies were retrieved from PubMed, Embase, and Web of Science from inception to November 2025. A random-effects meta-analysis was applied to calculate standardized mean differences (SMDs), mean differences (MDs), and risk ratios with 95% confidence intervals (CIs). The protocol was registered in PROSPERO (CRD420261277032). Fourteen randomized controlled trials enrolling 1260 participants were included. GLP-1RAs showed a small statistically significant improvement in global cognition (SMD 0.14, 95% CI 0.01 to 0.27; I[2] = 7%), supported by high-certainty evidence. Despite statistical significance, findings suggest only a trivial probability (1%) of a clinically important benefit. Conversely, GLP-1RAs were associated with poorer verbal fluency (SMD - 0.43, 95% CI - 0.79 to - 0.08; I[2] = 0%), supported by high-certainty evidence. For clinical severity, function, depression, and PD-related outcomes, pooled estimates generally favored GLP-1RAs, but none reached statistical significance. A significant between-disease subgroup difference was observed for function. In the PD subgroup, GLP-1RAs significantly improved depression symptoms relative to control (MD - 2.09, 95% CI - 3.99 to - 0.20; I[2] = 0%). Nevertheless, this magnitude of improvement remained below the threshold for clinically important benefit. Biomarker findings were inconsistent across trials. GLP-1RAs significantly reduced weight and were associated with poorer tolerability and increased gastrointestinal adverse events. Current evidence provides no convincing support for a clinically meaningful or disease-modifying effect of GLP-1RAs, and adverse effects may limit their clinical utility. Large-scale trials are needed to definitively weigh potential benefits against associated risks.},
}

@article {pmid42098564,
year = {2026},
author = {Oriquat, G and Hamed Ahmed, M and Al-Hasnaawei, S and Malathi, H and Mishra, S and Nanda, A and Arora, V and Chauhan, AS},
title = {Bridging neuroinflammation, oxidative stress, and neurogenesis: aromatic turmerone as a multifunctional modulator via NF-κB and Nrf2 pathways.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42098564},
issn = {1568-5608},
abstract = {Neuroinflammation and oxidative stress are central mechanisms driving neurodegenerative diseases, while impaired neurogenesis limits regeneration. Aromatic-turmerone (ar-turmerone), a bioactive sesquiterpenoid from Curcuma longa, has emerged as a multifunctional neuroprotective agent capable of modulating inflammatory and regenerative processes simultaneously. Evidence from in vitro and in vivo models demonstrates that ar-turmerone suppresses Toll-like receptor 4 (TLR4)-dependent NF-κB and MAPK signaling, thereby reducing microglial activation, nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory cytokines (TNF-α, IL-1β, IL-6). Concurrently, it activates the Nrf2/HO-1 antioxidant pathway and enhances cAMP/PKA-CREB signaling, restoring redox homeostasis and promoting neuronal survival. Importantly, ar-turmerone drives microglial polarization toward the M2 anti-inflammatory phenotype and stimulates neural stem cell (NSC) proliferation and neuronal differentiation in the subventricular zone and hippocampus. These dual anti-inflammatory and neurogenic actions position ar-turmerone as a unique bridge between neuroinflammation suppression and neuroregeneration enhancement. Recent structure-activity relationship studies further reveal that N-substituted amide and naphthyl derivatives exhibit superior inhibition of NO and TNF-α release and improved neuroprotective potency in Alzheimer's and Parkinson's disease models. Collectively, ar-turmerone represents a promising multi-target natural scaffold for developing therapeutics that counteract neurodegeneration by simultaneously modulating microglial activation, oxidative stress, and endogenous neurogenesis.},
}

@article {pmid42098640,
year = {2026},
author = {Mao, X and Zhang, D and Ying, D and Yu, J and Ge, Y and Jia, Z},
title = {Integration of glymphatic system function and hippocampal radiomics for diagnosis and conversion prediction of Alzheimer's disease.},
journal = {BMC medical imaging},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12880-026-02390-4},
pmid = {42098640},
issn = {1471-2342},
support = {SJCX24_2048//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; YJXYY202204-YSB73//Jiangsu Provincial Research Hospital/ ; BJ23030//Jiangsu Provincial Health Commission/ ; },
abstract = {BACKGROUND: Glymphatic system (GS) function and hippocampal microstructural changes are promising imaging markers of Alzheimer's disease (AD). This study aims to investigate the effectiveness of combining diffusion tensor image analysis along the perivascular space (DTI-ALPS) with hippocampal radiomics for diagnosing AD, and to develop an innovative multivariable model integrating hippocampal radiomics and clinical biomarkers for predicting mild cognitive impairment (MCI) progression.

METHODS: We included three cohorts from two databases retrospectively, using an internal (n = 210) and an external dataset (n = 430) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The ALPS index was employed to measure GS function, and 3D-T1WI hippocampal radiomics features were extracted to construct machine learning models for classifying and diagnosing AD. Conversion of MCI to AD was assessed through integrating the hippocampal radiomics features, ALPS index, and AD-related clinical biomarkers.

RESULTS: The ALPS index was lower in patients with AD than in healthy controls (HCs) in both the internal and external cohorts (p < 0.001). The combined hippocampal radiomics features and ALPS index model demonstrated good performance in AD classification. The multivariable prediction model of MCI progression to AD achieved an area under the curve of 0.97 and 0.92 for the training and testing cohorts, respectively.

CONCLUSIONS: Integrated ALPS index and hippocampal-based radiomics features can improve diagnostic performance in patients with AD, showing predictive capability for identifying the MCI conversion.},
}

@article {pmid42098663,
year = {2026},
author = {Tian, S and Lin, G and Zeng, Y and Wang, Q and Lin, Y and Yao, K and Wang, Z and Xiao, Z and Chen, J and Zheng, Y and Tan, H and Wu, Z and Yang, M and Xu, D and Li, X and Lao, J and Liang, S and Chen, Y and Liu, Q and Li, J and Gan, Y and Zeng, M and Chen, B and Ning, Y and Zhong, X},
title = {A multifeature machine learning and resting-state EEG study reveals differences in beta oscillation in late-life depression with or without mild cognitive impairment.},
journal = {BMC psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12888-026-08126-6},
pmid = {42098663},
issn = {1471-244X},
support = {2023B0303010003//Guangdong Province Key Areas Research and Development Programs-Brain Science and Brain-Inspired Intelligence Technology/ ; 2023HT022//Industry-University-Research Innovation Fund for Chinese Universities/ ; 2023B03J1296//Guangzhou Key Research and Development Program/ ; 20232A010014//Guangzhou Traditional Chinese Medicine and Integrated Traditional Chinese and Western Medicine Science and Technology Project/ ; 202201010491//Basic and Applied Basic Research Project of Guangzhou Basic Research Program/ ; Comprehensive Department of the National Administration of Traditional Chinese Medicine [2024] No. 3//National Traditional Chinese and Western Medicine Collaborative Project for Major and Complex Diseases/ ; Comprehensive Department of the National Administration of Traditional Chinese Medicine [2024] No. 221//National Integrated Traditional Chinese and Western Medicine "Flagship" Department Construction Project/ ; },
abstract = {BACKGROUND: Late-life depression (LLD) often co-occurs with mild cognitive impairment (MCI), and patients with LLD and MCI (LLD-MCI) have an increased risk of progression to Alzheimer's disease (AD). However, differences in resting-state neural oscillation and cognitive impairment in LLD patients remain unclear. In this cross-sectional study, electroencephalography (EEG) was used to analyse, local rhythm activity and large-scale network communication to differentiate LLD patients with and without MCI.

METHODS: We enrolled 113 participants: 74 with LLD (50 with LLD-MCI and 24 with LLD-non-MCI) and 39 healthy older adults (HOAs). All participants underwent comprehensive neuropsychological assessments. Spectral power and source-level functional connectivity (Phase-Locking Value, PLV) were analysed across multiple frequency bands. A machine learning framework using nested stratified cross-validation was implemented to evaluate the potential of EEG features in classifying LLD clinical subtypes.

RESULTS: LLD-MCI patients exhibited a distinct dissociation in the beta band: significantly reduced spectral power in the left frontal cortex contrasted with extensive hyperconnectivity primarily centred on the right lateral orbitofrontal cortex (rLOFC). Complementary analyses also revealed widespread hyperconnectivity in the theta band in the LLD-MCI group. The Linear Discriminant Analysis (LDA) model achieved superior performance in distinguishing LLD-MCI patients from LLD-non-MCI patients, with an area under the curve (AUC) of 0.82 and an accuracy of 78.38%. Feature importance analysis revealed rLOFC-mediated beta synchronisation as the most discriminative biomarker.

CONCLUSION: Our findings suggest that beta-band oscillatory disruption-characterised by local power deficits and network hyperconnectivity-may represent a potential neurobiological signature of cognitive vulnerability in LLD patients. Whether this hyperconnectivity reflects a compensatory or pathological process remains a hypothesis for further validation. EEG metrics provide significant diagnostic value for the precise clinical subtyping and early identification of cognitive decline in the LLD population.

CLINICAL TRIAL NUMBER: Not applicable.},
}

@article {pmid42098771,
year = {2026},
author = {Badot, C and Bini, A and Duplan, E and Checler, F and Lauritzen, I},
title = {Functional relationships linking C99/APP-βCTF dimerization, proteostasis disruption, and organelle dysfunction.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-02928-7},
pmid = {42098771},
issn = {1478-811X},
abstract = {BACKGROUND: The amyloid β (Aβ) precursor C99 (or APP-βCTF) accumulates in Alzheimer's disease and has been proposed to display Aβ-independent toxicity, notably by affecting the endosomal-lysosomal-autophagic (ELA) network. Our previous findings suggested that some ELA-associated C99 could correspond to dimeric and oligomeric species, but the intracellular sites of C99 dimerization, as well as the toxicity linked to it, remains unknown.

METHODS: We here developed a bimolecular fluorescence complementation (BiFC) probe to visualize de novo C99 dimerization and dimer trafficking, as well as to identify possible cellular responses specifically linked to C99 dimerization. Moreover, to confirm dimer localizations and toxicities, the localization and cellular effects of the dimerization mutant C99[G29L/G33L] was compared to that of wildtype C99. The C99 constructs were transfected into HeLa cells and dimer localizations, expression levels and intracellular toxicities were evaluated by Western blot and immunocytochemistry.

RESULTS: BiFC-C99 dimers were first detected within the TGN, in which monomers initially accumulate. The proteasomal inhibitor MG-132 led to increased dimer formation, indicating that the proteasomal activity status is a key determinant of C99 dimerization. Conversely, TGN-associated C99 dimerization had a negative impact on both the ubiquitin-proteasome system (UPS) and the TGN, as highlighted by the appearance of p62/SQSTM1-positive aggresomes and fragmented Golgi, then suggesting a two-way relationship between UPS function and C99 dimerization. Dimerization also led to lysosome repositioning and to the accumulation of LC3B-positive autophagy vesicles, agreeing with the well-known interplay between autophagy and proteasome in protein turnover. P62/SQSTM1 and LC3B accumulation could similarly be observed in cells expressing C99[G29L/G33L], a mutant favoring dimerization, while this was not the case in wildtype C99 expressing cells, confirming the dimerization-specific effect. While proteasomal inhibition caused TGN-associated dimer formation, repression of γ-secretase-mediated C99 proteolysis instead led to a redistribution of monomers to EEA1-positive endosomes, whereas already existing C99 dimers remained unaffected by this treatment. These new endosome-associated monomers were found also to dimerize, resulting in dimers destined for either secretion via small extracellular vesicles or autophagy-lysosomal degradation.

CONCLUSIONS: Taken together, our findings indicate that the cellular status of UPS, autophagy and γ-secretase activities are all determinant for C99 expression levels, and are thus crucial for both the level of C99 dimerization and for the fate of the dimers. Moreover, our data show that C99 dimerization itself negatively affects these activities thereby indicating a two-way relationship between C99 dimerization, proteostasis disruption and organelle dysfunction.},
}

@article {pmid42098772,
year = {2026},
author = {Laing, KK and Fialova, N and Wardlaw, J and Montagne, A},
title = {Impact of Apolipoprotein E4 on blood-brain barrier integrity in target replacement murine models: a systematic review and meta-analysis.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02018-3},
pmid = {42098772},
issn = {1758-9193},
abstract = {BACKGROUND: The E4 variant of Apolipoprotein E (APOE) is a primary genetic susceptibility risk factor for late-onset Alzheimer's disease and has been implicated in cerebrovascular dysfunction. Preclinical mouse models are widely used to study APOE4, but cohesive understanding of APOE's role is still inconsistent and lacking. The aim of this study was to systematically review and synthesise evidence from preclinical mouse studies assessing APOE4 related effects on blood-brain barrier (BBB) integrity, vascular morphology and cerebral blood flow (CBF). MAIN: A systematic search of MEDLINE, Embase, Scopus, and Web of Science was conducted (March-April 2025). Eligible studies included transgenic APOE-targeted replacement or knock-in mice reporting vascular outcomes (cerebral blood flow, blood brain barrier permeability, vascular measures). Risk of bias was assessed using SYRCLE and reporting quality with CAMARADES. Random-effects meta-analyses were conducted (where sufficient data was available), otherwise findings were narratively synthesised. Eighteen studies met inclusion. Outcome measures varied widely, including diverse approaches to CBF measurement (e.g. arterial spin labelling, autoradiography, DSC-MRI), immunohistochemical measures (e.g. collagen-IV, laminin, CD31), and diverse approaches to measurement of BBB leakage (e.g. fibronectin, fibrinogen, gadolinium-based ktrans). Seven studies contributed to meta-analysis: APOE4 mice showed a consistent reduction in CBF associated with APOE4 genotype (SMD = -2.87, 95% CI: -5.14 to -0.604, df = 2.66), and a negative non-significant trend towards reduced vascular morphology expression. Narrative synthesis identified three key mechanistic pathways linking APOE4 to vascular dysfunction: (i) insulin resistance and PI3K/AKT-mTOR signalling, (ii) Cyclophilin A-NFκB-MMP9 activation, and (iii) occludin/ECM remodelling. Risk of bias assessment revealed frequent shortcomings in randomisation, blinding, and sample size justification.

CONCLUSIONS: Preclinical evidence demonstrates that APOE4 drives alterations in vascular functioning primarily through involvement with pathways related to vascular metabolism, ECM remodelling and BBB leakage. However, heterogeneity in the model (e.g. age, sex, techniques), restricts direct comparability across studies. As such, standardisation or clarification of methodological approaches are necessary for rigorous assessment in the future.},
}

@article {pmid42098850,
year = {2026},
author = {Tarawneh, R and Moulder, KL and Topouza, DG and Kar, A and Qian, HT and Pankratz, VS and Timsina, J and Franklin, EE and Schindler, SE and Perrin, RJ and Ances, BM and Benzinger, TLS and Hassenstab, J and Morris, JC and Holtzman, DM and Cruchaga, C},
title = {Early syndecan-4 upregulation predicts cognitive and pathological trajectories in Alzheimer disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02043-2},
pmid = {42098850},
issn = {1758-9193},
support = {RF1AG083744/NH/NIH HHS/United States ; NCI P30CA118100-16/NH/NIH HHS/United States ; P30NS048056/NH/NIH HHS/United States ; P01AG03991/NH/NIH HHS/United States ; P01AG03991/NH/NIH HHS/United States ; R01AG044546/NH/NIH HHS/United States ; (P19-00559) for the Washington University-Centene ARCH Personalized Medicine Initiative//Centene Corporation/ ; },
abstract = {BACKGROUND: Brain endothelial dysfunction is an early pathological feature of Alzheimer disease (AD). We here investigate associations of the brain endothelial glycocalyx protein, syndecan-4 (SDC4), with amyloid and tau pathologies and cognitive impairment in a large longitudinal cohort of AD and controls.

METHODS: The study included n = 1,041 (n = 802 cognitively unimpaired and n = 239 cognitively impaired) participants who underwent biological classification using the NIA-AA "ATN" framework. Cognitive assessments included the Clinical Dementia Rating[®]-sum of boxes and the Knight- Preclinical Alzheimer's Cognitive Composite. Cerebrospinal fluid (CSF) measures of SDC4 and emerging AD biomarkers were obtained using Olink Proteomics. Amyloid-PET (n = 719) and tau-PET (n = 302) scans were performed in subsets of participants. Partial correlations and linear mixed models, respectively, examined cross-sectional and longitudinal associations of CSF SDC4 levels with amyloid-PET and tau-PET burden and cognition. Pseudo-time models estimated CSF biomarker trajectories across the course of AD progression.

RESULTS: CSF SDC4 levels were elevated in even the earliest preclinical stages of AD compared to controls and were closely associated with other CSF and imaging biomarkers of AD. Higher CSF SDC4 levels correlated with higher global and regional amyloid-PET and tau-PET burden and worse baseline cognition. Higher baseline CSF SDC4 levels predicted more rapid progression of brain amyloid and tau, and faster decline in global cognition, episodic memory, language, and executive functions over follow-up (mean, 8 years). CSF SDC4 associations with cognition were mainly mediated by global tau-PET burden. Importantly, our pseudo-time models estimate that SDC4 upregulation begins very early in AD pathogenesis near the point of amyloid-positivity and increases more robustly following the point of tau-positivity. SDC4 was among the top 10 most important proteins in predicting the pseudo-time models of AD progression and predicted these models to a potentially better extent than other emerging AD biomarkers.

CONCLUSION: Findings from this large longitudinal study suggest that CSF SDC4 levels are increased in the earliest preclinical stages of AD and are closely associated with the progression of amyloid and tau pathologies and future rates of cognitive decline. We propose that SDC4 upregulation is an important early event in AD pathogenesis which predicts cognitive and pathological disease trajectories.},
}

@article {pmid42099051,
year = {2026},
author = {Pereira da Silva, AM and Haddad Santos, D},
title = {Methodological considerations on the network meta-analysis of brexpiprazole dosing for agitation in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449394},
doi = {10.1177/13872877261449394},
pmid = {42099051},
issn = {1875-8908},
}

@article {pmid42099104,
year = {2026},
author = {Oriquat, G and Jasim, IK and Gajjar, TB and Hanumanthayya, M and Abdulhameed Ahmad, I and Singh, G and Maharana, L and Bainsal, N},
title = {SUMOylation in Neural Health and Disease: From Cellular Homeostasis to Neurodegeneration.},
journal = {DNA and cell biology},
volume = {},
number = {},
pages = {10445498261444640},
doi = {10.1177/10445498261444640},
pmid = {42099104},
issn = {1557-7430},
abstract = {Neurodegenerative diseases (NDDs) represent a growing global health burden, particularly in aging populations. These disorders primarily affect neurons and are characterized by progressive neuronal dysfunction and loss within specific regions of the central nervous system. Major NDDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and stroke. Although each disorder exhibits distinct genetic backgrounds and pathological protein aggregates, they share common pathogenic mechanisms, including chronic neuroinflammation, impaired autophagy and mitophagy, disrupted proteostasis, telomere instability, and epigenetic alterations. A hallmark feature across NDDs is the accumulation of misfolded proteins, leading to synaptic dysfunction and neuronal degeneration. Small ubiquitin-like modifiers (SUMOs) are a family of ∼100 amino acid proteins, including SUMO1 and the closely related SUMO2/3 isoforms. SUMOylation is a dynamic posttranslational modification that regulates protein function through the covalent attachment or removal of SUMO moieties. This reversible process is mediated by SUMO-specific E1 activating, E2 conjugating, and E3 ligating enzymes and is counterbalanced by SUMO/Sentrin-specific proteases. The SUMOylation status of target proteins depends on the tightly controlled balance between conjugation and deconjugation systems. Acting as a molecular switch, SUMOylation modulates diverse cellular processes such as DNA damage repair, RNA metabolism, transcriptional regulation, and protein quality control, all of which are essential for maintaining cellular homeostasis. Accumulating evidence links dysregulated SUMOylation to the pathogenesis of multiple neurological disorders, including polyglutamine and synucleinopathies. SUMOylation influences neuroinflammation, oxidative stress, protein aggregation, neuroangiogenesis, ischemic injury, and demyelination. This review highlights recent advances in understanding the role of SUMOylation in NDDs and explores its potential as a promising therapeutic target.},
}

@article {pmid42099124,
year = {2026},
author = {Cheng, B and Wei, W and Cheng, S and Yang, X and Pan, C and He, D and Feng, J and Zhang, F},
title = {Dynamic comorbidity trajectories spanning the diagnosis of depression: nationwide cohort study.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {},
number = {},
pages = {1-8},
doi = {10.1192/bjp.2026.10638},
pmid = {42099124},
issn = {1472-1465},
abstract = {BACKGROUND: Depression is often accompanied by multisystem comorbidities, but the time trajectories of these comorbidities remain unclear.

AIMS: We aimed to define the temporal sequence of comorbidity accrual relative to depression diagnosis, and examine how this trajectory differs in recurrent depression.

METHOD: A total of 32 953 individuals with depression were identified in the UK Biobank cohort, including 2402 with recurrent depression. The time between diagnosis of depression or recurrent depression and ten common comorbidities was established to determine the temporal order and rate of comorbidity diagnosis in relation to depression, based on the sequence of recorded diagnostic events. We further stratified the cohort by polygenic risk score, gender, age and history of antidepressant or antihypertensive medication use.

RESULTS: The study included 32 953 participants (mean age at diagnosis 52.6 years; 63.1% female). Hypertension and dorsopathies preceded depression diagnosis by a median of 2.6 years (interquartile range (IQR) -7.0 to 0.0) and 1.0 year (IQR -5.0 to 2.0), respectively. Alzheimer's disease and obesity emerged after diagnosis at medians of 2.5 years (IQR 0.0-5.0) and 0.8 years (IQR -2.0 to 3.0). High genetic risk was associated with an earlier onset of pre-depression cardiometabolic conditions, with hypertension occurring 2.8 years before diagnosis in individuals with a high polygenic risk score compared with 2.3 years in individuals with a low polygenic risk score. Crucially, individuals with recurrent depression exhibited a profoundly different trajectory, with most comorbidities manifesting many years after the index diagnosis. Stratification by medication history indicated that antihypertensive drug use was associated with an earlier recorded diagnosis of cardiometabolic conditions, whereas antidepressant use was linked to a later diagnosis of neurodegenerative diseases.

CONCLUSIONS: These findings identify three critical windows for intervention and reveal a distinct, delayed comorbidity trajectory in recurrent depression. This underscores the need for long-term, integrated surveillance strategies tailored to depression subtype and treatment history.},
}

@article {pmid42099162,
year = {2026},
author = {Kurmi, S and Shirodkar, S and Parab, SB and Doshi, G},
title = {A Multimodal Framework for Alzheimer's Prevention: Diet, Exercise, Fasting, Sleep, and Gut Microbiota.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050467997260323164241},
pmid = {42099162},
issn = {1875-5828},
abstract = {Alzheimer's Disease (AD) and related dementias arise from a multifactorial interplay of genetic susceptibility, metabolic dysfunction, neuroinflammation, and lifestyle determinants. With limited disease-modifying pharmacotherapies, lifestyle interventions have emerged as compelling, evidence-based avenues for prevention and early management. This review integrates mechanistic, translational, and clinical insights on major modifiable behaviours, physical activity, diet, intermittent fasting, sleep regulation, and gut-microbiome-based approaches that collectively shape cognitive ageing. Aerobic, anaerobic, and resistance exercises exert neuroprotective effects by activating BDNF-TrkB signalling, enhancing hippocampal neurogenesis, improving synaptic plasticity, and stimulating peripheral myokines (CTSB, IGF-1, GPLD1) that cross the blood-brain barrier to support neuronal resilience. Dietary interventions such as the Mediterranean, Mediterranean- DASH Intervention for Neurodegenerative Delay (MIND), and ketogenic diets mitigate AD pathology by reducing oxidative stress, inhibiting Aβ deposition, improving mitochondrial efficiency, and modulating APOE4-linked metabolic vulnerability. Intermittent fasting induces a metabolic shift toward ketone utilisation, activates autophagy pathways (AMPK, SIRT3, Nrf2), remodels the gut microbiome, and promotes angiogenesis through GDF11 signalling. The gut-brain axis contributes to cognitive health through microbial metabolites, such as Short-Chain Fatty Acids (SCFAs), tryptophan derivatives, modulation of neuroinflammation, and enhanced neuronal survival. Meanwhile, sleep quality, particularly slow-wave sleep, optimises glymphatic clearance and prevents the pathological accumulation of Aβ and tau. Collectively, the evidence suggests that multidomain lifestyle approaches offer synergistic benefits that exceed those of individual interventions, representing promising strategies for delaying cognitive decline. However, gaps remain regarding dose-response relationships, personalised protocols for APOE4 carriers, and long-term validation in diverse populations. Strengthening these research directions is crucial for integrating lifestyle medicine into preventive neurology and public health frameworks.},
}

@article {pmid42099163,
year = {2026},
author = {Li, Y and Li, L and Yang, Q and Xiong, J},
title = {Comparative Efficacy and Safety of Cholinesterase Inhibitors and NMDA Receptor Antagonists in Alzheimer's Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050437623260417063631},
pmid = {42099163},
issn = {1875-5828},
abstract = {INTRODUCTION: The study aims to evaluate and rank cholinesterase inhibitors, the NMDA antagonist memantine, anti-amyloid monoclonal antibodies, and non-drug modalities with respect to cognitive outcomes, functional status, neuropsychiatric symptoms, and tolerability.

METHODOLOGY: We registered a protocol in PROSPERO and searched PubMed/MEDLINE, Embase, CENTRAL, Web of Science, trial registries, and gray literature through June 2025. Eligible randomized phase II/III trials in adults with clinically diagnosed AD were screened in duplicate. Data on interventions, comparators, outcomes (e.g., MMSE, ADAS-Cog, CDR-SB), and adverse events were extracted. Risk of bias was assessed using Cochrane RoB 2. A Bayesian random-effects NMA synthesized 125 trials (n > 30,000), estimating standardized Mean Differences (SMDs) with 95% Credible Intervals (CrIs). Heterogeneity (I²) and inconsistency (design-by-treatment, node-splitting) were evaluated.

RESULTS: The network was well connected, with low-to-moderate heterogeneity (global I² = 38.5%) and no significant inconsistency (p = 0.48). Cognitive training (SMD = 0.45; 95% CrI 0.30-0.60; SUCRA 92%), aerobic exercise (SMD = 0.55; 95% CrI 0.35-0.75; SUCRA 87%), and galantamine (SMD = 0.40; 95% CrI 0.22-0.58; SUCRA 84%) ranked highest versus placebo. Donepezil (SMD = 0.21; 95% CrI 0.11-0.30; SUCRA 78%) and memantine (SMD = 0.24; 95% CrI 0.13-0.35; SUCRA 72%) showed modest benefits.

DISCUSSION: Risk-of-bias ratings were low in 37% of trials, some concerns in 48%, and high in 15%. Subgroup analyses confirmed greater cholinesterase inhibitor efficacy in mild AD and superior memantine effects in moderate-to-severe disease.

CONCLUSION: Non-pharmacological interventions demonstrated short-term cognitive benefits primarily in mild Alzheimer's disease populations and should be interpreted as adjunctive symptomatic strategies rather than direct substitutes for pharmacological therapy.},
}

@article {pmid42099164,
year = {2026},
author = {Nayak, RK and Mohapatra, SR and Sahoo, SK and Sahu, SK and Chowdhury, B and Banu, Z and Das, NR},
title = {Gut Microbiota Dysbiosis in Alzheimer's Disease and Possible Therapeutic Options.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050448298260303052535},
pmid = {42099164},
issn = {1875-5828},
abstract = {Human microbiota consists of trillions of microbial cells dominated by bacteria, which live in the human body, while the term microbiome refers to the collective genetic material of microorganisms. Among them, the gut microbiota has emerged as pivotal, producing its own metabolites, neurotransmitter precursors, and immune mediators that affect brain development and function. These signals function via the complex, bidirectional Gut-Brain Axis (GBA). This is a communication network that connects the gastrointestinal tract to the central nervous system. This axis plays an important role in the regulation of gastrointestinal homeostasis, neurodevelopment, emotional regulation, and cognitive processes. Increasing evidence suggests that microbial dysbiosis within the gastrointestinal tract is involved in the pathogenesis and progression of several neurological and neurodegenerative disorders, including mood disorders, schizophrenia, autism spectrum disorder, Alzheimer's Disease (AD), Parkinson's Disease (PD), and Huntington's Disease. These insights have opened new therapeutic possibilities, and multiple microbiota-targeted interventions, such as dietary modification, prebiotics, probiotics, postbiotics, psychobiotics, antibiotics, and Fecal Microbiota Transplantation (FMT), are now being explored for their therapeutic value, especially in Alzheimer's disease.},
}

@article {pmid42099165,
year = {2026},
author = {Yang, Y and Huang, X and Liu, H and Yu, C},
title = {The Role of Ectopic Fat in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050461650260406064722},
pmid = {42099165},
issn = {1875-5828},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder increasingly recognized to be associated with metabolic dysfunction. Accumulating evidence suggests that ectopic fat (abnormal fat deposition in non-adipose tissue) is a key factor. This review summarizes the crucial role that ectopic fat plays in the onset and progression of AD, as well as the interrelated pathways through which ectopic fat deposition promotes the pathological process of AD. Adipocytes have been reported to produce and secrete amyloid-β (Aβ), a hallmark pathological feature of AD. Accordingly, ectopic fat may aggravate cerebral Aβ accumulation by impairing peripheral Aβ clearance. In addition, ectopic fat can also cause Insulin Resistance (IR), adipokine dysregulation, inflammatory responses, and oxidative stress. Therefore, ectopic fat is closely associated with the progression of AD and may play a contributory role in its pathogenesis. The effects of ectopic fat on the occurrence and development of Alzheimer's Disease (AD) pathology were reviewed through mechanisms such as metabolic disorders, inflammatory pathways, and Aβ deposition, and potential intervention strategies for this harmful cycle were highlighted. As current therapies for AD remain limited, new opportunities for its prevention and treatment may be provided through a better understanding of these associations.},
}

@article {pmid42099166,
year = {2026},
author = {Chaudhari, DB and Barve, K},
title = {Targeting Shared Mechanisms in Atherosclerosis and Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050447493260327074829},
pmid = {42099166},
issn = {1875-5828},
abstract = {Atherosclerosis and Alzheimer's Disease are two significant health concerns characterised by overlapping pathophysiological mechanisms, including chronic inflammation, oxidative stress, and lipid metabolism dysregulation. Impaired vascular integrity in atherosclerosis enhances the accumulation of Aβ plaque in the brain by reducing cerebral perfusion and compromising the clearance of Aβ. This review examines the shared pathways linking these conditions, emphasizing the role of the NLRP3 inflammasome, Receptor for Advanced Glycation End Products, and the apolipoprotein E4 allele in exacerbating vascular dysfunction that promotes neurodegeneration. The interplay between these factors underscores the potential of targeting these common pathways as a therapeutic strategy for both diseases. In preclinical studies, emerging treatments, NLRP3 inflammasome inhibitors like MCC950 and CY-09, show promise in mitigating both arterial plaque formation and neuronal amyloid deposition, while innovative microRNA-based therapies targeting miR-146a and miR-155 offer novel approaches to reduce inflammatory responses. Additionally, modulation of lipid metabolism through liver X receptor agonists like T0901317 and cholesteryl ester transfer protein inhibitors, including Anacetrapib, offers potential dual benefits for cardiovascular and neurological health. However, challenges such as restricted BBB permeability, genetic and sex variability, and limited long-term clinical evidence continue to constrain the effectiveness of dual-targeted therapeutic approaches. Future perspectives suggest integrating multi-- modal therapies that combine anti-inflammatory, lipid-regulatory, and antioxidant strategies to effectively address these interrelated diseases. Advancements in molecular biology and imaging techniques may facilitate the development of personalised medicine approaches, ultimately improving outcomes for patients suffering from both atherosclerosis and Alzheimer's Disease.},
}

@article {pmid42099527,
year = {2026},
author = {Gong, T and Jiang, W and Han, Y and Liu, Y and Zhuo, W and Li, S and Hu, Z and Zeng, Z and Yue, R and Yang, M},
title = {Investigating the research trajectory and future trends in type 2 diabetes mellitus and aging: a bibliometric analysis from 2009 to 2025 based on big data.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1779773},
pmid = {42099527},
issn = {2673-6217},
abstract = {BACKGROUND: The relationship between type 2 diabetes mellitus (T2DM) and aging has attracted growing scientific attention. Growing evidence suggests that T2DM is not only a metabolic disorder but also a condition associated with accelerated biological aging. This study aimed to systematically map the global research landscape, intellectual structure, and emerging trends at the intersection of T2DM and aging using bibliometric approaches.

METHODS: Publications indexed in the Web of Science Core Collection from 1 January 2009 to 31 December 2025 were retrieved, yielding 3,048 records. Bibliometric analyses were conducted using VOSviewer, CiteSpace, and R to construct collaboration networks, co-citation structures, and keyword evolution patterns.

RESULTS: After a moderate growth phase from 2011 to 2015, publication output increased markedly from 2016 onward and reached a peak in 2025, accompanied by the progressive formation of an international collaboration network dominated by the United States and China. Mechanistic studies constituted the primary research focus, particularly those related to cellular senescence, oxidative stress, and inflammation. Cellular senescence emerged as a structurally central node within the knowledge network. Thematic evolution analysis further revealed increasing attention to aging-related comorbidities, including cardiovascular disease, Alzheimer's disease, erectile dysfunction, and cognitive impairment. Recent research fronts have increasingly focused on molecular pathways, including the senescence-associated secretory phenotype, the NLRP3 inflammasome, and epigenetic regulation.

CONCLUSION: This bibliometric analysis provides a comprehensive overview of the evolving research landscape linking T2DM and aging. The prominence of senescence-related pathways highlights a growing convergence between diabetes research and aging biology. Emerging strategies targeting fundamental aging mechanisms-including senolytic therapies and glucose-lowering drugs with potential geroprotective effects such as metformin and empagliflozin-represent promising directions for future research.},
}

@article {pmid42099528,
year = {2026},
author = {Patterson, SE and Caywood, K and Stinson, F},
title = {The sociological stakes of attitudes toward the families and care of older adults with dementia.},
journal = {Sociological forum (Randolph, N.J.)},
volume = {},
number = {},
pages = {},
pmid = {42099528},
issn = {0884-8971},
abstract = {This forum essay calls for greater sociological attention to the theoretical and empirical study of attitudes about the families and care of older adults living with Alzheimer's disease and related dementias (ADRD; dementia). Investigating these attitudes can help expand our understanding not only of the social experience of older adults with dementia, but also of family members and caregivers, as dementia is often highly stigmatized, memory loss changes relationships, and relationship dynamics influence care provision and inequalities. Attitudes and norms function at multiple levels - individual, family, and societal - and have large-scale consequences for social systems and inequality in an aging and increasingly diverse United States, where a growing number of older adults have dementia and family caregiving is normative. We briefly highlight demographic trends and interdisciplinary developments that underscore the urgency of and advantages to addressing these attitudes in sociology specifically. We conclude with a call to action and recommendations for scholars seeking to pursue related research within four relevant subfields within sociology: families, aging in the life course, stratification (race, gender, class), and medical sociology.},
}

@article {pmid42099715,
year = {2026},
author = {Dubois, JR and Kim, E and Pando-Bravo, J and Martin, LE and Yi, R},
title = {Scoping review of episodic future thinking and delay discounting observed in Alzheimer's disease, depression, and PTSD.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1764387},
pmid = {42099715},
issn = {1664-1078},
abstract = {Delay discounting (DD), the decrease in the subjective value of a reward as its receipt is delayed, is associated with a variety of risky health behaviors. Episodic Future Thinking (EFT), the capacity to imagine events that might occur in the future, is understood as a reliable intervention in reducing DD. While populations known to exhibit heightened DD rates may benefit from EFT-based interventions, impaired capacity for EFT may reduce their effectiveness. This scoping review examines the available evidence regarding the co-occurrence of steep DD rates and impoverished EFT across Alzheimer's disease (AD), post-traumatic stress disorder (PTSD), and depression to inform the transdiagnostic potential of EFT-based interventions. Searching and screening of articles were conducted on PsycINFO, PubMed, and Medline in February of 2025 following PRISMA guidelines. Across all disorders, clinical populations exhibited steeper DD rates, as well as impaired EFT characterized by marked reductions in specificity, detail, and novelty of the imagery. Cross-disorder comparisons highlighted reduced memory specificity impacting future simulation and physiological abnormalities in the hippocampus and vmPFC as potentially shared mechanisms in DD and EFT deficits. Despite a consistent pattern of steep DD and impoverished EFT occurring in each population and potentially influenced by similar mechanisms, the lack of studies examining DD and EFT in the same sample limits our conclusion and highlights where further research is warranted.},
}

@article {pmid42099804,
year = {2026},
author = {Rodrigues, KS and Yamashita, R and Katada, S},
title = {The choroid plexus- cerebrospinal fluid axis as a lifespan regulator of neural stem cells and circuit plasticity.},
journal = {Frontiers in neural circuits},
volume = {20},
number = {},
pages = {1818927},
pmid = {42099804},
issn = {1662-5110},
mesh = {*Choroid Plexus/physiology/metabolism ; Animals ; *Neural Stem Cells/physiology ; Humans ; *Neuronal Plasticity/physiology ; *Cerebrospinal Fluid/physiology/metabolism ; Neurogenesis/physiology ; },
abstract = {The choroid plexus-cerebrospinal fluid axis (ChP-CSF) functions as a dynamic signaling system that coordinates neural stem cell (NSC) behavior and neural circuit plasticity across the lifespan. Beyond its classical roles in cushioning the brain, CSF serves as a regulated conduit for growth factors, ions, extracellular vesicles, and other bioactive molecules. Emerging evidence suggests that the ChP contributes to shaping CSF composition through energy-dependent transport and state-responsive secretion. Ventricular-contacting NSCs sense CSF cues via apical endfeet and primary cilia, integrating signals to regulate their behavior. Lifespan-dependent remodeling of CSF composition and niche architecture reshapes NSC function from embryonic expansion to adult homeostasis and age-associated decline. Beyond the ventricular niche, ChP-derived factors influence circuit maturation and vulnerability to neurodegeneration. Orthodenticle homeobox 2 regulates critical period timing and neuroblast integration, whereas apolipoprotein E couples lipid metabolisms and amyloid-β homeostasis to neurogenesis with Alzheimer's disease risk. Additional ChP-secreted proteins, including transthyretin and clusterin, further shape the extracellular proteostatic and lipid environment. Together, these findings support the view of the ChP-CSF axis as an adaptive regulator across the lifespan that integrates stem cell dynamics, circuit plasticity, and neurodegenerative susceptibility.},
}

*Choroid Plexus/physiology/metabolism
Animals
*Neural Stem Cells/physiology
Humans
*Neuronal Plasticity/physiology
*Cerebrospinal Fluid/physiology/metabolism
Neurogenesis/physiology

@article {pmid42099973,
year = {2026},
author = {Chen, Y and Du, T and Lian, T and Jiang, Y and Yuan, T and Li, J and Meng, F and Yang, A and Zhang, W and Zhang, J},
title = {Clinical outcomes and anti-inflammatory mechanisms of nucleus basalis of Meynert deep brain stimulation in Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1773910},
pmid = {42099973},
issn = {1664-2295},
abstract = {AIM: Deep brain stimulation of the nucleus basalis of Meynert (NBM-DBS) represents an emerging therapeutic strategy for Alzheimer's disease (AD), yet clinical outcomes have been inconsistent and its mechanistic underpinnings are not fully elucidated. This study aimed to assess the cognitive and psychobehavioral effects of NBM-DBS and to explore its potential impact on systemic inflammatory markers.

METHODS: In this open-label trial, nine individuals with moderate-to-severe AD underwent bilateral NBM-DBS. Six participants (four with moderate and two with severe AD) completed the full 12-month protocol, which included serial neuropsychiatric assessments and serum cytokine profiling.

RESULTS: Stratification by baseline disease severity revealed divergent cognitive trajectories. Patients with moderate AD (CDR = 2) maintained their preoperative performance on the Montreal Cognitive Assessment (MoCA) and Boston Naming Test (BNT) over the 12-month follow-up. In contrast, patients with severe AD (CDR = 3) experienced significant decline on these measures. Serum analyses demonstrated a significant immunomodulatory effect, characterized by elevated levels of the anti-inflammatory cytokines IL-10 and IL-27, and reduced levels of the pro-inflammatory chemokines CXCL10 and RANTES at the 12-month timepoint.

CONCLUSION: Our findings indicate that NBM-DBS may be associated with stabilization of cognitive function in patients with moderate AD, potentially through the modulation of inflammation. The therapeutic benefit appears to be more pronounced in the moderate stage of the disease.},
}

@article {pmid42100106,
year = {2026},
author = {Bonnan, D and Kröger, E and Maheu, A and Morin, M and Bélanger, L and Vedel, I and Wilchesky, M and Sirois, C and Dallaire, C and Durand, É and Couturier, Y and Sourial, N and Guénette, L},
title = {Implementation of pharmacists' services into the care trajectory of older adults with neurocognitive disorder in multidisciplinary primary care clinics: A mixed-methods study.},
journal = {Exploratory research in clinical and social pharmacy},
volume = {23},
number = {},
pages = {100786},
pmid = {42100106},
issn = {2667-2766},
abstract = {INTRODUCTION: In Quebec, Canada, the "Alzheimer plan" encourages pharmacist participation in the care of older adults with neurocognitive disorders (NCDs) within multidisciplinary primary care clinics, known as Family Medicine Groups (FMGs). This study examined how these services were implemented from the perspective of physicians, nurses, and pharmacists.

METHODS: We conducted a convergent mixed-methods study combining cross-sectional questionnaires with semi-structured interviews across eight FMGs participating in a quasi-experimental project about the impact of pharmacists' activities on older adults' medication and well-being. Data collection and analysis were guided by the Normalization Process Theory and the Consolidated Framework for Implementation Research. A deductive thematic content analysis was carried out, using the five CFIR constructs as themes. Data from questionnaires were analyzed alongside interview data to gain a broader perspective on the implementation process.

RESULTS: Eighteen professionals (nine pharmacists, four physicians, five nurses) participated. From a quantitative perspective, pharmacists' integration was perceived positively: high agreement was reported regarding the intervention's potential value (90% pharmacists, 100% other professionals) and its adaptability (100% pharmacists, 80% other professionals). Also, 100% of physicians and nurses intended to continue to use pharmacists' services in the future. Qualitatively, facilitators included an easy-to-implement innovation (innovation characteristics), legislative changes (outer setting), the pharmacist's physical presence, strong interprofessional trust (inner setting), and proactive pharmacists' leadership (individuals) with regular team reminders (implementation process). Conversely, insufficient government funding (outer setting) and workload pressures were identified as primary barriers.

CONCLUSIONS: Implementing pharmacist services for older adults with NCDs in FMGs is feasible and beneficial, improving workflow and team efficiency beyond NCD care. Strong interprofessional collaboration, effective communication, and clear role definition were key facilitators, while insufficient funding and workload pressures remain major challenges to implementation. Co-construction between primary care teams and decision-makers is essential to achieve successful scale-up.},
}

@article {pmid42100263,
year = {2026},
author = {Wang, X and Yang, Z and Tang, T and Huang, H and Shi, J and He, J and Zhang, H},
title = {From neuroinflammation to neuroprotection: a bibliometric analysis of anesthesia-associated postoperative cognitive dysfunction to guide clinical research (2000-2024).},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1822901},
pmid = {42100263},
issn = {2296-858X},
abstract = {INTRODUCTION: Postoperative cognitive dysfunction is a common complication following anesthesia and surgery, particularly in elderly patients, yet its pathophysiology and optimal prevention strategies remain incompletely understood. This study employs bibliometric methods to analyze research trends in anesthesia-associated POCD from 2000 to 2024.

METHODS: A systematic review of 923 publications from the Web of Science Core Collection, cross-validated with the PubMed database, was conducted. Bibliometric analyses were performed using the R package "bibliometrix," VOSviewer, and CiteSpace to evaluate publication trends, key contributors, collaborative networks, co-citation patterns, and keyword evolution.

RESULTS: Research output has grown steadily since 2000, with notable acceleration after 2018. The United States leads in productivity and influence, followed by China and Germany. Duke University is the most prolific institution. The British Journal of Anaesthesia and Anesthesiology are the core journals in this field. Keyword analysis reveals an evolution from early focus on surgical types and cognitive assessment toward neuroinflammation as the central pathological mechanism, with increasing attention to the delirium-POCD continuum, anesthetic optimization, and multimodal prevention. Emerging frontiers include the intersection of POCD with Alzheimer's disease pathology, the role of the gut-brain axis, and the translation of mechanistic insights into targeted neuroprotective strategies.

CONCLUSION: This bibliometric analysis delineates the evolution of POCD research from descriptive epidemiology to mechanistic and translational inquiry. Neuroinflammation has emerged as the unifying pathological hub. Key challenges include heterogeneity in diagnostic criteria, difficulty isolating anesthesia effects from surgical trauma, and the gap between preclinical findings and clinical efficacy. Future research priorities should focus on harmonizing diagnostic standards, validating biomarkers, and conducting large-scale multi-center trials to translate mechanistic discoveries into perioperative brain health strategies.},
}

@article {pmid42100327,
year = {2026},
author = {Li, B and Cui, Z and Xu, Y and Xu, M},
title = {Modulation of programmed cell death by botanical drugs in Alzheimer's disease: a review from a traditional Chinese medicine perspective.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1811185},
pmid = {42100327},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) involves dysregulation of programmed cell death (PCD) pathways, such as apoptosis, ferroptosis, autophagy, and pyroptosis. Current therapeutic options are limited, prompting interest in multi-target regulators such as metabolites derived from traditional Chinese medicine (TCM) botanical drugs. This systematic review critically evaluates recent studies on TCM-derived metabolites that modulate PCD in AD models. We identify key limitations: many metabolites are pan-assay interference metabolites (PAINS) with questionable pharmacological relevance; preclinical models inadequately recapitulate sporadic AD; and translational challenges persist in bioavailability and brain targeting. Future research requires orthogonal validation, improved delivery systems, and stage-specific strategies. This review provides a critical foundation for the development of TCM-inspired therapies for AD.},
}

@article {pmid42100472,
year = {2026},
author = {Johnson, CN and Lysaker, CR and Cao, X and Csikos, V and Boakye, F and Kueck, PJ and Franczak, E and Geiger, PC and Morris, JK and Thyfault, JP and Wilkins, HM},
title = {APOE4 Drives Sex- and Diet-Dependent Effects on AD-Like Pathology, Cognition, and Mitochondrial Function.},
journal = {FASEB bioAdvances},
volume = {8},
number = {},
pages = {e70113},
pmid = {42100472},
issn = {2573-9832},
abstract = {Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), yet it's unclear how this allele promotes disease. While factors like diet and sex may modify AD susceptibility in APOE4 carriers, the interaction between these factors is poorly understood. Here, we sought to determine if APOE4, sex, and diet interact to influence AD related outcomes in mice. Male and female APOE3 and APOE4 targeted replacement (TR) mice were fed a low-fat diet or high-fat diet from 4 to 8 months old. Serum neurodegenerative disease biomarkers, brain amyloid beta (Aβ), APOE, and tau, learning and memory, hippocampal mitochondrial function and proteomics data were collected. Serum GFAP and NfL were unaffected by APOE4, while HFD was associated with greater serum NfL and GFAP. Whole brain Aβ was significantly altered by sex, diet, and genotype. There was a main effect of genotype on levels of brain APOE with levels being lower in APOE4 mice. APOE4 TR mice also exhibited impaired learning before diet. Proteomic analysis revealed that APOE4 exerts diet- and sex-dependent effects on mitochondrial pathways. This included downregulation of pyruvate metabolism in HFD males and oxidative phosphorylation in HFD females. Basal respiration was lower in APOE4 versus APOE3 TR females. We provide novel evidence that APOE4 may drive early sex- and diet-dependent reductions in pathways that support brain mitochondrial energy metabolism.},
}

@article {pmid42100481,
year = {2026},
author = {Khan, FF and Kim, JH and Kim, JI and Kwon, GR},
title = {APOE ε4 as a predictor of cognitive decline and its interaction with hippocampal volume in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1730265},
pmid = {42100481},
issn = {1663-4365},
abstract = {BACKGROUND/INTRODUCTION: The apolipoprotein E (APOE) ε4 allele is the strongest known genetic risk factor for late-onset Alzheimer's disease, and hippocampal atrophy is among the most reliable structural biomarkers of neurodegeneration. While both are independently associated with cognitive decline, whether APOE ε4 dose modulates the hippocampal volume-cognition relationship longitudinally in sporadic Alzheimer's disease remains underexplored at adequate statistical power.

METHODS: This study analyzed data from 2,417 Alzheimer's Disease Neuroimaging Initiative participants with complete APOE genotypes, intracranial volume-adjusted hippocampal volumes, and longitudinal cognitive assessments spanning a mean follow-up of 4.2 years and up to 19.3 years with an average of 4.9 visits per participant. Linear mixed-effects models with random intercepts and slopes per subject estimated cognitive trajectories across the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-SB), and Alzheimer's Disease Assessment Scale Cognitive Subscale 13 (ADAS-Cog13) as a function of time, APOE ε4 dose, and ICV-adjusted hippocampal volume, including their three-way interaction and adjusting for age, sex, education, baseline diagnosis, and depression. Cox proportional hazards models were used to assess conversion risk.

RESULTS: A clear APOE ε4 dose-response gradient was observed at baseline across all cognitive and hippocampal measures (all p < 0.001). Linear mixed-effects models revealed a significant three-way interaction of time × APOE ε4 dose × hippocampal volume on MMSE (β = -0.79, 95% CI [-1.51, -0.08], p = 0.030) and CDR-SB (β = +0.47, 95% CI [+0.03, +0.91], p = 0.037) trajectories, both significant under Bonferroni correction (α = 0.017), indicating that APOE ε4 amplifies the association between smaller hippocampal volume and faster cognitive deterioration over time. The time × hippocampal volume interaction was confirmed as highly significant by likelihood ratio test (LR = 3712.99, p < 0.001). Cox proportional hazards analyses of 845 conversion events showed that each additional ε4 allele conferred a 48% increase in conversion risk (HR = 1.48, 95% CI [1.29, 1.71], p < 0.001). Sensitivity analyses across diagnostic strata, after outlier exclusion, and in multi-visit subsamples confirmed the robustness of hippocampal volume effects.

DISCUSSION/CONCLUSION: These findings demonstrate that APOE ε4 genotype significantly modulates the longitudinal relationship between hippocampal volume and cognitive decline, supporting the integration of APOE genotype and structural hippocampal imaging for refined individual risk stratification in Alzheimer's disease.},
}

@article {pmid42100482,
year = {2026},
author = {Zhao, H and Wang, H and Li, W and Su, R and Li, J and Liu, Y and Wang, L},
title = {Integrated transcriptomic profiling combined with in vitro validation reveals the involvement of TMEM140 in the link between periodontitis and brain aging.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1761218},
pmid = {42100482},
issn = {1663-4365},
abstract = {OBJECTIVE: Periodontitis (PD) is a prevalent chronic inflammatory disorder in adults, and moderate-to-severe PD (Stage II-III/IV) may accelerate brain aging and neurodegenerative changes via the peripheral-central immune-neural axis, although the molecular connections and mechanisms of interaction have yet to be fully elucidated. This study sought to identify senescence-associated molecules potentially shared by PD and Alzheimer's disease (AD) using integrated transcriptomic analysis, machine learning, and in vitro RNA interference assays, and to further assess the role of TMEM140 in linking PD to brain aging.

METHODS: Transcriptomic datasets related to PD and AD were retrieved from the GEO database, and differential gene expression analysis was performed following batch effect correction; shared aging-associated genes were subsequently identified by combining weighted gene co-expression network analysis (WGCNA) with aging gene databases (HAGR and aging Atlas). Four machine learning algorithms, namely random forest (RF), support vector machine (SVM), generalized linear model (GLM), and extreme gradient boosting (XGB), were further applied to identify key genes, and their diagnostic value was assessed using receiver operating characteristic (ROC) analysis and nomogram models. DSigDB was used to predict candidate small-molecule compounds. In the in vitro experiments, a Porphyromonas gingivalis lipopolysaccharide (PG-LPS)-induced inflammatory model in human gingival fibroblasts (HGFs) and an Aβ1-42 and D-galactose-induced senescence model in SH-SY5Y neuron-like cells were established; TMEM140 in SH-SY5Y cells was then silenced using small interfering RNA (siRNA), and the neuron-like cells were treated with the same batch of standardized conditioned medium (CM; prepared from the supernatant of PG-LPS-treated HGFs) to observe changes in cellular responses to inflammatory stimulation after TMEM140 downregulation.

RESULTS: Seven aging-related genes common to PD and AD were identified, and comprehensive analysis using multiple algorithms selected TMEM140, TIMP1, and ALDH2 as key genes. Notably, TMEM140 was upregulated in PD and downregulated in AD, showed significant correlations with plasma cell and γδ T-cell infiltration, and single-cell analysis further revealed its cell type-specific expression in distinct brain cell subsets. In vitro experiments demonstrated that PG-LPS treatment markedly increased TMEM140 expression in HGFs, whereas treatment with Aβ1-42 and D-galactose reduced TMEM140 expression in neuron-like cells. When exposed to the same batch of conditioned medium, neuron-like cells with TMEM140 knockdown displayed more evident injury and senescence-related phenotypes, including reduced cell viability, increased reactive oxygen species (ROS) production, a higher percentage of senescence-associated β-galactosidase (SA-β-Gal)-positive cells, and marked upregulation of IL-1β, IL-6, TNF-α, p16, p21, RELA, NFKBIA, and TP53, indicating that reduced TMEM140 expression may contribute to enhanced susceptibility of neuron-like cells to inflammatory stress.

CONCLUSION: Through integrated transcriptomic analysis together with in vitro experimental validation, this study indicates that TMEM140 may be a candidate bridge molecule connecting PD and AD comorbidity. TMEM140 may participate in shaping the peripheral-central immunosenescence network and contribute to the cross-system transmission of inflammatory signaling.},
}

@article {pmid42100483,
year = {2026},
author = {Patel, A and Guiler, W and Pepper, S and Kemna, RE and Kueck, PJ and Weidling, IW and Mayfield, HD and John, CS and Mudaranthakam, DP and Wilkins, HM and Swerdlow, RH and Burns, JM and Morris, JK and Honea, RA},
title = {Limbic-predominant neuroimaging correlates of plasma p-Tau217 in preclinical and clinical Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1748524},
pmid = {42100483},
issn = {1663-4365},
abstract = {BACKGROUND: Plasma phosphorylated tau at threonine 217 (p-Tau217) has emerged as a highly sensitive and specific blood-based biomarker for Alzheimer's Disease (AD). However, its regional brain correlates with multimodal neuroimaging, beyond tau-PET, remain underexplored, particularly in early disease phases where limbic involvement may predominate. This study aimed to map the associations of plasma p-Tau217 with amyloid-PET burden, FDG-PET metabolism, and structural brain morphometry in a well-characterized cohort spanning cognitively unimpaired (CU) and cognitively impaired (CI) individuals across AD dementia stages, hypothesizing increased AD neuroimaging biomarkers in individuals with elevated p-Tau217.

METHODS: We analyzed data from 259 participants from the University of Kansas Alzheimer's Disease Research Center (KU ADRC) Clinical Cohort. Imaging outcomes included amyloid-PET, FDG-PET, gray matter volumetric regions of interest as well as whole brain voxel-based morphometry (VBM), and surface-based morphometry (SBM) for cortical thickness (CT), sulcal depth (SD), gyrification index (GI), fractal dimension (FD). Analyses were stratified by diagnostic and pTau-217 positivity (CU pTau + , CU pTau -, CI pTau + and CI pTau-). Spearman's correlations and voxel/surface-wise regressions evaluated p-Tau217 associations with imaging metrics, accounting for age and sex.

RESULTS: Plasma p-Tau217 was elevated in CI versus CU. Individuals with elevated plasma p-Tau217 had increased amyloid-PET deposition across the cortex, as well as significantly higher centiloids, both in CU and CI individuals. In CI individuals, elevated p-Tau217 was associated with reduced voxel-wise gray matter volume and cortical thickness in limbic, temporal, parietal, and frontal regions, plus increased cingulate FD. In both CU and CI pTau + individuals, p-Tau217 correlated with AD Signature gray matter decreases.

CONCLUSION: These findings show that CU and CI individuals with elevated plasma p-Tau217 have both increased amyloid-PET burden but also temporolimbic gray matter atrophy and hypometabolism. This supports p-Tau217 as a minimally invasive, scalable biomarker for early AD detection, risk stratification, and prognostic monitoring in preclinical stages, potentially guiding trial enrichment and personalized interventions.},
}

@article {pmid42100484,
year = {2026},
author = {Bellaali, Y and Sulcova, D and Salatino, A and Dricot, L and Hanseeuw, BJ and Woodard, JL and Ivanoiu, A},
title = {Modulating the default mode network with deep TMS: a proof-of-concept framework with potential relevance to circuits implicated in lack of awareness of cognitive decline.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1742759},
pmid = {42100484},
issn = {1663-4365},
}

@article {pmid42100486,
year = {2026},
author = {Park, EJ and Mun, BR and Kim, SY and Elangovan, M and Kim, SB and Choi, WS and Park, WJ},
title = {Secretory form of viral protease NIa ameliorates amyloid-β pathology and cognitive deficits in a mouse model of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1720518},
pmid = {42100486},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by extracellular amyloid-β (Aβ) accumulation. Immunotherapies targeting Aβ clearance show promise, highlighting the therapeutic value of enhancing Aβ removal. We previously identified that nuclear inclusion a (NIa), a plant viral protease, fortuitously cleaves Aβ with strict sequence specificity. Here, we engineered a secretory form, SecNIa, to degrade extracellular Aβ. SecNIa was efficiently secreted from transfected cells while retaining potent Aβ-cleaving activity. Adeno-associated virus (AAV)-mediated delivery of SecNIa into 5xFAD mice resulted in robust hippocampal expression and cerebrospinal fluid secretion. SecNIa expression significantly reduced soluble and insoluble Aβ, decreased hippocampal plaques, and improved cognition, fully normalizing recognition memory and enhancing spatial learning. These findings establish SecNIa as a promising therapeutic strategy to directly target pathogenic extracellular Aβ in AD.},
}

@article {pmid42100568,
year = {2026},
author = {Genguelou, M and Platel, H and Bourgeois, C and Gambonnet, M and Bayard, S},
title = {Social engagement, pleasure, and memory in musical reminiscence workshops for individuals with Alzheimer's disease.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1803210},
pmid = {42100568},
issn = {1662-5161},
abstract = {INTRODUCTION: Social bonding is essential in Alzheimer's Disease (AD), as social withdrawal reduces quality of life and can worsen Behavioral and Psychological Symptoms in Dementia. Music therapy offer a promising approach. This study examines the effects on social engagement in AD and explores links between verbal interaction, memory, and emotion.

METHODS: Nineteen voluntary residents with moderate to severe AD from four nursing homes participated. Nine musical reminiscence workshops were conducted. A single-group intervention study was conducted, with assessments at baseline, three points during the intervention, post-intervention, and one-month follow-up. Emotions were assessed using the Observed Emotion Rating Scale. Social engagement was measured via the social interaction domain of the Alzheimer's Disease-Related Quality of Life scale. Episodic memory was evaluated with the simplified Tempau Test and an observational grid. Reminiscences and verbal interactions during workshops were counted.

RESULTS: Verbal interactions and memory episodicity increased across workshops. Pleasure correlated positively with interaction frequency. Daily social engagement also improved after the intervention.

DISCUSSION: Musical reminiscence workshops enhance autobiographical memory and foster social engagement. Pleasure appears to be associated with social interactions. Music interventions can improve the social quality of life in people living with Alzheimer's disease.},
}

@article {pmid42100599,
year = {2026},
author = {Siette, J and Kim, JW and Zammit, JL and Butt, A and Sonego, S and Ginige, JA and Georgiou, A and Low, LF},
title = {The characteristics and performance of health data domains in supporting dementia identification: A systematic review.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70313},
pmid = {42100599},
issn = {2352-8729},
abstract = {Electronic health records (EHRs) offer growing potential for dementia identification, yet a synthesis of how specific data domains contribute to accurate detection is lacking. This systematic review assessed the role and performance of EHR-derived data in identifying dementia. Six databases were searched up to April 2025. Fifty studies met inclusion criteria, examining routinely collected health data across care settings. Ten key domains supported dementia identification, including demographics, diagnoses, medications, symptoms, and structured assessments. Most data were sourced from primary care EHRs (48%), with studies primarily conducted in the United Kingdom and United States. Case-control and retrospective cohort designs were commonly applied, often using logistic regression. Cognitive and behavioral domains contributed most to specificity (57.5%-99.9%). Alzheimer's-specific models had higher accuracy than general dementia models (mean accuracy: 74.6 vs. 67.1). Integrating diverse EHR data, especially cognitive and symptomatic variables, can improve dementia detection. Future research should focus on model validation, standardization, and clinical implementation.},
}

@article {pmid42100633,
year = {2026},
author = {Sahoo, SS and Sahu, PK and Sa, N and Behera, A},
title = {Neuroprotective cellular and molecular mechanisms of physical exercise on neurodegenerative diseases.},
journal = {ADMET & DMPK},
volume = {14},
number = {},
pages = {3058},
pmid = {42100633},
issn = {1848-7718},
abstract = {BACKGROUND: Neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease are characterized by a progressive loss of neuronal function and loss of synaptic capacity. Physical exercise (PE) is one of the non-clinical techniques for the management of brain health and neurodegeneration.

MECHANISMS: PE enhances the body's metabolic functions through cellular and molecular changes. It trades off metabolic functions, energy expenditure, and signalling processes to ensure physiological homeostasis and defence against disease. Exercise produces cascades, at the molecular level, including neurotrophic signalling, similar to those generated by drugs. It increases the levels of the brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). These elements favour the growth of new neurons, vascular enlargement, and synaptic plasticity. PE also induces microglial cells to attain a neuroprotective, anti-inflammatory phenotype, reduces detrimental cytokines, promotes cellular clearance through autophagy, restores neurotransmitter homogenisation, and induces hippocampal cell formation. Collectively, it acts as a powerful modulator of health and brain activity.

IMPLICATIONS: The aggregate processes enhance neuronal vulnerability to harm, aid cognitive functioning, and ensure the stability of neural networks.

CONCLUSION: PE is an exciting additive therapy for preventing and treating various neurodegenerative disorders by orchestrating a diverse array of cellular and molecular responses.},
}

@article {pmid42100721,
year = {2026},
author = {Emanuele, E and Santos-Lozano, A and López-Ortiz, S and Khoramipour, K and García-Chico, C and Lista, S and Minoretti, P},
title = {Magnetic fields as biophysical activators of autophagy: A preclinical systematic review.},
journal = {Biochemistry and biophysics reports},
volume = {46},
number = {},
pages = {102613},
pmid = {42100721},
issn = {2405-5808},
abstract = {While pharmacological inducers of autophagy have been extensively studied, their systemic adverse effects may limit clinical use. Increasing preclinical evidence suggests that magnetic fields (MFs) can represent a non-invasive alternative for autophagy modulation. In this systematic review, we sought to evaluate preclinical evidence on MF-mediated autophagy activation, including intervention parameters, mechanistic pathways, and therapeutic outcomes, to guide future translational research. Following PRISMA guidelines, we searched (January 2010-August 2025) four structured electronic databases (PubMed, Scopus, Embase, and IEEE Xplore) for studies investigating MF effects on autophagy in preclinical models. Eligible reports included in vitro and animal investigations with clearly defined MF parameters and validated autophagy markers. Nine studies met inclusion criteria, covering diverse MF modalities such as repetitive transcranial magnetic stimulation, rotating fields, pulsed and power-frequency fields, and radiofrequency exposures. Across a wide range of frequencies (1-50 Hz) and intensities (20 mT-1.5 T), most studies reported autophagy activation, as evidenced by LC3-II accumulation, Beclin-1 upregulation, p62 degradation, and autophagic flux confirmation in select experimental models. Mechanistic analyses converged on PI3K/AKT/mTOR inhibition. Functionally, MF-induced autophagy conferred neuronal protection and drove behavioral recovery in models of Alzheimer's disease, vascular dementia, and stress, whereas it triggered autophagic cell death in cancer. Some studies reported incomplete flux or autophagosome accumulation. Risk of bias was generally unclear due to methodological heterogeneity. In summary, preclinical evidence indicates that MFs can act as versatile, non-pharmacological activators of autophagy. Defining optimal stimulation parameters, clarifying mechanistic pathways, and advancing translational studies will be essential for clinical application.},
}

@article {pmid42100730,
year = {2026},
author = {Copeland, EN and Marais, AAT and Mohammad, A and Marcella, BM and Baranowski, RW and Beaudette, SM and MacPherson, REK and Fajardo, VA},
title = {Tideglusib improves novel object recognition memory in the preclinical DBA/2J mdx mouse model of Duchenne muscular dystrophy.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1812975},
pmid = {42100730},
issn = {1662-4548},
abstract = {INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder characterized by progressive muscle wasting. Approximately 1 in 3 DMD patients experience cognitive dysfunction, with research suggesting an Alzheimer's disease (AD)-like pathology. We have previously shown that treatment with the glycogen synthase kinase 3β (GSK3) inhibitor, tideglusib, improves muscle quality, function, and insulin sensitivity in the DBA/2J (D2) mdx mouse model of DMD. In this brief follow-up study, we report the effects of tideglusib treatment on cognitive function.

METHODS: Male D2 WT and mdx mice were purchased from Jackson Laboratories. Mice were separated into the following groups: (1) WT, (2) mdx-vehicle, and (3) mdx-tideglusib (10 mg/kg/day via oral gavage for 4 weeks). A novel object recognition test was performed to assess recognition memory. Hippocampus and serum samples were collected for BACE1 activity assays, amyloid beta (Aβ) ELISAs, and western blotting.

RESULTS: Compared to vehicle-treated mdx mice, tideglusib-treated mdx mice demonstrated improved recognition memory. These changes to recognition memory were accompanied by greater expression of beta-catenin, an indirect downstream marker of GSK3 inhibition. While there were no changes in BACE1 activity, tideglusib-treated mdx mice had higher concentrations of Aβ in the serum and lower protein levels of receptor of advanced glycation end products.

DISCUSSION: The results from this brief follow-up study offer preliminary support for tideglusib as a treatment for both muscle and brain impairments in mdx mice, potentially improving cognitive function through enhanced vascular Aβ clearance.},
}

@article {pmid42100765,
year = {2026},
author = {Zhu, Y and Ru, Y and Xie, J and Zuo, T and Hong, X and Wang, D},
title = {Development and application of an intelligent management and home care system for geriatric diseases under the 'Internet Plus' model: big data-based risk prediction and personalized intervention.},
journal = {Health information science and systems},
volume = {14},
number = {1},
pages = {63},
pmid = {42100765},
issn = {2047-2501},
abstract = {Under the "Internet Plus" model, this study aims to develop a proof‑of‑concept intelligent decision‑support system for elderly disease risk assessment, with a specific focus on Alzheimer's Disease (AD). The primary objective is to evaluate whether blood‑based transcriptomic biomarkers can be translated into an interpretable and scalable risk stratification framework suitable for home‑care and community health settings. Whole‑blood transcriptomic and associated clinical data were obtained from a publicly available microarray dataset comprising 329 individuals (144 AD, 104 MCI, and 81 cognitively normal controls). Transcriptomic features were used exclusively for model training, while clinical variables-including cognitive scores, frailty index, depression scores, and medication adherence-were used post hoc for risk annotation and alert simulation. Rigorous preprocessing and quality control were applied, followed by differential gene expression analysis using the limma framework and biologically informed biomarker selection. A Random Forest classifier trained on selected transcriptomic biomarkers achieved an accuracy of 91.2%, with sensitivity of 88.5% and specificity of 93.6% under stratified five‑fold cross‑validation. Model interpretability was supported through permutation‑based feature importance and SHAP analysis, enabling identification of key genes contributing to risk prediction. Based on probabilistic outputs, subjects were categorized into simplified alert states such as "Alzheimer's Risk Flagged" and "Monitoring Recommended." Although real‑time home monitoring data were not collected, the proposed system simulates how omics‑driven risk scores could be integrated into EMR‑compatible and IoT‑enabled care platforms. This study demonstrates a scalable and interpretable computational framework that bridges transcriptomic research and practical decision support, highlighting the potential of non‑invasive, individualized, and deployable risk assessment tools for elderly care, particularly in resource‑limited or home‑based environments.},
}

@article {pmid42100782,
year = {2026},
author = {Zhang, R and Sun, H and Di, Y and Cao, H and Zhang, C and Yao, H and Yan, H and Ding, D and He, Q and Wu, T},
title = {Sleep quality metrics combined with virtual reality motion parameters enhance early detection of mild cognitive impairment.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1727576},
pmid = {42100782},
issn = {1664-0640},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive and motor deficits. With its global prevalence increasing rapidly and no effective treatment available, early identification of high-risk individuals is critical. This study investigated the relationship between motor parameters extracted from virtual reality (VR) tasks, combined with sleep-related measures, and cognitive impairment in patients with mild cognitive impairment (MCI). Our goal was to determine whether integrating VR-derived digital markers with sleep quality metrics could provide an objective and clinically applicable tool for early detection.

METHODS: 66 participants were recruited, including 28 healthy controls (HC) and 38 patients with MCI. Cognitive status was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). All participants performed two scenario-based VR tasks, during which task completion time, accuracy, and overall performance scores were recorded. Group differences were evaluated using independent-samples t-tests, and these behavioral features and sleep quality metrics were further incorporated into ROC analyze to assess predictive performance for distinguishing MCI from HC.

RESULTS: Compared with HC, patients with MCI reported significantly poorer sleep quality based on the Pittsburgh Sleep Quality Index (PSQI) and subdomains such as sleep latency and habitual sleep efficiency. In the VR tasks, MCI patients required more time and achieved lower accuracy than HC, consistent with MoCA and MMSE scores. Correlation analysis confirmed strong associations between VR performance metrics and cognitive test scores. Importantly, integrating VR-derived digital markers with sleep parameters yielded superior predictive accuracy for MCI (AUC = 0.863; sensitivity = 86.84%; specificity = 71.43%; p < 0.001) compared with single-modality models.

CONCLUSION: VR-based cognitive and sensorimotor tasks, when combined with sleep quality assessments, offer a robust and noninvasive approach for the early identification of prodromal AD. This multimodal strategy holds promise for enhancing clinical decision-making and enabling timely interventions.},
}

@article {pmid42100836,
year = {2026},
author = {Kaczmarek-Kryszak, KA and Dobrzyńska, M and Banaszak, M and Drzymała-Czyż, S},
title = {A comprehensive systematic review of human trials investigating herbal treatments for Alzheimer's disease and dementia.},
journal = {Acta neuropsychiatrica},
volume = {},
number = {},
pages = {1-55},
doi = {10.1017/neu.2026.10085},
pmid = {42100836},
issn = {1601-5215},
abstract = {OBJECTIVE: Dementia is a group of symptoms, characterized by a loss of cognition that interferes with everyday tasks, difficulty focusing, planning, problem solving, and behavioral changes, such as apathy, anxiety, or depression. The leading cause of dementia is Alzheimer's disease, but vascular dementia or mild cognitive impairment are also frequently occurring. There are six drugs legislated in Europe for use in the treatment of dementia. There are unmet clinical needs to find more effective, better tolerated or complementary therapeutic options. The aim of this study is to comprehensively analyze the results of clinical trials and other human studies regarding the efficacy and safety of herbal interventions used in patients with dementia.

METHODS: We enrolled a total of 48 studies for this systematic review, of which 27 were included into the statistical analysis of effect size (Cohen's d).

RESULTS: We found significant improvements mainly after administration of Ginkgo biloba, Crocus sativus, Salvia officinalis, and Melissa officinalis.It should be emphasized that some herbs and herbal formulations demonstrated efficacy comparable to that of donepezil, a widely used and approved medication, suggesting potential for phytopharmaceutical therapies as complementary approaches. In some studies, the observed effects were similar to those reported for conventional treatments, indicating promising directions for further research in Alzheimer's disease and dementia.

CONCLUSION: In light of the evidence, phytopharmaceuticals have a promising role as a co-therapeutic option or alternative for patients with dementia who do not tolerate or have contraindications to standard medications. However, further research is necessary to translate these initial promising results into clinical practice.

SUMMATIONS: Phytopharmaceuticals have a promising role as a complementary or alternative option for dementia patients who cannot tolerate or respond to standard medications. Certain phytopharmaceuticals demonstrated comparable short-term symptomatic effects to standard treatments in small trials; however, evidence is insufficient to support equivalence or superiority.

CONSIDERATIONS: Many of the studies reviewed are limited by very small sample sizes, which is associated with a high risk of bias when interpreting large effect sizes (Cohen's d). The short duration of interventions (often only 3 to 6 months) is insufficient to assess whether phytotherapeutics can constitute disease-modifying treatments (DMTs).},
}

@article {pmid42101083,
year = {2026},
author = {Cheng, J and Aung, CTZ and Suslavich, SF and Sahingur, SE and Hernandez-Kapila, YL},
title = {From senescence and inflammaging to systemic comorbidities: Drivers of aging-associated periodontitis.},
journal = {Periodontology 2000},
volume = {},
number = {},
pages = {},
doi = {10.1111/prd.70049},
pmid = {42101083},
issn = {1600-0757},
abstract = {BACKGROUND: Aging is accompanied by a chronic low-grade inflammatory process, known as inflammaging, as well as immunosenescence, an age-related decline and dysregulation of immune function, and cellular senescence, a process in which cells enter a state of irreversible growth arrest while actively releasing pro-inflammatory factors. These processes alter the host immune regulation and tissue homeostasis. Aging-associated mechanisms are being explored for their role in periodontal and peri-implant diseases because of their promotion of dysregulated inflammation, impaired healing, and heightened susceptibility to tissue destruction. Rather than viewing periodontitis as a condition driven solely by microbial burden, it should be understood as a multifactorial disease shaped by complex host-microbe interactions, in which host-driven processes, particularly senescence and inflammaging, play a central role in amplifying bidirectional oral-systemic interactions.

AIM: This scoping review aims to (i) highlight the current understanding of the role of aging and its alterations in host inflammatory responses on immune function, tissue homeostasis, and cellular stress responses; (ii) explore the potential impact of "inflammaging" on the periodontium and interactions with systemic health; and (iii) explore possible therapeutic targets for senotherapy.

MATERIALS AND METHODS: A literature search of the PubMed database was conducted using Boolean search strategies to identify publications related to the potential connections between aging and inflammation in the context of the oral cavity.

RESULTS: Of the total 283 articles that were screened, 87 met the eligibility criteria and were included in this scoping review. An additional 51 articles were obtained via manual search. The evidence demonstrates a link between inflammaging, age-related cellular senescence, and periodontal vulnerability to periodontal pathogens and periodontal destruction. Both experimental and clinical studies have shown increased senescence markers, dysregulated immune responses, and enhanced osteoclastic activity that lead to greater tissue destruction and alveolar bone loss. Systemic conditions such as Alzheimer's disease, diabetes, and cardiovascular disease can also amplify the inflammatory burden through shared pathways. Overall, our findings support the idea that older adults undergo immune dysregulation when challenged with microbes that ultimately cause a chronic periodontal inflammatory state.},
}

@article {pmid42101470,
year = {2026},
author = {Panchal, D and Solanki, D and Solanki, R and Yadav, AK and Bhatia, D and Yadav, P},
title = {Biomaterials and Nanoparticle-Based Therapeutics in Neurodegenerative Diseases: Bridging the Gap Between Innovation and Translation.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00245},
pmid = {42101470},
issn = {1948-7193},
abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and multiple sclerosis, represent a growing global health crisis characterized by irreversible neuronal loss, protein aggregation, chronic neuroinflammation, and mitochondrial dysfunction. Central to their therapeutic intractability is the blood-brain barrier (BBB), a highly selective neurovascular interface that excludes nearly 98% of conventional pharmacological agents from the central nervous system (CNS). Nanoparticle- and biomaterial-based delivery platforms have emerged as promising strategies to overcome these barriers, encompassing liposomes, polymeric nanoparticles, engineered exosomes, inorganic nanoparticles, and hydrogel scaffolds capable of enabling targeted CNS drug delivery. This Review systematically evaluates the landscape of nanomaterial-based neurotherapeutics across disease-specific pathological contexts, critically analyzing translational failure mechanisms including limited parenchymal brain exposure, receptor saturation during transcytosis, protein corona-mediated immune clearance, and nanoscale toxicity in postmitotic neural tissue. Preclinical-to-clinical translational gaps arising from interspecies BBB transporter heterogeneity and pharmacokinetic divergence are examined alongside manufacturing and regulatory barriers impeding Good Manufacturing Practice (GMP)-scale production. Emerging convergence strategies─including AI-integrated design, hybrid physiologically based pharmacokinetic modeling, theranostic nanoplatforms, and wearable bioresponsive delivery systems─are evaluated for their capacity to address these limitations. The review concludes by proposing a framework for developing clinically viable, disease-modifying CNS nanomedicines.},
}

@article {pmid42101516,
year = {2026},
author = {Zhou, B and Wu, X and Wang, J and Li, L and Xu, H and Shao, W},
title = {Compatibility of Acorus tatarinowii Schott and Polygala tenuifolia Willd. alleviate Alzheimer's disease through regulating Nos2-mediated calcium signaling pathway.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42101516},
issn = {1573-6903},
support = {ZY2023M027//the General Project of the Administration of Traditional Chinese Medicine of Hubei Province/ ; },
mesh = {PC12 Cells ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; Amyloid beta-Peptides/metabolism ; *Polygala/chemistry ; *Calcium Signaling/drug effects/physiology ; *Nitric Oxide Synthase Type II/metabolism ; *Acorus/chemistry ; *Plant Extracts/pharmacology/therapeutic use ; Cell Survival/drug effects ; Peptide Fragments/metabolism ; },
abstract = {Herb pair of Acorus tatarinowii Schott (ATS) and Polygala tenuifolia Willd. (PTW) is a classic drug pair in the treatment of Alzheimer's disease (AD), However, the mechanism by which the drug pair acts on AD is currently unknown. To address this, we constructed a PC12 cellular AD model using amyloid-beta peptide (Aβ) (25-35), follow by treating with different concentrations of ATS and PTW alone or their combination (1:1). The cell viability and Aβ-40, Aβ-42 and AQP4 expression were detected. In addition, RNA-sequencing combined with network pharmacology was performed to investigate the action mechanism of ATS and PTW, and the results were validated using in vitro experiments. The results showed that at drug-acting concentrations less than 100 mg/L, both single-agent and combined treatments of ATS and PTW increased the protective effects on PC12 cell, and the herb pair was superior to single-agent. In addition, both single-agent and combined treatments of ATS and PTW (at concentration of 100 mg/L) decreased Aβ-40, Aβ-42 and AQP4 expression compared with AD model. Further RNA-sequencing combined with network pharmacology analysis suggested that the underline action mechanism might be associated with Nos2-mediated calcium signaling pathway regulated. In vitro validation experiments showed that Nos2 overexpression increase the levels of Aβ-40, Aβ-42, AQP4, p-Tau, CaM, and p-CaMKII, which were reversed by the combination treatment of ATS and PTW. In conclusion, this work indicates that ATS and PTW combination might alleviate an Aβ-induced cellular model through regulating Nos2 - mediated calcium signaling pathway.},
}

PC12 Cells
Animals
*Alzheimer Disease/drug therapy/metabolism
Rats
Amyloid beta-Peptides/metabolism
*Polygala/chemistry
*Calcium Signaling/drug effects/physiology
*Nitric Oxide Synthase Type II/metabolism
*Acorus/chemistry
*Plant Extracts/pharmacology/therapeutic use
Cell Survival/drug effects
Peptide Fragments/metabolism

@article {pmid42101517,
year = {2026},
author = {Poli, M and Bonomi, CG and Di Donna, MG and Barberis, I and Ginevra, EL and Nuccetelli, M and Bernardini, S and Centonze, D and Martorana, A and Motta, C},
title = {Streamlining Alzheimer's disease diagnosis: real-world validation of two-cut-off diagnostic models based on plasma p-tau/Aβ42 ratios.},
journal = {Journal of neurology},
volume = {273},
number = {6},
pages = {},
pmid = {42101517},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood/cerebrospinal fluid ; *tau Proteins/blood/cerebrospinal fluid ; *Amyloid beta-Peptides/blood/cerebrospinal fluid ; Female ; Male ; Aged ; *Peptide Fragments/blood/cerebrospinal fluid ; Biomarkers/blood/cerebrospinal fluid ; Aged, 80 and over ; Middle Aged ; Cohort Studies ; Sensitivity and Specificity ; },
abstract = {INTRODUCTION: Anti-amyloid monoclonal antibodies have increased the need for scalable, minimally invasive biomarkers for Alzheimer's disease (AD). In this single-center cohort study, we evaluated plasma biomarkers performance in detecting biologically defined AD, assessing diagnostic accuracy and generalizability outside dedicated laboratory settings and exploring suitability for clinical implementation.

METHODS: We enrolled 204 outpatients referred to the memory clinic of Policlinico "Rome Tor Vergata" who underwent standard work-up, lumbar puncture for cerebrospinal fluid (CSF) biomarkers and paired blood sampling. Among plasma biomarkers, phosphorylated tau (p-tau) 181, p-tau217, and their ratios adjusted for Aβ42 were measured on the Lumipulse platform. AD pathology was defined by CSF p-tau181/Aβ42 ≥ 0.069. ROC analyses estimated AUCs, and a two-cut-off approach targeting 90% sensitivity and specificity classified individuals as low, intermediate, or high AD risk. Subgroup analyses examined the impact of sex, age (< 75, ≥ 75 years), chronic kidney disease, and cognitive impairment (MMSE ≥ 26/30, < 26/30) on plasma biomarker levels.

RESULTS: Among single analytes, plasma p-tau217 showed the highest discriminative capacity (AUC 0.883). Combined ratios improved overall performance (p-tau181/Aβ42, AUC 0.928; p-tau217/Aβ42, AUC 0.894) and reduced intermediate-risk classifications to < 15%, with slightly better performance in women, patients < 75 and cognitively unimpaired. The two-cut-off model improved accuracy and rule-in ability.

DISCUSSION: Plasma p-tau/Aβ42 ratios show high and robust accuracy for detecting CSF-defined AD pathology. A two-step approach based on p-tau181/Aβ42 or p-tau217/Aβ42 could streamline diagnostic workflows in memory clinics, reserving second-line assessments to indeterminate cases and supporting selection of candidates for disease-modifying anti-amyloid therapies.},
}

Humans
*Alzheimer Disease/diagnosis/blood/cerebrospinal fluid
*tau Proteins/blood/cerebrospinal fluid
*Amyloid beta-Peptides/blood/cerebrospinal fluid
Female
Male
Aged
*Peptide Fragments/blood/cerebrospinal fluid
Biomarkers/blood/cerebrospinal fluid
Aged, 80 and over
Middle Aged
Cohort Studies
Sensitivity and Specificity

@article {pmid42101744,
year = {2026},
author = {Barrett-Young, A and Cawston, EE and Ryan, B and Abraham, WC and Ambler, A and Anderson, T and Cheyne, K and Goodin, E and Hogan, S and Houts, RM and Ireland, D and Knodt, AR and Kokaua, J and Melzer, TR and Ramrakha, S and Sugden, K and Williams, B and Wilson, P and Caspi, A and Hariri, AR and Moffitt, TE and Poulton, R and Theodore, R},
title = {Plasma pTau181 is associated with subjective cognitive concerns but not objective cognitive decline or structural brain integrity measures in midlife.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42101744},
issn = {2509-2723},
support = {2208-PRG//Neurological Foundation of New Zealand/ ; 16/604//Health Research Council of New Zealand/ ; 23/133//Health Research Council of New Zealand/ ; 24/690//Health Research Council of New Zealand/ ; R01AG069939/AG/NIA NIH HHS/United States ; R01AG032282/AG/NIA NIH HHS/United States ; R01AG049789/AG/NIA NIH HHS/United States ; MR/X021149/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Although plasma pTau181 has been shown to accurately discriminate patients with Alzheimer's disease from healthy older adults, there are few studies of plasma biomarkers among middle-aged populations. Given the potential utility of plasma AD biomarkers such as pTau181 in screening for disease risk, examining pTau181 in a middle-aged cohort without AD is important for future implementation. The objectives of this study were to characterise plasma pTau181 in a middle-aged birth cohort aged 45 years and to investigate associations with early indicators of dementia risk. Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of 1037 people born in New Zealand in 1972-1973. Plasma pTau181, self-reported cognitive concerns, MRI-based brain structure, and DunedinPACE (an epigenetic biomarker of biological ageing) were measured at age 45; cognition was measured in childhood and age 45. Plasma pTau181 concentrations at age 45 (n = 854, 49% female) were associated with self-reported cognitive concerns (β = 0.09, p = .008); however, no significant associations were observed with objective cognitive decline, worse structural brain integrity, or biological ageing. Higher plasma pTau181 was associated with self-reported cognitive concerns at age 45, but not objective AD-related measures. The association of plasma pTau181 and self-reported cognitive concerns in this cohort suggests that AD pathology may begin to accumulate by age 45 and may be associated with subtle changes in cognition that are not at objectively measurable levels.},
}

@article {pmid42101765,
year = {2026},
author = {Wong, WJ and Yang, SL and Subramaniam Kalianan, R and Teoh, CCO and Hwong, WY},
title = {Place of Death for People with Life-Limiting Illnesses in Malaysia: Trends (2005-2019) and Projections to 2030.},
journal = {Journal of epidemiology and global health},
volume = {},
number = {},
pages = {},
doi = {10.1007/s44197-026-00572-5},
pmid = {42101765},
issn = {2210-6014},
abstract = {BACKGROUND: Place of death (PoD) is an important component of end-of-life care as studies showed that home deaths are preferred among patients and caregivers. Studying trends in PoD is therefore essential to examine shifts in the distribution of PoD over time and inform decisions on future end-of-life care provision and policies. This study aimed to examine the past trends and future projections of PoD of patients with life-limiting illnesses in Malaysia.

METHODS: We analysed decedents aged 15 years and above who died from life-limiting illnesses between 2005 and 2019 using national mortality registry. PoD was categorized as home, hospital, care home and other. Future PoD trends were projected to 2030 using simple linear modelling, accounting for projected changes in the age and sex distribution of deaths. Multinomial logistic regression model was used to assess factors associated with PoD.

RESULTS: Between 2005 and 2019, 1,423,942 deaths were due to life-limiting illnesses; the most frequent cause was Alzheimer's disease, dementia and senility (37.0%, reflecting inclusion of non-medically certified senility deaths), followed by heart disease (22.9%) and malignant neoplasm (15.4%). The percentage of home deaths declined from 59.9% in 2005 to 49.2% in 2019. Contrastingly, percentages of hospital and care home deaths increased (35.1-45.2% and 0.6-1.1%). Based on current trend continuing, the proportion of home deaths is projected to decline further to 44.3% by 2030. Projection intervals were not calculated given the linear model assumptions; results should be interpreted as indicative trend extrapolations. Hospital deaths are projected to become the most common PoD and the largest proportion of deaths (48.3%). Decedents with Alzheimer's disease, dementia or senility had higher odds of dying at home than in hospital (AOR 31.66; 95% CI 31.14-32.19), while care home deaths were lower among females (AOR 0.85; 95% CI 0.82-0.89).

CONCLUSIONS: This study demonstrated an increasing trend in hospital deaths, a reduction in home deaths over time; hospitals are projected to become the most common PoD by 2030. The projected increase in hospital deaths raises considerations regarding the future sustainability of inpatient end-of-life care. These findings suggest potential needs to strengthen community palliative care services to meet future end-of-life care needs.},
}

@article {pmid42101771,
year = {2026},
author = {Seydi, KA and Kaya, D and Yavuz, I and Mahser, AC and Mutlay, F and Dost, FS and Isik, AT},
title = {Utility of the 4-meter backward walking speed test in older adults with neurodegenerative diseases.},
journal = {Irish journal of medical science},
volume = {},
number = {},
pages = {},
pmid = {42101771},
issn = {1863-4362},
abstract = {BACKGROUND AND AIM: Less is known about backward walking speed (BWS) in older adults. This study aims to establish a cutoff value for BWS to distinguish cognitively impaired individuals from healthy controls and to assess the association between backward walking slowing and risk of neurodegenerative diseases.

METHODS: 389 older patients, grouped into cognitively healthy (CH), amnestic mild cognitive impairment (aMCI), Alzheimer's disease (AD), Parkinson's disease (PD), and non-AD groups. BWS was measured using a standardized 4-meter protocol. Cognitive and functional status were evaluated via the comprehensive geriatric assessment. ROC analysis was used to determine the diagnostic threshold for BWS, and multinomial logistic regression was used to assess the associations.

RESULTS: A BWS cutoff of 0.395 m/s effectively distinguished CH individuals from those with neurodegenerative diseases (AUC=0.723). After adjusting for age, each 0.1 m/s decrease in BWS was associated with 22% increased odds of having aMCI, 37% increased odds of AD, 28% increased odds of PD, and 59% increased odds of having non-AD dementia. BWS showed a positive association with global cognitive scores in patients with CH and aMCI (p< 0.05) and with semantic verbal fluency scores in those with AD and aMCI (p< 0.05).

CONCLUSION: BWS is associated with an increased risk of neurodegenerative diseases, which can cause cognitive impairment, and may help indicate individuals at risk of cognitive decline.},
}

@article {pmid42101927,
year = {2026},
author = {Njume, CM and Petracci, I and Bellini, S and Goljanek-Whysall, K and Quinlan, LR and Fiszer, A and Borroni, B and Ghidoni, R and Kumbasar, A and Cakmak, A},
title = {When complexity does not pay: benchmarking deep learning and ensemble methods for biomarker discovery.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {3},
pages = {},
doi = {10.1093/bib/bbag211},
pmid = {42101927},
issn = {1477-4054},
support = {//Scientific and Technological Research Council of Turkey/ ; 124N069//EU Joint Programme-Neurodegenerative Disease Research/ ; TGA-2025-46998//Scientific Research Projects Unit of Istanbul Technical University/ ; 1009742021//National Center for High-Performance Computing/ ; //Italian Ministry of Health-EU Joint Programme-Neurodegenerative Disease Research/ ; 2023/05/Y/NZ3/00160//Polish National Science Centre/ ; JPND-2023-1/HRBI_/Health Research Board/Ireland ; },
mesh = {Humans ; *Deep Learning ; *Benchmarking ; *Biomarkers ; Alzheimer Disease/metabolism/genetics ; Breast Neoplasms/metabolism/genetics ; *Computational Biology/methods ; Female ; Support Vector Machine ; },
abstract = {The integration of multi-omics data holds great promise for identifying robust and clinically relevant biomarkers, yet the increasing complexity of computational methods raises questions about their practical utility. In this study, we present a comprehensive benchmarking framework that evaluates 27 feature selection strategies and 11 predictive models across three real-world disease cohorts: Alzheimer's disease, progressive supranuclear palsy, and breast cancer. We compare traditional machine learning, ensemble-based methods, and state-of-the-art deep learning models in terms of predictive performance, stability, and biological interpretability. Our results reveal that ensemble feature selection consistently improves robustness and accuracy, particularly for compact biomarker panels. Surprisingly, deep learning models did not outperform simpler classifiers such as logistic regression (L.Regression), support vector machines, or multilayer perceptrons, which often achieved comparable or superior results with lower computational cost and greater interpretability. Triple-omics yielded the highest validation, followed by dual-omics and then single-omics (Triple > Dual > Single). Biological validation against five independent databases confirmed the clinical relevance of the identified biomarkers, including both well-established and novel candidates. To support reproducibility and community adoption, we provide a web-based tool for applying our benchmarking pipeline. Our findings advocate for a pragmatic approach to biomarker discovery-prioritizing methodological transparency, reproducibility, and biological insight over algorithmic complexity.},
}

Humans
*Deep Learning
*Benchmarking
*Biomarkers
Alzheimer Disease/metabolism/genetics
Breast Neoplasms/metabolism/genetics
*Computational Biology/methods
Female
Support Vector Machine