@article {pmid42312459,
year = {2026},
author = {Banik, A and Pal, S and Pal, A and Pal, M and Dutta, I and Roy, D and Chattopadhyay, A and Benito-Leon, J},
title = {Qualitative clock-drawing errors across dementia etiologies and mild cognitive impairment: a clinically interpretable six-class framework.},
journal = {CNS spectrums},
volume = {31},
number = {1},
pages = {e20},
doi = {10.1017/S1092852926101072},
pmid = {42312459},
issn = {2165-6509},
abstract = {OBJECTIVE: To characterize qualitative Clock Drawing Test (CDT) error profiles across dementia etiologies and mild cognitive impairment (MCI), and to propose a clinically interpretable six-class framework.

METHODS: In a hospital-based study in Kolkata, India, consecutive adults with cognitive impairment completed a free-drawn "ten past ten" CDT. Errors were coded using classical qualitative categories and clock components (face, numbers, hands), then collapsed into six classes: conceptual, stimulus-bound/perseveration, spatial, planning, number-related, and graphic-conceptual. For nonexclusive domains, omnibus Pearson χ² tests summarized error distributions across diagnoses; Cramér's V quantified effect size.

RESULTS: Participants included Alzheimer's disease (AD; n = 36), vascular dementia (VaD; n = 16), behavioral variant frontotemporal dementia (bvFTD; n = 9), MCI (n = 19), and other conditions (n = 22). Although 50.0% drew a normal clock face, only 11.8% achieved perfect numbering and 12.7% set the hands correctly. Conceptual errors were most frequent (70.6%), followed by spatial errors (47.1%); neglect and counterclockwise numbering were rare (3.9% each). Error distributions differed by diagnosis for face, numbers, and hands (all p < 0.001; V = 0.4-0.5). The six-class scheme retained a significant distributional association with diagnosis (χ² = 43.365, p = 0.002; V = 0.3): bvFTD showed prominent conceptual and graphic-conceptual failures, AD combined conceptual and spatial errors, MCI emphasized spatial and number-related errors, and VaD was heterogeneous.

CONCLUSIONS: Qualitative CDT profiles vary meaningfully across cognitive disorders. This concise six-class framework captures clinically salient patterns, especially in severely degraded drawings, and may complement brief memory screening and digital CDT metrics.},
}

@article {pmid42418497,
year = {2026},
author = {Zhang, Y and Lee, JH and Yu, Z and Tao, Y and Rimal, S and He, Y and Lv, L and Lu, B and Ping, Y},
title = {Dopamine-driven mitochondrial reverse electron transport in immune cells mediates gut-brain ROS signaling during sleep deprivation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {28},
pages = {e2530907123},
doi = {10.1073/pnas.2530907123},
pmid = {42418497},
issn = {1091-6490},
support = {R01AG089752 R01NS084412 and R37NS083417//Foundation for the National Institutes of Health (FNIH)/ ; 25X010301278//Shanghai Jiao Tong University (SJTU)/ ; 25ZR1401188//Science and Technology Commission of Shanghai Municipality (STCSM)/ ; },
mesh = {Animals ; *Reactive Oxygen Species/metabolism ; *Mitochondria/metabolism ; Signal Transduction ; *Dopamine/metabolism ; *Brain/metabolism ; *Sleep Deprivation/metabolism/immunology ; Electron Transport ; Drosophila melanogaster/metabolism ; Hemocytes/metabolism/immunology ; Drosophila Proteins/metabolism/genetics ; Oxidative Stress ; },
abstract = {Sleep deprivation (SD), together with inevitable stress inherent to conventional SD protocols, can induce oxidative stress and inflammation, thereby increasing the risk of premature death. However, the source and signaling pathways underlying reactive oxygen species (ROS) generation remain unclear. Here, we demonstrate that both mechanical and thermogenetic SD, along with possible stress induced by both protocols, lead to initial ROS accumulation in Drosophila gut subregions, including the proventriculus (PV) and PV-resident hemocytes, via upregulation of dopamine (DA) biosynthesis. Intriguingly, DA acts unconventionally by activating mitochondrial reverse electron transfer (RET), presumably through modifying interactions between the respiratory complex I proteins NDUFV1 and NDUFS3. RET-ROS elicits hemolymphatic IMD/Relish-mediated antibacterial defense. However, during chronic SD, downregulation of the Drosophila APOE/D ortholog Neural Lazarillo promotes the recruitment of hemocytes to the central brain and, together with this process, leads to widespread neuronal ROS accumulation in an Alzheimer's disease (AD) fly model. Inhibiting RET or hemocytic DA levels extends the survival of animals under chronic SD. Our work reveals DA-driven RET-ROS in innate immune cells during SD, highlights the pivotal role of a gut-innate immune-brain crosstalk in mediating the effect of SD manipulation on aging and AD pathogenesis, and suggests ways to lessen the consequence of SD, a profound health issue in modern society.},
}

Animals
*Reactive Oxygen Species/metabolism
*Mitochondria/metabolism
Signal Transduction
*Dopamine/metabolism
*Brain/metabolism
*Sleep Deprivation/metabolism/immunology
Electron Transport
Drosophila melanogaster/metabolism
Hemocytes/metabolism/immunology
Drosophila Proteins/metabolism/genetics
Oxidative Stress

@article {pmid42418504,
year = {2026},
author = {Cai, Y and Wang, Y and Huang, W and Su, Y and Lei, M and Jia, R and Wu, C and Zhang, T and Sun, L and Peng, B and Cheng, J and Yu, J and Chen, X and Ye, Q and Yu, J and Xin, J},
title = {Lecanemab treatment improves B cell subpopulation immune homeostasis in patients with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71655},
pmid = {42418504},
issn = {1552-5279},
support = {82571602//National Natural Science Foundation of China/ ; 82371188//National Natural Science Foundation of China/ ; 2022ZD0211603//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; ADB510200//Lingang Laboratory/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology ; *Homeostasis/drug effects ; Female ; Male ; *B-Lymphocyte Subsets/drug effects/immunology ; Aged ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *B-Lymphocytes/drug effects/immunology ; Leukocytes, Mononuclear/drug effects ; },
abstract = {INTRODUCTION: Lecanemab, the first disease-modifying therapy for Alzheimer's disease (AD), mitigates pathology primarily by clearing amyloid plaques, but its impact on peripheral immunity remains unclear.

METHODS: To assess Lecanemab's immunological effects, we performed antibody array analysis of serum and single-cell RNA sequencing of peripheral blood mononuclear cells collected from healthy controls and patients with AD at baseline, 3, and 6 months post-treatment.

RESULTS: Lecanemab restored multiple serum chemokines to healthy levels in patients with AD. Compared to controls, baseline samples from patients with AD showed altered frequencies and functions of naïve and unswitched memory (UswM) B cells. Lecanemab treatment corrected the abnormal naïve and UswM B cell proportions and rebuilt their functional homeostasis by alleviating chronic inflammation and reversing the dysregulation of key pathways including immune response, NF-κB, RAGE, and cell adhesion.

DISCUSSION: These findings uncover a novel peripheral immunomodulatory mechanism of Lecanemab, offering new insights into AD therapeutics.},
}

Humans
*Alzheimer Disease/drug therapy/immunology
*Homeostasis/drug effects
Female
Male
*B-Lymphocyte Subsets/drug effects/immunology
Aged
*Antibodies, Monoclonal/therapeutic use/pharmacology
*B-Lymphocytes/drug effects/immunology
Leukocytes, Mononuclear/drug effects

@article {pmid42418748,
year = {2026},
author = {Kivisild, A and Aaltonen, M and Aho, K and Heikkinen, SV and Lehtonen, A and Leppänen, L and Rinnankoski, I and Tervonen, L and Soppela, H and Haapasalo, A and Martikainen, J and Hartikainen, PH and Katisko, K and Krüger, J and Solje, E},
title = {Long-Term Income and Productivity Losses in Individuals With Early-Onset Dementia: Evidence From 15 Years Preceding the Diagnosis.},
journal = {Neurology},
volume = {107},
number = {3},
pages = {e218268},
doi = {10.1212/WNL.0000000000218268},
pmid = {42418748},
issn = {1526-632X},
mesh = {Humans ; Female ; *Income/statistics & numerical data ; Finland/epidemiology ; Male ; Retrospective Studies ; Longitudinal Studies ; Middle Aged ; *Dementia/economics/epidemiology/diagnosis ; *Cost of Illness ; Age of Onset ; *Efficiency ; Aged ; Alzheimer Disease/economics ; Frontotemporal Dementia/economics ; },
abstract = {BACKGROUND AND OBJECTIVES: Early-onset dementia (EOD), affecting individuals younger than 65 years, imposes a substantial socioeconomic burden. However, evidence on long-term income trajectories and productivity loss across EOD subtypes remains limited. The aim of this study was to evaluate income trajectories and societal productivity loss in individuals with different EOD subtypes.

METHODS: This retrospective, population-based longitudinal cohort study included all patients with EOD from Kuopio University Hospital and Oulu University Hospital referral area between January 2010 and December 2021. Diagnoses were re-validated through clinical data review. For each study case, 10 randomly selected matched controls were used. Demographics, education, and comorbidities were obtained from national registers. Annual gross income was retrieved from Statistics Finland tax records. The Human Capital Approach was used to calculate productivity losses, in effect by estimating the annual income difference relative to controls using a generalized estimating equation regression model, with panel data spanning 15 years before diagnosis and the year of diagnosis.

RESULTS: The EOD cohort comprised 793 patients (50.4% women; mean age 59.6 years): 421 with Alzheimer disease (AD), 179 with frontotemporal dementia (FTD) spectrum disorders, 46 with α-synucleinopathies (α-SYNUs), and 147 with other EOD etiologies. Compared with 7,926 age-matched and sex-matched controls, patients with EOD showed substantial and progressively increasing productivity loss up to 15 years before diagnosis, with cumulative losses of €74,577 (46,423-102,732) per patient. In the AD group, productivity loss emerged 6 years before diagnosis (€2,767; 95% CI 18-5,515; p = 0.024) and reached €11,431 at diagnosis (95% CI 8,676-14,184; p < 0.001). In the FTD group, loss appeared 11 years before diagnosis (€4,799; 95% CI 433-9,166; p = 0.031) and increased to €16,116 at diagnosis (95% CI 11,671-20,561; p < 0.001). In the α-SYNU group, differences were variable and significant only at diagnosis (€11,284; 95% CI 2,574-19,993; p < 0.011). In the "other EOD" group (predominantly vascular and mixed dementias), productivity loss remained consistently high across the follow-up (e.g., €8,744 at diagnosis; p < 0.001).

DISCUSSION: This large-scale longitudinal study demonstrates significant productivity loss up to 15 years before EOD diagnosis, with variation across dementia subtypes. Earlier recognition and targeted interventions are needed in the future to mitigate the substantial socioeconomic burden of EOD.

This study is part of DEGE-RWD-research project (protocol registered to ClinicalTrials.gov: NCT06209515), coordinated by Neurocenter Finland.},
}

Humans
Female
*Income/statistics & numerical data
Finland/epidemiology
Male
Retrospective Studies
Longitudinal Studies
Middle Aged
*Dementia/economics/epidemiology/diagnosis
*Cost of Illness
Age of Onset
*Efficiency
Aged
Alzheimer Disease/economics
Frontotemporal Dementia/economics

@article {pmid42418847,
year = {2026},
author = {de La Seiglière, H and Letourneur, Æ and Ichas, F and De Giorgi, F},
title = {Phase separation and protein aggregation in neurodegenerative diseases.},
journal = {Biophysical chemistry},
volume = {338},
number = {},
pages = {107678},
doi = {10.1016/j.bpc.2026.107678},
pmid = {42418847},
issn = {1873-4200},
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, frontotemporal dementia, and ALS are characterized by amyloid protein aggregation involving intrinsically disordered proteins that are also capable of liquid-liquid phase separation (LLPS). LLPS, known to drive the formation of dynamic membraneless organelles essential for cellular functions, can play a role in limiting fibrillation process or aberrantly transition into solid aggregates under pathological conditions. Here we review how mutations, post-translational modifications, and environmental factors can modulate LLPS of proteins like Tau, TDP-43, FUS, and α-synuclein, potentially regulating amyloid aggregation. We also examine the interplay of these proteins exploring how LLPS and condensate maturation could impinge on the emergence of co-pathologies contributing to disease progression. Finally we discuss emerging therapeutic strategies, aimed at modulating phase separation dynamics.},
}

@article {pmid42419155,
year = {2026},
author = {Pegoraro, G and MacBean, LF and Smith, AR and Soanes, DM and Smith, RG and Imm, J and Harvey, J and Kouhsar, M and Laroche, V and Weymouth, L and Castanho, I and Hide, W and Palmer, L and Lett, DJ and Robinson, AC and Woodman, N and McDade, K and Boche, D and Pishva, E and Lunnon, K},
title = {Systemic infections alter cortical transcriptional signatures in Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {167},
number = {},
pages = {155-167},
doi = {10.1016/j.neurobiolaging.2026.06.010},
pmid = {42419155},
issn = {1558-1497},
abstract = {Alzheimer's disease (AD) is characterized by neuroinflammation, yet the impact of concurrent systemic infections on the AD brain remains poorly understood. We investigated the molecular mechanisms underlying the central nervous system response to systemic infections in AD by analyzing RNA sequencing data generated in the prefrontal cortex from 202 post-mortem donors (113 AD, 89 controls), where we stratified by the presence of a respiratory infection at the time of death. We identified 763 significant differentially expressed genes (DEGs) between AD and controls without infection, which were enriched for oxidative phosphorylation and neurodegenerative pathways. In contrast, 122 DEGs distinguished AD from controls during infection, with 57 genes uniquely altered in AD in the presence of infection, including MAPK4, VAV3, and POU3F4, implicating infection-dependent mechanisms of vascular and immune regulation. Pathway activity analysis revealed that infection in AD suppresses some immune and vascular pathways, while enhancing transcriptional and developmental programs. Weighted gene co-expression network analysis uncovered three key modules: one module strongly associated with AD, enriched for aging and signal transduction; one module linked to both AD and infection, highlighting cytoskeletal remodeling and host-pathogen interactions; and one module specific to infection, enriched in astrocytes, pericytes, and endothelial cells, implicating blood-brain barrier dysfunction. These findings suggest that systemic respiratory infections reshape transcriptional programs in the AD brain, dampening immune effector pathways and engaging vascular and host-pathogen processes in blood-brain-barrier-associated cell types. Our results highlight the complex interplay between systemic infection, neuroinflammation, and vascular responses in AD.},
}

@article {pmid42419161,
year = {2026},
author = {Jiang, W and Lin, Y and Guo, Q and Miao, Y},
title = {Dietary patterns and Alzheimer's disease: East-west perspectives and future intervention strategies.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100636},
doi = {10.1016/j.tjpad.2026.100636},
pmid = {42419161},
issn = {2426-0266},
abstract = {Among various modifiable risk factors, dietary patterns (DPs), as a holistic lifestyle intervention, have become a focus of current research due to their protective effects on cognitive health. Classic Western DPs, such as the Mediterranean diet (MedDiet), have been widely confirmed to effectively improve cognitive function, thereby reducing the risk of Alzheimer's disease (AD). However, existing evidence mainly concentrates on Western populations and their DPs, including the MODERN (Machine learning-assisted Optimizing Dietary intERvention against demeNtia risk) diet optimized using machine learning. Given the significant differences in food types, dietary habits, and cooking methods among Asian populations, research on localized DPs optimized for cognitive health in Asian populations remains insufficient. In this context, the team at the Department of Geriatrics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine has taken the lead in systematically defining the Shanghai Cognitive Diet Pattern (SCDP). This review aims to comprehensively outline the core features and potential biological mechanisms relevant to AD in both classic Western DPs and the emerging East Asian DP. Subsequently, this review will systematically compare Eastern and Western DPs. In conclusion, this review proposes shifting dietary strategies from population-level adaptation to individual precision, in conjunction with multimodal lifestyle management, and offers novel strategies for the prevention and management of AD.},
}

@article {pmid42419451,
year = {2026},
author = {Raadani, A and Hamdi, A and Yangui, I and Jiménez-Araujo, A and Rodríguez-Arcos, R and Moreno, JMM and Ruiz, MJM and Messaoud, C and Ali, IBE and Guillén-Bejarano, R},
title = {Novel oligomeric caffeoyl derivatives and acylated flavone glycosides from Satureja nervosa Desf.: Chemical characterisation, structure-activity relationships, and multi-target bioactivity in Caenorhabditis elegans disease models.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {107377},
doi = {10.1016/j.fitote.2026.107377},
pmid = {42419451},
issn = {1873-6971},
abstract = {Satureja nervosa Desf. (Lamiaceae) contains structurally complex phenolic compounds, yet comprehensive chemical characterisation and mechanisms of bioactivity remain unexplored. This investigation identified and characterized bioactive constituents from eighteen wild Tunisian populations using water and ethanol extraction, established structure-activity relationships through systematic correlation analysis, and validated multi-target biological activities using in vivo disease models. HPLC-DAD-MS analysis with authentication against 13 commercial standards identified 49 phenolic compounds, including eleven previously unreported hydroxycinnamic acid-acylated flavone O-glycosides representing the first comprehensive report of such structures in Satureja, alongside multiple bioactive oligomeric caffeoyl derivatives (lithospermic acids, salvianolic acids, clinopodic acids). Water extracts demonstrated superior chemical diversity (31 vs 25 compounds) and phenolic content (97-1843 vs 2-161 mg/100 g DW) compared to ethanol extracts. Structure-activity correlation analysis identified specific oligomeric depsides as principal bioactive constituents: lithospermic acid-2 (R = 0.682, P < 0.01) for acetylcholinesterase inhibition and clinopodic acid K (R = 0.624, P < 0.01) for α-amylase inhibition. Elite water extracts demonstrated exceptional in vivo efficacy at 4 mg/mL in three Caenorhabditis elegans disease models: 63-64% increased survival against juglone-induced oxidative stress (wild-type N2), 75-78% metabolic rescue in daf-2(e1370) insulin-signalling mutants, and 62-75% neuroprotection against amyloid-β paralysis in the GMC101 Alzheimer's model, significantly outperforming ethanol extracts. The superior bioactivity of structurally complex oligomeric and acylated compounds compared to simple phenolic acids (rosmarinic acid constituting 58-83% of ethanol extracts) demonstrates multi-mechanistic effects beyond predictable phenolic antioxidant activity, establishing S. nervosa oligomeric phenolic derivatives as pharmacologically distinct bioactive natural products with validated multi-target therapeutic potential in vivo disease-relevant models.},
}

@article {pmid42419491,
year = {2026},
author = {Ellappan, S and Kujur, PP and Mondal, AC},
title = {The Autophagy-Senescence-Inflammasome Axis: A Novel Triad in Neurodegenerative Diseases?.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103248},
doi = {10.1016/j.arr.2026.103248},
pmid = {42419491},
issn = {1872-9649},
abstract = {Chronic neuroinflammation is a defining feature of brain ageing and neurodegenerative disorders, yet the molecular mechanisms responsible for its persistence remain incompletely understood. Although autophagy dysfunction, glial senescence, and inflammasome activation are well-established contributors to progressive neurodegeneration, these processes are often analysed independently or through pairwise interactions, leaving their collective contribution to persistent neuroinflammation and disease progression insufficiently defined. Here, we synthesise emerging evidence supporting an integrated 'Autophagy-Senescence-Inflammasome (ASI) axis', in which reciprocal interactions among impaired autophagy, senescent glia, and inflammasome signalling establish a self-sustaining cycle of neuroinflammation. We discuss how defective autophagy promotes mitochondrial dysfunction, oxidative stress, and danger signalling, while senescent astrocytes and microglia amplify inflammatory responses through the senescence-associated secretory phenotype (SASP). These intertwined processes converge on chronic inflammasome activation, with mitochondrial dysfunction emerging as a central mechanistic hub. Evidence across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and chronic neuropathic pain highlight the broad relevance of this pathological network. We further analyse current therapeutic strategies targeting autophagy, senescence, and inflammasome pathways, emphasising the limitations of single-target approaches and the potential of multi-target interventions. By integrating these processes into a unified framework, this review provides new insights into the possible molecular mechanisms underlying neuroinflammaging and identifies the 'ASI axis' as a promising target for neurodegenerative disease-modifying therapies.},
}

@article {pmid42419611,
year = {2026},
author = {Bolon, M and Barbereau, A and Aimard, M and Monge, C and Bouvet, P and Meissirel, C and Richard, S},
title = {Nose-to-brain delivery of an amyloid beta blocking peptide using polylactic acid-poloxamer 188 nanocarriers.},
journal = {Nanomedicine : nanotechnology, biology, and medicine},
volume = {75},
number = {},
pages = {102987},
doi = {10.1016/j.nano.2026.102987},
pmid = {42419611},
issn = {1549-9642},
abstract = {BACKGROUND: Alzheimer's disease, characterized by a progressive cognitive decline, represents a major global health challenge. A novel blocking peptide (seq: KRKKSRYKSWSVYVG) which binds with high affinity for toxic amyloid beta oligomers implicated in the early stages of the disease pathogenesis, has shown promising therapeutic potential. To overcome the challenges of brain drug delivery, nanoparticles combined with a nose-to-brain delivery approach were used to enhance brain biodistribution and drug delivery efficiency. In this study, we evaluated the feasibility of using these nanoparticles to deliver the blocking peptide to the brain.

RESULTS: Nanoparticles composed of polylactic acid and poloxamer P188 were synthesized and successfully functionalised with surface-adsorbed blocking peptide, exhibiting physicochemical characteristics suitable for nose-to-brain delivery. The nanoparticles preserved the blocking peptide therapeutic activity against amyloid beta aggregation and, in addition, protected it from enzymatic degradation. Functional cellular evaluation showed biocompatibility of the nanoparticle-blocking peptide compound and potential internalization by neuronal cells. Importantly, in vivo experiments demonstrated the successful delivery of the nanoparticles from the nasal cavity to the brain, representing a significant step forward in targeted brain delivery.

CONCLUSION: Nanoparticles functionalised with an anti-amyloid beta aggregation peptide successfully reached the brain following intranasal administration, suggesting their potential as a therapeutic strategy against the Alzheimer's disease.},
}

@article {pmid42419633,
year = {2026},
author = {Cauzzi, E and Ficchì, S and De Paolis, ML and Saba, L and Montanari, M and Loffredo, G and La Barbera, L and Krashia, P and Nobili, A and D'Amelio, M},
title = {Midbrain dopamine loss drives parvalbumin interneuron vulnerability through tissue plasminogen activator-linked perineuronal-net breakdown and hippocampal disinhibition.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107527},
doi = {10.1016/j.nbd.2026.107527},
pmid = {42419633},
issn = {1095-953X},
abstract = {Midbrain dopaminergic degeneration is an early feature of Alzheimer's Disease (AD), dementia with Lewy bodies (DLB), and AD-Parkinson's disease overlap (AD-PD). However, its direct contribution to the failure of hippocampal inhibitory-circuits, a pathological feature shared across these conditions, remains unresolved. Parvalbumin-positive interneurons (PV-INs) regulate hippocampal excitation-inhibition balance and are directly modulated by dopamine (DA). These neurons are protected by perineuronal nets (PNNs), extracellular-matrix structures supporting fast GABAergic signaling and neuronal resilience. We tested whether midbrain-derived DA loss is sufficient to destabilize hippocampal PV-IN function, potentially promoting their vulnerability or affecting PNN integrity. Through stereotaxic unilateral 6-hydroxy-dopamine lesion of the Ventral Tegmental Area/Substantia Nigra pars compacta in C57BL/6 N mice, we reduced the hippocampal DA tone and midbrain-derived synaptic input onto PV-INs. At 1-month post-lesion, PV-IN numbers were preserved, but the PNN integrity was reduced, accompanied by increased expression of tissue plasminogen activator (tPA), a PNN-remodeling protease. In CA1 pyramidal neurons, spontaneous inhibitory postsynaptic currents showed reduced frequency with faster decay, and bicuculline unmasked heightened population-spike excitability. By 6-months post-lesion, PV-IN numbers declined significantly, especially in CA1, demonstrating progressive vulnerability. D2/D3 receptor (D2/D3R) activation with quinpirole normalized tPA levels in PV-INs ex vivo, restored PNN integrity after sub-chronic treatment in vivo and increased inhibitory postsynaptic-event frequency, indicating functional recovery of GABAergic drive. These findings support the involvement of a DA-D2/D3R-tPA axis contributing to PV-IN extracellular-matrix integrity and hippocampal inhibitory tone. They also demonstrate that DA depletion is sufficient to trigger PNN breakdown, reduce GABAergic inhibition, network hyperexcitability, and cause progressive PV-IN loss independently of canonical protein aggregates like Aβ, tau or α-synuclein, characteristic of AD, DLB or AD-PD. This mechanism links midbrain degeneration to hippocampal circuit failure, highlighting D2/D3R signaling and extracellular proteolysis as actionable targets for early circuit stabilization across AD, DLB, and AD-PD.},
}

@article {pmid42420047,
year = {2026},
author = {Li, L and Gu, Y and Luo, X and Wang, J and Jia, Y and Yan, T},
title = {Corrigendum to "Chrysin reprograms microglial metabolism and function via targeting SYK to alleviate the symptoms of Alzheimer's disease" [J. Ethnopharmacol. (2026) 122056].},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122169},
doi = {10.1016/j.jep.2026.122169},
pmid = {42420047},
issn = {1872-7573},
}

@article {pmid42420075,
year = {2026},
author = {Chew, V},
title = {Exercise-induced liver-to-brain communication in aging and Alzheimer's disease.},
journal = {Journal of hepatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jhep.2026.06.003},
pmid = {42420075},
issn = {1600-0641},
}

@article {pmid42420092,
year = {2026},
author = {Newberg, AB and Hua, Y and Ayubcha, C and Monti, DA},
title = {Fluorodeoxyglucose PET Scans in the Integrative Medicine Setting.},
journal = {PET clinics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cpet.2026.06.001},
pmid = {42420092},
issn = {1879-9809},
abstract = {Functional imaging with fluorodeoxyglucose (FDG) PET has substantially advanced our understanding of the biological processes underlying a wide range of neurologic and systemic disorders. In particular, brain FDG PET enables the visualization of regional metabolic activity associated with different mental states and neuropsychiatric conditions. By assessing patterns of cerebral glucose metabolism, FDG PET can provide insight into an individual's current brain function, including age-related metabolic changes and early alterations suggestive of neurodegenerative disorders such as Alzheimer's disease. This article reviews potential indications for FDG PET scanning in integrative medicine practice and situates it within the broader landscape of functional imaging modalities.},
}

@article {pmid42420222,
year = {2026},
author = {Sobol, KV},
title = {Effects of Metabolites of Lactic Acid Bacteria on Nerve Cells of the Microbiota-Gut-Brain Axis.},
journal = {Biochemistry. Biokhimiia},
volume = {91},
number = {6},
pages = {867-892},
doi = {10.1134/S0006297926600377},
pmid = {42420222},
issn = {1608-3040},
mesh = {Humans ; Animals ; *Brain/metabolism ; *Lactobacillales/metabolism ; *Neurons/metabolism ; *Gastrointestinal Microbiome ; Probiotics ; },
abstract = {This review examines the key pathways of bidirectional communication between the gut and brain along the microbiota-gut-brain axis, with particular emphasis on the effects of metabolites of lactic acid bacteria (metLABs) on neurons of the enteric and central nervous systems. Special attention is given to the role of metLABs in intracellular signaling. The review further explores the direct effects of metLABs on mitochondrial function in nervous tissue, neuronal plasticity, and neuritogenesis. Potential mechanisms for the release of neurotrophic factors in both cells and host organism following exposure to metLABs or probiotic products are analyzed. Although clinical evidence remains limited, existing studies suggest that regular consumption of metLAB-containing fermented foods may positively influence brain functions through modulation of the microbiota-gut-brain axis. At least two ongoing clinical trials currently investigate whether normalization of the gut microbiota through probiotic interventions can slow the progression of Alzheimer's disease. As this field continues to advance rapidly, further studies are expected to provide important insights into the therapeutic potential of microbiota-targeted strategies for neurological health.},
}

Humans
Animals
*Brain/metabolism
*Lactobacillales/metabolism
*Neurons/metabolism
*Gastrointestinal Microbiome
Probiotics

@article {pmid42420230,
year = {2026},
author = {Blagova, AV and Perepelitsa, ES and Satish, A and Lifanov, DA and Zhdankina, VI and Kopylova, AA and Guk, PV and Salmina, AB and Illarioshkin, SN},
title = {Development of Metabolic Stress in Vascular Organoids under Normal Conditions and with AD/PD-Associated Genetic Backgrounds.},
journal = {Biochemistry. Biokhimiia},
volume = {91},
number = {6},
pages = {992-1005},
doi = {10.1134/S0006297926600286},
pmid = {42420230},
issn = {1608-3040},
mesh = {Humans ; *Organoids/metabolism/pathology ; *Parkinson Disease/metabolism/genetics/pathology ; Induced Pluripotent Stem Cells/metabolism/cytology ; *Alzheimer Disease/metabolism/genetics/pathology ; Mitochondria/metabolism ; Oxidative Stress ; Connexin 43/metabolism ; Endothelial Cells/metabolism ; *Stress, Physiological ; NAD/metabolism ; },
abstract = {Vascular organoids derived from human induced pluripotent stem cells (iPSCs) are promising models for studying vascular pathology, including neurodegenerative diseases. In this study, we investigated signs of mitochondrial dysfunction in the vascular organoids derived from the iPSCs of a healthy donor, as well as patients with Alzheimer's disease (AD) and Parkinson's disease (PD). In the conditioned medium of vascular organoids from the PD patient-derived cells, but not from the AD patient-derived cells, a trend toward a disrupted NAD[+]/NADH balance was observed, accompanied by the reduced expression of the connexin 43 (Cx43) protein. A sign of metabolic vulnerability of endothelial cells in the vascular organoids from the PD patient-derived cells, but not from normal or AD patient-derived organoids, manifested as reduced expression of c-Myc was observed. Changes in the membrane potential were detected in the vascular organoids from the AD and PD patient-derived, as well as increase in the mitochondrial superoxide anion production were observed, which may indicate development of oxidative stress in the microvessel cells during neurodegeneration.},
}

Humans
*Organoids/metabolism/pathology
*Parkinson Disease/metabolism/genetics/pathology
Induced Pluripotent Stem Cells/metabolism/cytology
*Alzheimer Disease/metabolism/genetics/pathology
Mitochondria/metabolism
Oxidative Stress
Connexin 43/metabolism
Endothelial Cells/metabolism
*Stress, Physiological
NAD/metabolism

@article {pmid42420256,
year = {2026},
author = {He, CY and Wang, XY and Fan, J and Wang, YN and Masters, CL and Wang, YJ},
title = {Could the cognitive benefits of amyloid-beta clearance grow in time for Alzheimer's disease?.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04188-y},
pmid = {42420256},
issn = {2158-3188},
support = {82588301//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82120108010//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82401695//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Alzheimer's disease (AD) is characterized histologically by amyloid-β (Aβ) deposition in the brain. Immunotherapies targeting Aβ clearance have become a leading treatment strategy. Although these therapies effectively reduce cerebral Aβ burden, their cognitive benefits remain modest during the trial period. This review systematically assesses the extent of Aβ clearance by immunotherapies and its related cognitive outcomes, focusing on whether cognitive benefits increase over time. We refine a model of the "lag effect" between plaque clearance and cognitive benefit, which is potentially influenced by clearance rate, treatment duration, disease stage, genetic factors, and aging. We also discuss the underlying biological mechanisms and potential neuroprotective targets. Future research should prioritize long-term studies, early intervention, personalized therapies, and combination approaches addressing multiple pathological pathways. Given limited short-term cognitive gains, optimizing outcomes will require tailoring treatments to individual patient factors-including genetics, disease progression, and aging-to minimize side effects and enhance long-term cognitive function.},
}

@article {pmid42420546,
year = {2026},
author = {Nour, H and Mounadi, N and Samadi, A and Chtita, S},
title = {Stylopine as multi-target anti-Alzheimer agent.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61364-2},
pmid = {42420546},
issn = {2045-2322},
support = {#12R282//Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University/ ; },
abstract = {Alzheimer's disease is a complex neurodegenerative disorder involving multiple enzymes, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), monoamine oxidase B (MAO-B), and β-secretase (BACE-1). Currently available treatments are limited to acetylcholinesterase inhibitors, which offer purely symptomatic relief and do not halt disease progression. Consequently, the development of multi-target ligands represents a promising therapeutic approach. In this study, Alkaloids were evaluated using in silico approaches. Predictions of biological activity performed using the PASS software revealed stylopine as a promising candidate with potential anti-Alzheimer activity. Furthermore, this compound demonstrated strong binding affinity for key targets (Torpedo AChE, BuChE, and BACE-1), as well as a promising pharmacokinetic profile. Molecular dynamics simulations and MM-GBSA calculations have demonstrated the stability of stylopine-target interactions. Taken together, these studies suggest that stylopine could be a promising multitarget agent for the treatment of Alzheimer's disease, although further experimental data are needed to confirm its efficacy.},
}

@article {pmid42420985,
year = {2026},
author = {Liu, Z and Ao, WL and Luo, AD and Guan, SQ and Wang, J and Yu, CY and Xu, ZC and Xu, P and Huang, H},
title = {Microglia-mediated synaptic pruning in neural circuit remodeling: multidimensional control in homeostasis and neuropathology.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-026-05016-2},
pmid = {42420985},
issn = {1741-7015},
support = {Qiankehe Foundation - ZSYS(2025)030//the Key Laboratory of Brain Function and Brain Disease Prevention and Treatment of Guizhou Province/ ; CXTD[2022]013//the Guizhou Basic and Clinical Research Scientific and Technological Innovation Talent Team Project/ ; GCC-2022-038-1//the Guizhou Provincial "Hundred" Level Innovative Talents Fund/ ; },
abstract = {BACKGROUND: Microglia, the resident immune cells of the central nervous system, are key regulators of synaptic plasticity and neural circuit homeostasis.

MAIN BODY: This review summarizes the mechanisms by which microglia shape synaptic structure and function, including dynamic synaptic interactions, selective pruning, epigenetic regulation, extracellular matrix remodeling, metabolic adaptation, and communication with other glial cells. Under physiological conditions, these processes support circuit refinement, synaptic stability, and cognition, which are modulated by circadian rhythms and the microbiota-gut-brain axis. In Alzheimer's disease, schizophrenia, and related disorders, microglial dysfunction can shift synaptic pruning from a controlled homeostatic process to pathological synapse loss. Excessive complement-mediated pruning, disrupted excitation-inhibition balance, neuroinflammation, and metabolic dysregulation may jointly impair synaptic integrity and circuit function.

CONCLUSION: This review highlights microglial heterogeneity, state transitions, and targeted modulation as important directions for understanding synaptic remodeling and developing therapeutic strategies for neurological diseases.},
}

@article {pmid42421081,
year = {2026},
author = {Watkins, MM and Xhafkollari, G and Zhao, N and Ross, OA},
title = {Understanding the genetic imperfections of Lewy body dementia.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00961-1},
pmid = {42421081},
issn = {1750-1326},
support = {AG087165/NH/NIH HHS/United States ; U54-NS110435/NH/NIH HHS/United States ; NA//American Brain Foundation/ ; NA/ALZ/Alzheimer's Association/United States ; NA//Michael J. Fox Foundation for Parkinson's Research/ ; NA//American Parkinson Disease Association/ ; NA//Lewy Body Dementia Association/ ; },
abstract = {Lewy body dementia (LBD) is a clinically and pathologically complex neurodegenerative disease. Its etiology remains poorly understood and, as such, it is likely underdiagnosed in clinical practice. Clinically, LBD is defined by fluctuations in cognition, visual hallucinations, rapid eye movement (REM) sleep behavior disorder (RBD), and motor dysfunction. The disease is pathologically defined by the presence of Lewy bodies in the brain, which are protein aggregates made up of misfolded α-synuclein; however, co-pathologies are often present and greatly complicate both symptom presentation and research interpretation. This heterogeneous pathology paired with overlapping clinical features of Alzheimer's disease and Parkinson's disease hinder diagnostic clarity. With no specific biological biomarkers currently identified, it is the hope that genetics can help with diagnosis and to clarify the pathomechanistic nature of this multifaceted disorder. Through rare familial studies, SNCA, the gene which encodes α-synuclein, was implicated in disease risk and development, underscoring its central role in α-synucleinopathies. Shortly after this discovery, a genome wide association study (GWAS) confirmed this risk, and identified two other major genes, APOE and GBA, to be associated with LBD. The APOE ε4 allele, which is a well-established risk factor for AD, is also associated with an increased risk for LBD. This common association demonstrates that APOE is implicated in a broader role in neurodegenerative disease pathogenesis. Meanwhile, GBA mutations, which are associated with lysosomal dysfunction and are also a known risk factor for PD, are linked to a more severe cognitive decline and earlier disease onset. However, even with these advances, our understanding of LBD's genetic architecture remains incomplete. Overcoming these limitations will require larger, more diverse study cohorts, comprehensive analyses, technological advances, and improved phenotyping upon clinical presentation of disease. Current clinical diagnostic strategies often struggle to capture the full spectrum of LBD symptoms and commonly lead to misdiagnosis/misclassification. By combining genetic data with improved phenotyping and the latest novel technologies, we can greatly improve our mechanistic understanding of LBD. These insights will not only improve diagnostic accuracy but will also lead to the development of disease modifying treatments specifically designed to best treat each individual patient.},
}

@article {pmid42421403,
year = {2026},
author = {Lim, EY and Han, K and Cho, AH},
title = {Role of Physical Activity in Protecting Against Dementia According to Menopausal Status.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {4},
pages = {427-436},
doi = {10.3988/jcn.2025.0615},
pmid = {42421403},
issn = {1738-6586},
support = {SC21ZISE0149/SSMH/Seoul St. Mary's Hospital, Catholic University of Korea/Korea ; },
abstract = {BACKGROUND AND PURPOSE: This study evaluated the impact of physical activity on dementia risk in females while considering their menopausal status and body mass index (BMI) as potential modifiers.

METHODS: This population-based retrospective cohort study utilized the Korean National Health Insurance Service database, and stratified 2,163,842 females aged ≥40 years who underwent health examinations in 2009 into pre- and postmenopausal groups. Cox proportional-hazards models were used to estimate the adjusted hazard ratios (aHRs) for all-cause dementia, Alzheimer's dementia (AD), and vascular dementia (VaD) according to physical activity levels. Interaction terms were used to assess effect modification by BMI.

RESULTS: Regular physical activity was associated with a reduced risk of all-cause dementia and AD, but not VaD in premenopausal females (aHR=0.830, 95% confidence interval [CI]=0.739-0.931) and a reduced risk of all-cause dementia, AD, and VaD in postmenopausal females (e.g., aHR=0.884, 95% CI=0.868-0.900). The association between physical activity and dementia risk was largely consistent across BMI categories. However, a modest interaction was observed for light physical activity (LPA) (p=0.046), with a significant risk reduction in postmenopausal women with BMI ≥25.0 kg/m² (aHR=0.942, 95% CI=0.921-0.964).

CONCLUSIONS: Physical activity is associated with a lower risk of dementia in both pre- and postmenopausal females. Among postmenopausal females, even LPA such as walking may confer protective benefits, particularly in those with higher BMIs.},
}

@article {pmid42421594,
year = {2026},
author = {Medina, C and Fernández, RS and Krawczcyk, MC and Boccia, MM},
title = {Hippocampal prediction errors and claustral control at the perception-memory crossroads.},
journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences},
volume = {381},
number = {1954},
pages = {},
doi = {10.1098/rstb.2025.0253},
pmid = {42421594},
issn = {1471-2970},
support = {//Secretaría de Ciencia y Técnica, Universidad de Buenos Aires/ ; },
mesh = {Animals ; *Hippocampus/physiology ; *Memory/physiology ; *Perception/physiology ; Humans ; *Claustrum/physiology ; Bayes Theorem ; Models, Neurological ; },
abstract = {Prediction errors (PEs)-the mismatches between what the brain expects and what it encounters-drive the continual alignment of perception with memory. Here, we review cross-species evidence showing that this cycle depends on hippocampal predictions that bridge sensory perception and declarative memory. The hippocampus generates probabilistic forecasts via pattern completion and separation, while the claustrum-a multisensory hub-constrains those forecasts with integrated perceptual evidence, jointly shaping the magnitude of the resulting PE signal. We combine two explanatory lenses: Bayesian inference, which prescribes how strongly a PE should update prior beliefs, and connectionist models, which reveal how local, neuromodulator-gated plasticity approximates that normative update in real circuits. Dopaminergic and cholinergic signals tune PE precision and experimental inactivation of the claustrum in mice impairs hippocampal-dependent memory reconsolidation, establishing causality in this perception-to-memory loop. We propose that aberrant PE calibration accounts for cognitive symptoms in Alzheimer's disease, schizophrenia and learning disorders. We also outline pharmacological and circuit-level strategies to normalize PEs, and a research agenda combining ultra-high-field imaging, causal manipulations and hybrid Bayesian-connectionist modelling. Clarifying how the hippocampus and claustrum cooperate to align perception with memory promises biomarkers and precision therapies for cognitive disorders. This article is part of the theme issue 'The role of hippocampal predictions in cognition: bridging perception and memory'.},
}

Animals
*Hippocampus/physiology
*Memory/physiology
*Perception/physiology
Humans
*Claustrum/physiology
Bayes Theorem
Models, Neurological

@article {pmid42421820,
year = {2026},
author = {Brosch, JR and Wang, S and Apostolova, LG and Agarwal, A and Allen, JW and Gutmann, L and Tobar, M and Gonzalez, L and Johnson, D and Treadway, L and Connolly, J and Tang, A and Lettich, E and Davies, S and Kuhn, N and Hammers, DB and Clark, D and Farlow, M and Willis, DR and Fowler, N and Wilcock, DM},
title = {The Indiana University Brain Health Program to deliver amyloid-targeted therapy to Alzheimer's disease patients.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70291},
pmid = {42421820},
issn = {2352-8737},
abstract = {INTRODUCTION: The Indiana University Brain Health Program was developed to support safe implementation of amyloid-targeting therapies (ATTs) for early Alzheimer's disease (AD).

METHODS: We established Neurology Brain Health Navigators (neuroBHNs) to extend our Brain Health Navigator model into specialty care. NeuroBHNs pre-screen patients for ATT eligibility, coordinate biomarker and imaging evaluation, provide structured education, and guide treatment initiation and monitoring. The program includes a dedicated social worker and insurance pre-authorization specialist to streamline infusion access. Blood pressure is monitored at each visit, and infusions are deferred if readings exceed 140/90 mmHg.

RESULTS: Through December 16, 2025, 243 patients initiated lecanemab therapy. Apolipoprotein E (APOE) ε4 homozygotes were not excluded; 74% of treated patients carried at least one Apoε4 allele. The ARIA rate was 13.2%, and 40% of patients experienced infusion-related reactions.

CONCLUSIONS: A navigator-centered model can efficiently deliver ATT while supporting structured education, screening, and safety monitoring, potentially contributing to favorable safety outcomes.},
}

@article {pmid42421969,
year = {2026},
author = {Xu, G and Cheng, Z and Zhou, Y and Guo, L and Zhu, H and Shen, Z},
title = {Osteoimmuno-brain axis: a bridge connecting osteoporosis and cognitive decline and its clinical significance in dementia and Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1866071},
pmid = {42421969},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism ; *Osteoporosis/immunology/metabolism ; *Brain/immunology/metabolism ; Animals ; *Cognitive Dysfunction/immunology/metabolism ; *Bone and Bones/immunology/metabolism ; *Dementia/immunology/metabolism ; Cytokines/metabolism ; },
abstract = {Osteoporosis and cognitive dysfunction, particularly Alzheimer's disease (AD), frequently co-occur in the elderly population, suggesting shared pathophysiological links. The emerging concept of the "osteoimmune-brain axis" provides a framework that emphasizes the immune system as the central mediator connecting skeletal and cerebral pathology. This review explores how the osteoimmune system-the dynamic interface between bone and immune interactions-influences brain function through pathways including systemic inflammation, cytokine release, and bone-derived hormones. We systematically synthesize evidence from basic mechanisms to clinical studies, with a critical appraisal of the strength and directionality of the evidence. Key questions addressed include: whether the observed associations are causal or merely associative; which bone-derived factors have human validation; and whether the axis primarily operates as a unidirectional driver, a bidirectional amplifier, or an epiphenomenon of shared aging processes. This review aims to provide a balanced theoretical foundation for future research and for developing prevention strategies targeting both skeletal and neurodegenerative diseases.},
}

Humans
*Alzheimer Disease/immunology/metabolism
*Osteoporosis/immunology/metabolism
*Brain/immunology/metabolism
Animals
*Cognitive Dysfunction/immunology/metabolism
*Bone and Bones/immunology/metabolism
*Dementia/immunology/metabolism
Cytokines/metabolism

@article {pmid42422091,
year = {2026},
author = {Herrera-Calderon, O and Calva, J and Guzmán-Flores, JM and Peña-Rojas, G and Andia-Ayme, V and Loyola-Gonzales, E and Pari-Olarte, JB and Almeida-Galindo, JS},
title = {Chemical and enantioselective GC-MS characterization of Minthostachys mollis (Benth.) Griseb. Essential oil from Peru and its acetylcholinesterase inhibitory activity.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1864128},
pmid = {42422091},
issn = {1663-9812},
abstract = {BACKGROUND: Minthostachys mollis (Benth.) Griseb., an aromatic medicinal plant widely used in traditional medicine in Peru, was investigated using an integrated chemical, enantioselective, and acetylcholinesterase (AChE) inhibitory approach.

AIM: To characterize the chemical and enantiomeric composition of M. mollis essential oil by GC-MS, evaluate its AChE inhibitory activity in vitro, and explore the molecular interactions of its volatile constituents with human AChE through molecular docking and molecular dynamics simulations.

METHODS: The essential oil (EO) collected from the leaves via steam distillation was analyzed using Gas Chromatography-Mass Spectrometry (GC-MS). Enantioselective GC-MS analysis was performed for the first time on this species. AChE inhibitory activity was evaluated in vitro using Ellman's assay, and molecular docking and molecular dynamics studies were performed on human AChE (PDB: 4EY7).

RESULTS: GC-MS analysis revealed 33 volatile compounds, of which 30 were structurally identified, accounting for 100% of the total EO composition. Oxygenated monoterpenes were the predominant chemical class (86.24%), with pulegone (63.82%) as the major constituent, followed by carvacrol (5.52%), 1,8-cineole (5.50%), and (E)-isocitral (4.98%). Enantioselective analysis revealed a marked stereochemical preference, including enantiomerically pure (S)-(-)-limonene and (1R,5R)-(+)-sabinene, as well as the predominance of (1S,5S)-(-)-α-pinene (92.54%, e.e. = 84.97%) and (1S,5S)-(-)-β-pinene (80.63%, e.e. = 61.86%). The AChE inhibitory activity showed a moderate inhibitory effect of the EO, with an IC50 value of 466.4 ± 1.01 μg/mL. Sesquiterpenes such as γ-muurolene, δ-amorphene, and β-bourbonene exhibited the most favorable binding affinities (ΔG values ranging from -7.3 to -7.0 kcal/mol), mainly mediated by hydrophobic interactions within the catalytic and peripheral anionic sites.

CONCLUSION: This study provides a comprehensive chemical and stereochemical characterization of M. mollis EO, supporting its relevance as a source of bioactive volatile compounds with moderate AChE inhibitory activity.},
}

@article {pmid42422111,
year = {2026},
author = {Wang, J and Fu, X and Liu, J and Yang, Y},
title = {Non-invasive brain stimulation in frontotemporal dementia: syndrome-specific signals and priorities for future trials.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1842455},
pmid = {42422111},
issn = {1663-4365},
abstract = {Frontotemporal dementia is the second most common cause of young-onset dementia after Alzheimer's disease and lacks disease-modifying treatment. This narrative review summarizes human studies of non-invasive brain stimulation, including repetitive transcranial magnetic stimulation and theta-burst stimulation, transcranial electrical stimulation, and transcranial photobiomodulation, in frontotemporal dementia and primary progressive aphasia. We review stimulation targets, protocols, outcomes, and safety, and organize the evidence by clinical subtype and modality. Current data remain preliminary, but recurrent signals support prefrontal and cerebellar repetitive transcranial magnetic stimulation/theta-burst stimulation and prefrontal or temporoparietal transcranial direct current stimulation, particularly in primary progressive aphasia. By contrast, controlled evidence in behavioral-variant frontotemporal dementia is limited and heterogeneous. Future trials should be sham-controlled, multicenter, and syndrome-stratified; combine stimulation with symptom-relevant cognitive or language therapy; and incorporate biomarker-informed targeting, target-engagement measures, and longer follow-up to determine durability and clinical relevance.},
}

@article {pmid42422112,
year = {2026},
author = {Ye, P and Li, Z and Cui, X and Wu, H and Jiang, H},
title = {ZBTB7A-mediated regulation of astrocytic glycolysis in neurodegenerative diseases: insights from literature review and bioinformatics prediction.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1852019},
pmid = {42422112},
issn = {1663-4365},
abstract = {The incidence of neurodegenerative diseases, including Alzheimer's disease (AD), continues to increase with the extension of human lifespan. However, their pathogenesis remains incompletely understood. Altered energy metabolism, particularly glucose metabolism involving glycolysis and oxidative phosphorylation, is widely recognized as an early pathological feature of neurodegenerative diseases. Astrocytes, the most numerous and widely distributed functional cells in the central nervous system (CNS), support neuronal energy demands through the astrocyte-neuronal lactate shuttle (ANLS). Glycolysis is a major pathway of astrocyte energy metabolism, and enhanced astrocytic glucose uptake and glycolytic flux may help attenuate the progression of neurodegenerative diseases such as AD. Zinc Finger and BTB Domain Containing 7A (ZBTB7A) is a POZ/BTB and Krüppel (POK) family transcription factor that has been implicated in the regulation of metabolic genes, including glycolysis-related genes, in several cellular contexts. However, its role in astrocyte glycolytic regulation under neurodegenerative conditions remains unclear. In this review, we summarize current knowledge of ZBTB7A biology, astrocyte glycolysis, and glial metabolic dysfunction in neurodegenerative diseases, and integrate published evidence with bioinformatics-based transcription factor binding prediction. Our analysis identified putative ZBTB7A-binding motifs in promoter regions of genes involved in glucose uptake, glycolytic flux, lactate production, and lactate transport. These findings suggest a potential association between ZBTB7A and the astrocytic glycolytic/lactate metabolic network. Therefore, this review provides a conceptual basis for future studies on ZBTB7A-associated transcriptional regulation in astrocyte metabolic remodeling and its potential relevance to neurodegenerative diseases.},
}

@article {pmid42422228,
year = {2026},
author = {Sukreet, S and Donohue, MC and Ngolab, J and Belsha, A and Salazar, J and Cohen, P and Jaiswal, S and Tan, V and Aggarwal, NT and Alber, J and Johnson, K and Jicha, GA and van Dyck, CH and Ramanan, S and Lah, JJ and Salloway, S and Verdooner, SR and Rafii, MS and Aisen, PS and Sperling, RA and Rissman, RA},
title = {Relationships between longitudinal retinal amyloid imaging and amyloid PET in the A4 Trial.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70422},
pmid = {42422228},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is associated with retinal amyloid-related changes, which may help identify amyloid positron emission tomography (PET) positive (+) individuals. Previously, in a small cross-sectional study, we reported higher retinal spot counts (RSCs) in preclinical amyloid PET (+) individuals screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial compared to control individuals enrolled in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) trial before drug treatment.

METHODS: Eligible volunteers had retinal scans 48 hours after consuming curcumin. Scans were processed and quantified via NeuroVision. Participants were grouped by amyloid status and treatment to assess the effect of solanezumab on RSC.

RESULTS: RSC did not differ significantly over time between groups and was not modified by treatment, diverging from the cross-sectional retinal amyloid findings observed in A4/LEARN.

DISCUSSION: Curcumin-based retinal amyloid labeling shows promise but needs standardized protocols and validation in larger cohorts to understand its relationship to amyloid PET.},
}

@article {pmid42422229,
year = {2026},
author = {Jarholm, JA and Tecelão, S and Kirsebom, BE and Ghazi, MM and Pålhaugen, L and Gísladóttir, B and Gonzalez-Ortiz, F and Akhavi, MS and Hopp, E and Fjell, AM and Timón-Reina, S and Nielsen, M and Blennow, K and Aarsland, D and Bjørnerud, A and Selnes, P and Fladby, T},
title = {Independent prognostic value of peak width of skeletonized mean diffusivity on clinical progression in Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70416},
pmid = {42422229},
issn = {2352-8729},
abstract = {INTRODUCTION: Peak width of skeletonized mean diffusivity (PSMD) is a candidate magnetic resonance imaging marker for global white matter integrity. We investigated the value of PSMD in predicting clinical progression in amyloid-positive and amyloid-negative individuals.

METHODS: PSMD, cognition, and amyloid status were measured in 254 subjects from the Dementia Disease Initiation (DDI) cohort and 211 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Survival analysis was conducted on 166 DDI subjects and validated in 178 ADNI subjects using Clinical Dementia Rating scale.

RESULTS: High PSMD amyloid-positive individuals had an increased risk of clinical progression relative to those with low PSMD, driven by independent additive effects of amyloid pathology and PSMD. Higher PSMD was predominantly associated with slower processing speed and reduced executive function, but not with memory performance.

DISCUSSION: Combining PSMD with amyloid status may improve the prediction of clinical progression in Alzheimer's disease, particularly in relation to executive and processing speed domains.},
}

@article {pmid42422257,
year = {2026},
author = {Tian, C and Yang, S and Zhang, X and Yan, H},
title = {Ligand-specific duality of aryl hydrocarbon receptor signaling in cognitive health: from environmental neurotoxicity to microbiome-mediated neuroprotection.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1823961},
pmid = {42422257},
issn = {1662-4548},
abstract = {The aromatic hydrocarbon receptor (AhR) is a key molecular interface integrating environmental chemical signals with host-microbiome metabolism, with profound effects on brain function. This review systematically addresses the ligand-specific duality of AhR signaling in cognitive health, comparing the predominantly neurotoxic signaling driven by environmental polycyclic aromatic hydrocarbons (PAHs) with the predominantly neuroprotective signaling mediated by gut microbiota-derived tryptophan metabolites. However, this dichotomy is context-dependent rather than absolute. PAHs activate AhR in a sustained, high-affinity manner, engaging downstream NF-κB neuroinflammation, NLRP3 inflammasome activation, oxidative stress, synaptic dysfunction, and transgenerational epigenetic alterations. In contrast, microbiota-derived metabolites such as indole-3-propionic acid (IPA) and kynurenic acid (KYNA) elicit transient, low-affinity AhR activation that engages cell-type-specific programs promoting anti-inflammatory responses, neurogenesis, blood-brain barrier integrity, and neuronal homeostasis. Critically, the outcome of AhR activation is modulated by ligand pharmacokinetics, cell-type identity, temporal dynamics of receptor engagement, and tissue-specific co-factor availability. These contextual variables determine whether AhR functions as a driver of neurodegeneration or a guardian of cognitive resilience. We further examine the divergent roles of AhR in Alzheimer's and Parkinson's diseases, where the balance between detrimental and protective ligands determines disease progression. Finally, we discuss therapeutic strategies targeting the AhR-gut-brain axis, including dietary modulation, probiotic interventions, and selective AhR modulators. Understanding the context-dependent outcomes of AhR activation provides a framework for developing precision approaches to preserve cognitive function and prevent neurodegeneration.},
}

@article {pmid42422260,
year = {2026},
author = {Akhbari, M and Babaei, F and Navidi-Moghaddam, A and Ghafghazi, S and Khodabandehloo, F and Sarookhani, MR and Dargahi, L and Mohammadi, G and Nassiri-Asl, M},
title = {The effects of Saccharomyces boulardii on TLR4/NF-κB neuroinflammatory pathway in the hippocampus of LPS-induced rats.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {199-206},
pmid = {42422260},
issn = {2667-2421},
abstract = {Saccharomyces boulardii (Sb), a probiotic yeast, is known for its positive effects on gastrointestinal and metabolic health. Recent research has explored its potential to influence neurological conditions by modulating neuroinflammatory responses via the gut-brain axis. Toll-like receptor 4 (TLR4) is recognized as a key molecular target in regulating neuroinflammation, particularly in disorders like Alzheimer's disease (AD). This study investigated whether Sb could alleviate downstream elements of the TLR4 neuroinflammatory pathway in a lipopolysaccharide (LPS)-induced rat model relevant to AD. Rats were randomly assigned to four groups: 1) control, 2) LPS, 3) Sb + LPS, and 4) Sb alone. All groups received either normal saline or Sb (a volume of 1 ml containing 10 [10] CFU) by oral gavage for four weeks. From day 14, LPS (250 μg/kg/day) or saline was administered intraperitoneally for nine days. Researchers assessed spatial memory, levels of TLR4 pathway-associated proteins in the hippocampus, pro-inflammatory cytokine expression, and neuronal survival using Nissl staining. The results showed that pre-treatment with Sb partially ameliorated spatial learning deficits, significantly reducing the LPS-induced elevation of nuclear factor kappa B (NF-κB) and interleukin-1β (IL-1β) in the hippocampus and protecting against neuronal loss in the hippocampal CA1 region. Sb mitigates LPS-induced neuroinflammation by modulating downstream elements of the TLR4 pathway-specifically NF-κB and IL-1β-rather than acting directly on the TLR4 receptor, likely through mechanisms involving the gut-brain axis.},
}

@article {pmid42422474,
year = {2026},
author = {Bosco, C and Shojaei, F and Theisz, AA and Nguyen, V and Song, H and Han, R and Torres, JO and Chheda, D and Lin, J and Peng, X and Waseem, NZ and Simpkins, C and Cureton, B and Himes, AK and Jessup, NM and Indiana, YL and Hendrie, HC and Barnes, PA and Hill, CV and Shih, PC},
title = {"I don't see anything specifically about Black/African Americans." Testing an Alzheimer-specific generative AI tool tailored for African American/Black communities.},
journal = {ACM transactions on computing for healthcare},
volume = {7},
number = {3},
pages = {},
pmid = {42422474},
issn = {2637-8051},
abstract = {Low levels of health literacy concerning Alzheimer's Disease and related dementias (ADRD) impact African American/Black communities access to appropriate ADRD care. Additionally, a legacy of mistrust in medical research due to systemic racism, has resulted in insufficient participation in ADRD clinical trials among African American/Black adults. This study explores the potential of generative AI to improve ADRD literacy and encourage participation in clinical trials among African American/Black older adults. We designed a mobile health intervention featuring AI-driven conversational agents - a chatbot and a voice assistant - specifically developed for this population. We tested the quality of the intervention using heuristics methodology adapted to the target population along with inputs from African American/ Black medical professionals and UX designers. Key findings highlight the unique needs of the African American/Black communities for culturally relevant content that is accessible to users with varying language levels and tailored to users' geographical location. Concerning the interaction, high levels of personalization and control over the interaction can promote the use of the tool, by minimizing complexity and maximizing accessibility. These findings show the novel contribution offered by our study in the domain of designing health technology with generative AI, particularly LLMS, for African American/Black communities.},
}

@article {pmid42422539,
year = {2026},
author = {Geron, C and Maquet, P},
title = {ABCA7 Mutation in Behavioral Variant of Frontotemporal Dementia: A Case Report.},
journal = {Case reports in neurology},
volume = {18},
number = {1},
pages = {317-324},
pmid = {42422539},
issn = {1662-680X},
abstract = {INTRODUCTION: Frontotemporal lobar degeneration (FTLD), a major cause of early-onset dementia, includes a heterogeneous group of neurodegenerative disorders with a strong genetic component. Mutations in MAPT, GRN, and C9orf72 are found in about 40% of patients with the behavioral variant (bvFTD). More recently, rarer pathogenic variants have been identified in other genes, such as ABCA7, initially linked to Alzheimer's disease but increasingly implicated in other neurodegenerative conditions. Here we describe a specific variant which has not previously been reported in the literature.

CASE PRESENTATION: We report the case of a 42-year-old woman who presented with progressive behavioral changes and executive dysfunction, consistent with a bvFTD. A whole-exome sequencing was conducted in a family trio, revealing a heterozygous nonsense variant in the ABCA7 gene (c.5260C>T, p.Arg1754*).

CONCLUSION: This case highlights support the hypothesis of an ABCA7 loss-of-function associated with early-onset bvFTD. It contributes to expand the genetic spectrum of frontotemporal dementia and underscores the importance of broad genetic testing.},
}

@article {pmid42422549,
year = {2026},
author = {Ruesga Mundo, S},
title = {Hierarchical-circular model of biological memory: a multilevel hypothesis for pathogenesis and allostatic integrity in Alzheimer's disease and related dementias.},
journal = {Frontiers in dementia},
volume = {5},
number = {},
pages = {1841647},
pmid = {42422549},
issn = {2813-3919},
abstract = {INTRODUCTION: Alzheimer's disease and related dementias remain largely resistant to disease-modifying therapies, despite decades of research focused on linear neuropathological pathways such as beta-amyloid and tau. Persistent paradoxes-including the dissociation between pathology burden and clinical expression, the impact of early-life stress, and the role of systemic factors-indicate the need for integrative theoretical frameworks. This article proposes a multilevel hypothesis conceptualizing dementias as disorders of biological memory and allostatic integrity rather than isolated brain pathologies.

HYPOTHESIS: The Hierarchical-Circular Model of Biological Memory posits that dementia emerges from progressive disruptions in a circular, multilevel system that encodes and stabilizes biological information across the lifespan. The model is organized around the unifying principle "Signal → Plasticity → Stable State" and integrates five interconnected levels: (1) morphogenetic programming and genetic architecture, (2) epigenetic molecular memory, (3) allostatic load and systemic physiological adaptation, (4) the Psychological-Neurological-Endocrine-Immunological (PNEI) network, and (5) interoceptive-neuronal integration. At any level, perturbation can propagate bidirectionally through the system, establishing maladaptive stable states that manifest clinically as dementia.

DEVELOPMENT OF THE HYPOTHESIS: Through a structured synthesis of longitudinal, mechanistic, and multisystem studies (2010-2025), the model specifies how gene-environment interactions, epigenetic modifications, cumulative allostatic load, neuroimmune dynamics, and altered interoceptive timescales jointly shape vulnerability and resilience. The concept of allostatic integrity is introduced as a dynamic systems-level property-distinct from allostatic load-that explains why similar neuropathological burdens may result in divergent clinical trajectories. Distinct dementia phenotypes are proposed to reflect different patterns of circular reinforcement across the five levels.

TESTABLE PREDICTIONS: This framework generates concrete, falsifiable predictions: (1) composite indices of allostatic integrity will outperform single biomarkers in predicting conversion from mild cognitive impairment to dementia; (2) multidomain interventions targeting more than one system level will have multiplicative, rather than additive, effects on slowing cognitive decline; (3) patients with similar amyloid/tau profiles but contrasting allostatic integrity will show markedly different trajectories of clinical progression; and (4) allostatic integrity moderates the protective effect of cognitive reserve, a pattern not predicted by reserve frameworks alone.

CONCLUSION: The Hierarchical-Circular Model of Biological Memory offers a unifying hypothesis for Alzheimer's disease and related dementias that bridges genetic, epigenetic, physiological, neuroimmune, and interoceptive processes across the lifespan. By reframing dementias as failures of biological memory and allostatic integrity, the model provides a conceptual roadmap for mechanistic research, multidomain prevention, and personalized treatment strategies.},
}

@article {pmid42422561,
year = {2026},
author = {Riccardi, N and Martin, A and Pytel, D and Newman-Norlund, S and Carroll, SL and Rorden, C and Fridriksson, J and Bonilha, L},
title = {Brain age gradients as intermediate phenotypes linking plasma p-tau217 to cognition in community-dwelling older adults.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {54},
pmid = {42422561},
issn = {3005-1940},
abstract = {Deep learning-based brain age models quantify regional deviations from normative aging and may capture structural changes relevant to dementia risk. Plasma phosphorylated tau-217 (p-tau217) is a scalable Alzheimer's disease biomarker, but its relationship to brain aging and cognition in cognitively unimpaired adults is unclear. In this cross-sectional study, we tested whether brain age patterns serve as indirect pathways linking plasma p-tau217 to cognition in the Aging Brain Cohort (ABC). Neuroimaging data from 518 adults (mean age = 43.7 years, 70.8% female) were analyzed using a validated deep learning brain age model, and decomposed via exploratory factor analysis into six gradients: frontal, dorsal, ventral, left frontotemporal, right frontotemporoparietal, and bilateral parietal. In a parallel mediation model including all six gradients as simultaneous mediators in adults aged ≥60 years (N = 71), a significant specific indirect effect of plasma p-tau217 on Montreal Cognitive Assessment (MoCA) scores was observed through accelerated right frontotemporoparietal aging (β = -0.111, 95% CI [-0.313, -0.010], p = 0.031). No other indirect pathways were significant, and neither the total nor direct effect was significant. These findings suggest a specific brain aging phenotype as a potential intermediate pathway linking tau-related pathology to cognition prior to clinical impairment.},
}

@article {pmid42422911,
year = {2026},
author = {Secco, GL and Qureshi, K and Shafeea, MS and Karpinski, PH and Wouters, K and Merlim da Silva, MC and Ganta, SR and von Quednow, E and Guzmán-Ríos, ED and Brice, KS and Dsouza, M and Fernandes, A and Noori, NN and Chaurasia, B and Yangi, K},
title = {Clinical, Radiological, and Immunohistological Distinctions Between Limbic-Predominant and Typical Alzheimer's Disease: A Systematic Review.},
journal = {Brain and behavior},
volume = {16},
number = {7},
pages = {e71586},
pmid = {42422911},
issn = {2162-3279},
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/physiopathology/classification/metabolism ; *Limbic System/pathology/diagnostic imaging ; Atrophy ; Hippocampus/pathology/diagnostic imaging ; Temporal Lobe/pathology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide and one of the leading causes of morbidity and mortality among elderly people. It is characterized by generalized brain atrophy, especially affecting the hippocampus and medial temporal lobe. In this context, new subtypes of AD have been documented, including a limbic-predominant subtype (LP), and the current literature is insufficient to clarify the similarities and differences between these subtypes and the typical presentation. Recently, new studies have proposed a clinical criterion for LP amnestic syndrome, separating it from AD. Therefore, this study aims to evaluate the clinical, radiological, and immunohistological distinctions between those two presentations.

METHODS: This study was conducted in accordance with the PRISMA guidelines. Notable databases were utilized for sources: PubMed, Embase, and Web of Science. Baseline characteristics, clinical, radiological, and immunohistological features, and follow-up times were recorded. Screening was performed using the Rayyan system, and quality assessment was conducted using appropriate tools.

RESULTS: After reviewing 211 articles, screening yielded 21 articles, totaling 11,315 patients. Among these, 1178 (15.7%) presented with LP and 4159 (36.7%) with AD. A total of 5378 (47.6%) had a different presentation, including hippocampal sparing only and the association of LP and typical AD. The weighted average for education in years was 24.31 for LP patients and 17.15 for typical AD patients. The weighted average for age at onset was 72.33 for typical AD patients and 77.36 for LP patients. For the duration of the disease, the weighted average for typical AD was 8.95, and it was 8.43 for LP. There were no differences in clinical presentation, with cognitive impairment and memory deficits being the most cited manifestations. MRI and FDG-PET are the most commonly used imaging techniques; in typical AD patients, different levels of hippocampal and medial, lateral parietal, and frontotemporal lobe atrophy are observed. In LP patients, imaging findings revealed lower hippocampal volume and higher metabolic rates than in typical AD patients. MRI R2 relaxometry in LP patients revealed lower R2 relaxation rates in the amygdala, hippocampus, and temporal lobe white matter compared with typical AD patients. Tau-PET imaging in typical AD patients demonstrated elevated standardized uptake value ratios in the parietal and posterior cingulate cortex. The immunohistological findings revealed a greater hippocampal tau burden than in cortical regions and a greater number of TDP-43 inclusions in LP patients than in typical AD patients. Typical AD patients had a weighted average of 20.06 and LP patients 17.7.

CONCLUSION: Our analysis of clinical, radiological, and immunohistological features revealed significant differences between LP and typical AD presentations. However, those findings alone cannot reliably determine accuracy, whether both presentations are stages of the same pathology or different diseases. More studies need to explore this field to further examine this topic.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/physiopathology/classification/metabolism
*Limbic System/pathology/diagnostic imaging
Atrophy
Hippocampus/pathology/diagnostic imaging
Temporal Lobe/pathology

@article {pmid42423023,
year = {2026},
author = {Kim, S and Oda, H and Oyama, R and Makishi, R and Bade, S and Bade, S and Ally, I and Iijima, Y and Gibo, Y and Minami, K and Fukuzawa, F and Sanji, S and Inamine, K and Kishi, H and Huh, S and Tanifuji, T and Nagahiro, M and Watanabe, N},
title = {Efficacy, safety and policy implications of anti-amyloid monoclonal antibodies for Alzheimer's disease: protocol for a living systematic review and meta-analysis.},
journal = {BJPsych open},
volume = {12},
number = {4},
pages = {e182},
doi = {10.1192/bjo.2026.12044},
pmid = {42423023},
issn = {2056-4724},
abstract = {BACKGROUND: Dementia affects approximately 6-13% of adults aged 65 years and older, with Alzheimer's disease accounting for most cases. Established symptomatic therapies, including acetylcholinesterase inhibitors and memantine, provide limited benefit and do not modify disease progression. Multiple monoclonal antibodies (mABs) targeting different amyloid-β species have been developed as potential disease-modifying therapies; because some agents have entered clinical use whereas others remain investigational, a continuously updated synthesis of their efficacy and safety is needed.

AIMS: To evaluate the efficacy and safety of all anti-amyloid mABs for adults with Alzheimer's disease, using a living systematic review and meta-analysis.

METHOD: We will conduct a living systematic review and meta-analysis in accordance with the Cochrane Handbook, Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 and the PRISMA extension for living systematic reviews. Randomised controlled trials comparing any approved or investigational anti-amyloid mAB with placebo, standard care or active comparators will be included. Searches of Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform will be updated every 6 months. Meta-analyses will be conducted separately for each antibody molecule using random-effects models. Critical outcomes include global clinical change and disease severity, cognitive abilities, functional ability and dependency, and safety (serious adverse events, treatment discontinuation and amyloid-related imaging abnormalities). Important outcomes include neuropsychiatric symptoms, quality of life and health system outcomes. Certainty of evidence will be assessed using the methodology Grading of Recommendations, Assessment, Development and Evaluation.

RESULTS: This article describes a protocol; therefore, no review findings are available at this stage.

CONCLUSIONS: This living systematic review will provide an up-to-date synthesis of the benefits and harms of anti-amyloid monoclonal antibodies to inform clinical decision-making and health-system planning in Alzheimer's disease.},
}

@article {pmid42423068,
year = {2026},
author = {Lagartos-Donate, MJ and Escobar-Doncel, B and Zhang, CS and Fang, EF},
title = {NAD[+] modulates REST isoform expression and its downstream mitophagy in Alzheimer's disease.},
journal = {Autophagy},
volume = {},
number = {},
pages = {},
doi = {10.1080/15548627.2026.2701599},
pmid = {42423068},
issn = {1554-8635},
abstract = {Repressor Element 1-Silencing Transcription factor (REST) emerges as a metabolism-sensitive transcriptional hub that supports basal mitophagy, mitochondrial quality, and synaptic function in neurons. In Alzheimer's disease, REST becomes mislocalized and functionally impaired, coinciding with early defects in mitochondrial quality control. Activation of the NAD[+] -SIRT1 axis enhances REST nuclear activity, restores its mitochondrial and neuroprotective gene programs, and attenuates pathological and cognitive decline in experimental AD models. Our study highlights REST as a promising target to preserve mitochondrial and neuronal function.Abbreviations:Alzheimer's disease, AD; Repressor Element 1-Silencing Transcription factor, REST; Nicotinamide Adenine Dinucleotide, NAD[+].},
}

@article {pmid42423373,
year = {2026},
author = {Lang, J and Liu, Y},
title = {Unsupervised optimal deep transfer learning for classification under general conditional shift.},
journal = {Biometrics},
volume = {82},
number = {3},
pages = {},
doi = {10.1093/biomtc/ujag123},
pmid = {42423373},
issn = {1541-0420},
support = {JYB2025XDXM904//Ministry of Education of China/ ; 12571283//National Natural Science Foundation of China/ ; 12171157//National Natural Science Foundation of China/ ; },
mesh = {*Transfer Machine Learning ; Classification Algorithms ; Neural Networks, Computer ; *Deep Learning ; Humans ; Algorithms ; Likelihood Functions ; *Unsupervised Machine Learning ; },
abstract = {Classifiers trained on labeled source data may yield misleading results when applied to unlabeled target data drawn from a different distribution. Transfer learning can rectify this by transferring knowledge from source to target data, but its effectiveness frequently relies on stringent assumptions, such as label shift or strong separation conditions. We introduce a novel general conditional shift assumption, which encompasses label shift as a special case and facilitates the identifiability of both the target distribution and the shift function without requiring a separation condition. Our classifier is constructed by integrating deep neural networks (DNNs) and a pseudo-maximum likelihood approach. We establish asymptotic error bounds for our DNN-based classifier and estimators of the conditional probabilities ${ \boldsymbol{\eta }_
{P}}
$ for source data and the target label distribution $\boldsymbol{\pi }_
{Q}$
, in terms of the intrinsic dimension of ${ \boldsymbol{\eta }_
{P}}
$. Notably, the excess risk of the proposed classifier achieves the optimal minimax rate, up to a logarithmic factor. Our method not only eliminates the need to estimate the shift function, but also alleviates the curse of dimensionality when ${ \boldsymbol{\eta }_
{P}}
$ exhibits a low-dimensional structure. Numerical simulations, along with an analysis of an Alzheimer's disease dataset, underscore its exceptional performance.},
}

*Transfer Machine Learning
Classification Algorithms
Neural Networks, Computer
*Deep Learning
Humans
Algorithms
Likelihood Functions
*Unsupervised Machine Learning

@article {pmid42423483,
year = {2026},
author = {Solfrizzi, V and Imbimbo, BP},
title = {Frailty as an underrepresented dimension in clinical trials of Alzheimer's disease therapies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261466693},
doi = {10.1177/13872877261466693},
pmid = {42423483},
issn = {1875-8908},
abstract = {Population aging is redefining the clinical reality of Alzheimer's disease and increasing the need for outcome measures that reflect the complexity of older adults. Although recent trials on putative disease-modifying drugs have moved beyond cognition-only endpoints and now include integrated cognitive-functional measures, frailty remains underrepresented in trial design. We discuss the demographic context of aging societies, the relevance of frailty to dementia expression, and the implications of recent amyloid-β-targeting antibody trials, which include substantial numbers of older adults. We propose that frailty can improve external validity, refine biomarker interpretation, and strengthen precision medicine approaches linking biological measures with functional outcomes.},
}

@article {pmid42423489,
year = {2026},
author = {},
title = {Jacob Labonte, BS, and Michael L Alosco, PhD, are the recipients of the 2026 Alzheimer Award.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261468905},
doi = {10.1177/13872877261468905},
pmid = {42423489},
issn = {1875-8908},
}

@article {pmid42423522,
year = {2026},
author = {Lohman, T and Kapoor, A and Engstrom, AC and Joyce, J and Quiring, M and Alitin, JPM and Gaubert, A and Nguyen, A and Head, E and Rodgers, KE and Bradford, D and Lashin, B and Han, SD and Mather, M and Nation, DA},
title = {Low frequency blood-oxygen-level-dependent oscillations, APOE4, and plasma pTau217.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467275},
doi = {10.1177/13872877261467275},
pmid = {42423522},
issn = {1875-8908},
abstract = {BackgroundLow frequency oscillations in blood-oxygen-level-dependent signal (BOLD-LFOs) are generally considered nuisance signal in connectivity analysis and discarded. However, recent evidence suggests BOLD-LFOs shed light on cerebrovascular dysfunction and preclinical Alzheimer's disease, but the mechanisms remain unclear. No investigations have assessed the relationship between BOLD-LFOs and plasma pTau217, or how it differs in apolipoprotein ε4 (APOE4) carriers who are vulnerable to cerebrovascular dysfunction and genetically predisposed to AD.ObjectiveTo study the relationship between BOLD-LFOs and plasma p-Tau217 in APOE4 carriers compared to non-carriers.MethodsIndependently living older adults (N = 118) were recruited and underwent resting-state fMRI and venipuncture. BOLD-LFOs were quantified as signal power within the 0.01-0.10 Hz frequency range. Plasma pTau217 was assessed and linear regression quantified the interactive effect of APOE4 carrier status and BOLD-LFOs on plasma pTau217. 2×2 ANCOVA was used to compare BOLD-LFOs across APOE4 carrier and amyloid positivity statuses based on previously reported pTau217 cutoffs.ResultsThe interactive effect of APOE4 carrier status and BOLD-LFO power was significantly associated with plasma pTau217 (β = -0.78, p = 0.001). This relationship was driven by an inverse relationship between BOLD-LFOs and plasma pTau217 in APOE4 carriers (β = -0.57, p = 0.0007). Amyloid-β (+) APOE4 carriers displayed lower BOLD-LFOs than amyloid-β (-) APOE4 carriers (p = 0.008) and amyloid-β (+) non-carriers (p = 0.03). Models were adjusted for age, sex, vascular risk factors, and total intracranial volume.ConclusionsFindings suggests BOLD-LFOs are implicated in preclinical AD in an APOE4 dependent manner, adding support for the continued study of BOLD-LFOs in the context of cerebrovascular contributions to AD genetic risk.},
}

@article {pmid42423590,
year = {2026},
author = {Cai, W and Li, J and Chen, C and Mei, J and Liu, Y},
title = {Network toxicology screening of plastic-associated chemicals reveals candidates with structural mimicry to Alzheimer's disease-relevant molecules and predicted neurotoxicity.},
journal = {SAR and QSAR in environmental research},
volume = {},
number = {},
pages = {1-26},
doi = {10.1080/1062936X.2026.2697791},
pmid = {42423590},
issn = {1029-046X},
abstract = {Alzheimer's disease (AD) pathogenesis involves environmental factors, with plastic-associated chemicals emerging as potential neurotoxicants. This study employed a computational toxicology framework to screen plastic-associated chemicals for potential interference with AD-related pathways. From a compiled library of 12,751 plastic-associated chemicals, 2,315 compounds with high blood-brain barrier (BBB) permeability were identified. Using Morgan fingerprints and Tanimoto similarity (threshold ≥ 0.6), we pinpointed chemicals structurally analogous to known AD-active molecules, including 3,5-Dimethoxystilbene (similarity 0.731 to a resveratrol derivative) and Isoeugenol (similarity 0.710 to isorhapontigenin). Structural similarity alone does not imply toxicity; therefore, we further evaluated these candidates using target prediction, molecular docking, and in silico toxicity profiling. Target prediction and molecular docking indicated that several compounds may interact with core AD-related targets (e.g. AChE, MAOB, APP). Notably, ProTox-3.0 profiling revealed that both 3,5-Dimethoxystilbene and Isoeugenol exhibit a potential dual profile of concern: high predicted BBB penetrance (probability > 0.7) and predicted potential for neurotoxic effects (probability 0.54-0.68), although these moderate probability scores warrant cautious interpretation. High-affinity binding was validated for 3,5-Dimethoxystilbene with AChE (-9.1 kcal/mol), comparable to known AChE inhibitors in our docking validation. This study prioritizes plastic-associated chemicals with a 'brain-penetrating and potentially neurotoxic' profile based on integrated computational evidence, providing a data-driven foundation for experimental validation.},
}

@article {pmid42423628,
year = {2026},
author = {Luu, PV and Nguyen, CQ and Ton-Nu, HL and Phan, TT and Huynh, QT and Pham, NT and Le, HG and Chen, LY and Chang, YC and Su, JH and Peng, BR and Lai, KH},
title = {Xeniaphyllane-Type Diterpenoids from the Soft Coral Sclerophytum humesi: Resolving Absolute Configurations and Anti-Alzheimer's Potential.},
journal = {Journal of natural products},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jnatprod.6c00535},
pmid = {42423628},
issn = {1520-6025},
abstract = {A combined bioassay- and [1]H NMR-guided isolation strategy led to the discovery of four new terpenoids, including three xeniaphyllane-type diterpenoids, sclerohumins P-R (1-3), and a norcaryophyllene-type, sclerophyllene A (4), from the soft coral Sclerophytum humesi. The structures and absolute configurations of these compounds were elucidated by comprehensive spectroscopic analysis, including NMR, HRESIMS, SOR, TDDFT-ECD, and DP4+ probability analysis. The stereogenic centers at C-15 in related xeniaphyllanes were proposed for the first time based on comparative SOR analysis. Compounds 1 and 2 possess a tricyclic 4/9-fused carbocyclic framework featuring an epoxide moiety, whereas compounds 3 and 4 exhibit related bicyclic scaffolds. A plausible biogenetic pathway originating from geranylgeranyl pyrophosphate (GGPP) was proposed to account for their structural diversity. Compounds 1 and 2 showed potent AChE inhibitory activity (IC50 = 1.7 and 4.4 μM, respectively), while being inactive against BChE and noncytotoxic toward normal cell lines (HEK293 and Vero). Mechanistic studies combining enzyme kinetics and molecular docking revealed that 1 and 2 act as mixed-type AChE inhibitors, with Ki values of 1.02 and 1.87 μM, respectively. These findings represent the first report of xeniaphyllane-type diterpenoids with potential for neurotherapeutic development.},
}

@article {pmid42423667,
year = {2026},
author = {Huang, Q and Zuo, Y and Xie, Y and Liu, Z and Wang, L and Xu, H and Yu, M and Liu, C},
title = {A nose-to-brain drug delivery system targeting mitochondrial dysfunction: application potential and future prospects of chitosan nanogels in Alzheimer's disease.},
journal = {Biomaterials science},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6bm00624h},
pmid = {42423667},
issn = {2047-4849},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal degeneration and cognitive impairment. One of its core pathologies involves energy metabolism disruption and oxidative stress resulting from mitochondrial dysfunction. Traditional drugs struggle to effectively cross the blood-brain barrier (BBB), while the nasal-brain drug delivery system offers a novel approach for achieving direct brain access. Chitosan, a biodegradable natural polymer with strong mucosal adhesion properties, has been extensively utilized in recent years to construct nanogel carriers. This approach enhances drug retention and absorption in the nasal epithelium, enabling targeted delivery to the brain via the olfactory or trigeminal nerve pathways. This paper provides a systematic review of research progress on chitosan nanogel-based naso-cerebral drug delivery systems targeting mitochondrial dysfunction, focusing on their molecular mechanisms in improving mitochondrial energy metabolism, scavenging excess reactive oxygen species (ROS), suppressing neuroinflammation, and regulating apoptosis. Additionally, this paper analyzes the design principles of various modification strategies-such as triphenylphosphine (TPP) modification, pH/ROS responsiveness, and drug-loaded nanozyme complexes-along with their efficacy validation in AD models. It further explores the future development trends of chitosan nanogel-mediated multi-target intervention and smart-responsive nasal-brain delivery systems, offering new directions for precision treatment of AD.},
}

@article {pmid42423799,
year = {2026},
author = {Cui, H and Zhang, Y},
title = {Cistanoside A decreases Tau hyperphosphorylation and neuronal apoptosis through the AKT/GSK3β pathway in okadaic acid-induced in vivo and in vitro models of Alzheimer's disease.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42423799},
issn = {1573-4978},
support = {(2022YX085)//2022 Weifang Science and Technology Development Plan Project/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/chemically induced ; *tau Proteins/metabolism ; Apoptosis/drug effects ; Glycogen Synthase Kinase 3 beta/metabolism ; Rats ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphorylation/drug effects ; Okadaic Acid/pharmacology ; Neurons/metabolism/drug effects ; Humans ; Signal Transduction/drug effects ; Disease Models, Animal ; Male ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Cell Line, Tumor ; Rats, Sprague-Dawley ; Neuroprotective Agents/pharmacology ; },
abstract = {BACKGROUND: The multifactorial nature of Alzheimer's disease (AD) pathogenesis has driven the search for therapeutic agents with low toxicity that can act on multiple targets. Cistanoside A (Cis A), a bioactive compound derived from Cistanches Herba, exhibits anti-inflammatory, antioxidant, and antiapoptotic effects. Given that these processes are implicated in AD progression, we propose that Cis A may be a promising candidate for AD therapy.

METHODS: We employed an okadaic acid (OA)-induced rat model in vivo and SH-SY5Y cells in vitro. Cognitive function was assessed using the Morris water maze and novel object recognition tests. Hematoxylin and eosin and Nissl staining were performed to evaluate histopathological changes. Neuronal damage was assessed using the Cell Counting Kit-8 assay for cell viability, TUNEL staining for apoptosis, and western blotting for protein expression. Mitochondrial damage was examined using JC-1 and MitoSOX Red staining.

RESULTS: Cis A significantly improved cognitive deficits. It attenuated OA-induced apoptosis, restored mitochondrial membrane potential, and reduced reactive oxygen species levels in rats and SH-SY5Y cells by inhibiting hyperphosphorylation of Tau protein via the AKT/GSK3β pathway. Furthermore, the protective effect of Cis A was attenuated by MK-2206 and AKT knockdown in vitro.

CONCLUSION: Cis A significantly improves cognitive function and reduces AD-related pathology, highlighting its potential as a therapeutic candidate for AD.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/chemically induced
*tau Proteins/metabolism
Apoptosis/drug effects
Glycogen Synthase Kinase 3 beta/metabolism
Rats
Proto-Oncogene Proteins c-akt/metabolism
Phosphorylation/drug effects
Okadaic Acid/pharmacology
Neurons/metabolism/drug effects
Humans
Signal Transduction/drug effects
Disease Models, Animal
Male
Reactive Oxygen Species/metabolism
Membrane Potential, Mitochondrial/drug effects
Cell Line, Tumor
Rats, Sprague-Dawley
Neuroprotective Agents/pharmacology

@article {pmid42423809,
year = {2026},
author = {Yousef, AI and El-Twab, SMA and Khadrawy, SM and Abdel-Moneim, A and Khalil, RG},
title = {Polydatin inhibits hippocampal neurodegeneration in diabetic rats via modulation of oxidative stress and NF-kB/COX-2/IL-6 inflammatory pathway.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42423809},
issn = {1573-7365},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Glucosides/pharmacology/therapeutic use ; *Stilbenes/pharmacology/therapeutic use ; *Hippocampus/drug effects/metabolism/pathology ; Male ; Rats ; Cyclooxygenase 2/metabolism ; *Diabetes Mellitus, Experimental/metabolism/drug therapy ; *NF-kappa B/metabolism ; Interleukin-6/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Molecular Docking Simulation ; *Neurodegenerative Diseases/metabolism/drug therapy ; },
abstract = {Impaired insulin function and persistent hyperglycemia damage the brain of diabetics and raise the risk of Alzheimer's disease (AD). Although polydatin (PLD) possesses promising biological effects, no major study has yet explored its anti-neurodegenerative efficacy in the hippocampus. This study therefore aims to investigate the probable protective effects of PLD against hippocampal neurodegeneration in diabetic rats, as well as explore its in-silico inhibitory activity against two key enzymes implicated in the progression of AD. Experimental diabetes was induced in male albino rats then PLD was administered orally to the diabetic rats (50 mg/kg b.wt.) daily for four weeks. In silico molecular docking was used to predict the interactions of PLD against BACE1 and AChE. PLD treatment significantly improved diabetic parameters, lowering blood glucose and raising serum insulin. Excitingly, PLD markedly alleviated oxidative stress by reducing lipid peroxidation and nitric oxide levels while enhancing antioxidant defenses (elevated GPx activity and GSH content) in the hippocampus of diabetic rats. PLD also suppressed neuroinflammation by down-regulating NF-κB, COX-2, and IL-6 mRNA expression. Furthermore, PLD significantly elevated the protein level of IDE while lowered Aβ1-42 level. In silico, PLD revealed potent binding affinity for BACE1 (-8.6 Kcal/mol) and AChE (-10.5 Kcal/mol), interacting with key residues, indicating its inhibition potential. Overall, PLD effectively reduced neurodegeneration in the hippocampus of diabetic rats via inhibiting oxidative stress, inflammation, and Aβ1-42 accumulation. PLD may act as a promising multi-target anti-neurodegenerative candidate, capable of simultaneously modulating multiple pathways and more experimental validation are needed in the future.},
}

Animals
*Oxidative Stress/drug effects
*Glucosides/pharmacology/therapeutic use
*Stilbenes/pharmacology/therapeutic use
*Hippocampus/drug effects/metabolism/pathology
Male
Rats
Cyclooxygenase 2/metabolism
*Diabetes Mellitus, Experimental/metabolism/drug therapy
*NF-kappa B/metabolism
Interleukin-6/metabolism
Neuroprotective Agents/pharmacology/therapeutic use
Signal Transduction/drug effects
Molecular Docking Simulation
*Neurodegenerative Diseases/metabolism/drug therapy

@article {pmid42423830,
year = {2026},
author = {Chen, P and Qiang, X and Zhao, Z and Wang, W and Zhen, H and Liu, Y},
title = {Inhibition of miR-25-3p Alleviates Neuroinflammation in Alzheimer's Disease By Targeting ADAM10.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42423830},
issn = {1559-1182},
mesh = {Humans ; *MicroRNAs/genetics/antagonists & inhibitors/metabolism ; *Alzheimer Disease/genetics/metabolism/blood/pathology ; *ADAM10 Protein/metabolism/genetics ; *Amyloid Precursor Protein Secretases/metabolism/genetics ; Female ; Male ; *Membrane Proteins/metabolism/genetics ; Amyloid beta-Peptides/toxicity ; *Neuroinflammatory Diseases/genetics/metabolism/pathology/blood ; Cell Line, Tumor ; Apoptosis/drug effects/genetics ; Aged ; Cell Proliferation ; Up-Regulation/genetics ; Peptide Fragments/toxicity ; },
abstract = {As a neurodegenerative disorder, Alzheimer's disease (AD) is defined by progressive cognitive decline and involves intricate pathological mechanisms. This study aimed to investigate the clinical role and regulatory mechanism of miR-25-3p in AD. This investigation enrolled 115 AD patients and 110 healthy control subjects. Serum levels of miR-25-3p were quantified using quantitative real-time PCR (qRT-PCR), and the diagnostic performance of miR-25-3p for AD was assessed via receiver operating characteristic (ROC) analysis. In vitro, cellular models of AD were established by treating SH-SY5Y and HMC3 cells with amyloid-beta peptide 25-35 (Aβ25-35). Cellular proliferation and apoptosis were evaluated using the CCK-8 assay and flow cytometry, respectively. ELISA was employed to measure the concentrations of pro-inflammatory and anti-inflammatory cytokines. Furthermore, the direct targeting relationship between miR-25-3p and ADAM10 was confirmed through dual-luciferase reporter assays. miR-25-3p was significantly upregulated in the serum of AD patients and Aβ25-35-induced AD cell models, suggesting its potential diagnostic relevance for AD. Inhibition of miR-25-3p attenuated Aβ25-35-mediated neurotoxicity and neuroinflammation, whereas ADAM10 knockdown abrogated the neuroprotective effects of the miR-25-3p inhibitor in SH-SY5Y and HMC3 cells, which suggests that inhibition of miR-25-3p may alleviate the disease progression of AD by targeting ADAM10. Therefore, inhibition of miR-25-3p may alleviate the disease progression of AD by targeting ADAM10, providing a novel potential regulatory axis for AD intervention.},
}

Humans
*MicroRNAs/genetics/antagonists & inhibitors/metabolism
*Alzheimer Disease/genetics/metabolism/blood/pathology
*ADAM10 Protein/metabolism/genetics
*Amyloid Precursor Protein Secretases/metabolism/genetics
Female
Male
*Membrane Proteins/metabolism/genetics
Amyloid beta-Peptides/toxicity
*Neuroinflammatory Diseases/genetics/metabolism/pathology/blood
Cell Line, Tumor
Apoptosis/drug effects/genetics
Aged
Cell Proliferation
Up-Regulation/genetics
Peptide Fragments/toxicity

@article {pmid42423842,
year = {2026},
author = {Liu, Y and Li, M and Yu, H and Liu, H and Xu, Q and Li, F},
title = {Regulatory Effects of the PDE8B Inhibitor PF-04957325 on Cognitive Impairment and Neuroinflammation in Aβ-Induced Alzheimer's Disease Mouse Models.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42423842},
issn = {1573-6903},
support = {No. 20250232//Medical Science Research Project of Hebei/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; *Amyloid beta-Peptides/toxicity ; Male ; Mice ; *Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced ; Peptide Fragments/toxicity ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Signal Transduction/drug effects ; Mice, Inbred C57BL ; Maze Learning/drug effects ; Cyclic AMP Response Element-Binding Protein/metabolism ; Myeloid Differentiation Factor 88/metabolism ; Toll-Like Receptor 4/metabolism ; NF-kappa B/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, chronic neuroinflammation, and dysregulation of the cAMP/PKA/CREB pathway that impairs synaptic plasticity. PF-04957325 (PF), a selective PDE8B inhibitor, elevates intracellular cAMP; however, its systems-level effects and mechanisms in Aβ-driven AD are unclear. Here, we evaluate PF in an Aβ1-42 mouse model and delineate its modulation of cAMP/PKA/CREB and TLR4/MyD88/NF-κB signaling. An AD model was induced by intracerebroventricular injection of Aβ1-42, followed by oral PF administration (0.1 mg/kg/day). Cognitive performance was evaluated with the Morris water maze. Hippocampal pathology, Aβ burden, and apoptosis were assessed by H&E, immunohistochemistry, and TUNEL assays. IL-1β and IL-6 were measured by ELISA in hippocampal tissue and BV2 supernatants. Western blotting quantified APP, p-tau, and pathway proteins. BV2 cells and si-PDE8B served to validate mechanisms in vitro. PF significantly shortened escape latency (p < 0.01) and increased both platform crossings and target-quadrant dwell time (p < 0.01). It alleviated hippocampal neuronal injury, reduced Aβ burden, and decreased TUNEL-positive cells. Molecularly, PF elevated cAMP and increased p-PKA/PKA and p-CREB/CREB ratios (p < 0.01), while decreasing TLR4, MyD88, and p-NF-κB p65/NF-κB p65 (p < 0.01). PF also lowered IL-1β and IL-6 levels in hippocampal tissue and BV2 supernatants (both p < 0.01). In vitro, 300 nM PF phenocopied PDE8B knockdown, restoring cAMP/PKA/CREB activity and suppressing TLR4/MyD88/NF-κB activation. PF exerts dual protective effects by activating cAMP/PKA/CREB to enhance synaptic plasticity and survival, while inhibiting TLR4/MyD88/NF-κB to mitigate neuroinflammation. These findings highlight PDE8B inhibition as a promising therapeutic strategy for AD.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/metabolism
*Amyloid beta-Peptides/toxicity
Male
Mice
*Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced
Peptide Fragments/toxicity
*Cognitive Dysfunction/drug therapy/metabolism/chemically induced
Disease Models, Animal
Hippocampus/drug effects/metabolism
Signal Transduction/drug effects
Mice, Inbred C57BL
Maze Learning/drug effects
Cyclic AMP Response Element-Binding Protein/metabolism
Myeloid Differentiation Factor 88/metabolism
Toll-Like Receptor 4/metabolism
NF-kappa B/metabolism

@article {pmid42423959,
year = {2026},
author = {Övüt, AR and Toyran, R and Bülbül, NG and Urhan, M},
title = {A real-world decision tree model based on [18]F-FDG PET/CT Z scores and Mini-Mental State Examination for differentiating mild cognitive impairment from clinically diagnosed Alzheimer disease.},
journal = {Annals of nuclear medicine},
volume = {},
number = {},
pages = {},
pmid = {42423959},
issn = {1864-6433},
abstract = {OBJECTIVE: To evaluate the ability of regional metabolic Z scores derived from [18]F-fluorodeoxyglucose positron emission tomography/computed tomography ([18]F-FDG PET/CT), medial temporal atrophy (MTA) scores, and Mini-Mental State Examination (MMSE) results to distinguish mild cognitive impairment (MCI) from clinically diagnosed Alzheimer disease (AD), and to develop an interpretable decision-tree model based on these parameters.

METHODS: This retrospective single-center study included 124 patients who underwent ¹⁸F-FDG PET/CT for suspected cognitive impairment between 2023 and 2025. Patients were classified as AD or MCI according to final clinical diagnoses established by experienced neurologists using National Institute on Aging-Alzheimer's Association criteria. Regional metabolic Z scores were generated with CortexID Suite by comparison with an age-matched healthy normative database. MTA was graded on structural magnetic resonance imaging using the Scheltens scale by two blinded nuclear medicine physicians. MMSE scores were retrieved from clinical records. A random forest algorithm was used to identify discriminative variables, which were then incorporated into a transparent decision-tree classifier. The dataset was divided into a training cohort (n = 100) and a split-sample test cohort (n = 24).

RESULTS: The final decision tree integrated regional metabolic Z scores and MMSE values in a hierarchical classification structure. In the split-sample test cohort, the model achieved an accuracy of 95.8% and a balanced accuracy of 96.4%, with 100% sensitivity and 92.9% specificity for AD classification. The area under the receiver operating characteristic curve was 0.964 (95% confidence interval, 0.894-1.000).

CONCLUSIONS: An interpretable decision-tree approach integrating quantitative ¹⁸F-FDG PET/CT metrics with cognitive assessment showed promising performance for distinguishing clinically diagnosed AD from MCI in a real-world clinical cohort.},
}

@article {pmid42423996,
year = {2026},
author = {Khaitin, AM and Lebedeva, AA and Kunitsyna, AE and Demyanenko, SV},
title = {The role of mitochondrial Na[+]/Ca[2+] exchanger in brain cell aging.},
journal = {Journal of bioenergetics and biomembranes},
volume = {58},
number = {1},
pages = {},
pmid = {42423996},
issn = {1573-6881},
support = {25-25-00452//Russian Science Foundation/ ; },
mesh = {Humans ; *Sodium-Calcium Exchanger/metabolism ; *Brain/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; *Cellular Senescence ; Aging ; Neurons/metabolism ; },
abstract = {Considering the world's population aging and the importance of mitochondrial calcium regulation for all brain pathologies, researchers cannot neglect the role of mitochondrial sodium/calcium exchanger (NCLX) not only in pathologies like Alzheimer's and Parkinson's diseases, but in physiological "healthy" aging as well. Despite its critical role in mitochondrial metabolism upon neurodegeneration, the role of NCLX in physiological aging of CNS is almost unknown. NCLX interacts with regulatory partners like TMEM65 and signal pathways of PKA and HIF, connecting to broader metabolic networks of hypoxia, inflammation, oxidative stress, and autophagy. Understanding precise mechanisms of NCLX regulation and its cell-specific roles remains critical for developing targeted interventions to preserve brain function in aging. NCLX is functioning differently in neurons and glial cells, which should be investigated further and considered when studying brain aging. In this review we aim to encompass the current state and connections of this understudied topic and discuss the future prospects and implications.},
}

Humans
*Sodium-Calcium Exchanger/metabolism
*Brain/metabolism/pathology
*Mitochondria/metabolism/pathology
Animals
*Cellular Senescence
Aging
Neurons/metabolism

@article {pmid42424076,
year = {2026},
author = {Lyndon, S and Behlke, LM and Urizar, JC and Daffner, KR},
title = {Alzheimer Disease Biomarkers and Assisted Dying: When Diagnosis Becomes a Deadline.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.11317},
pmid = {42424076},
issn = {1538-3598},
}

@article {pmid42424084,
year = {2026},
author = {Zhang, Y and Yang, Y and Thunell, J and Miller, KEM},
title = {Days at Home Among Dually Eligible Medicare Beneficiaries With Alzheimer Disease and Related Dementias.},
journal = {JAMA network open},
volume = {9},
number = {7},
pages = {e2622670},
doi = {10.1001/jamanetworkopen.2026.22670},
pmid = {42424084},
issn = {2574-3805},
}

@article {pmid42424231,
year = {2026},
author = {Szyłak, E and Czarnowska, A and Kulczyńska-Przybik, A and Kopitelow, J and Mroczko, B and Kochanowicz, J and Kułakowska, A},
title = {Neurofilament Light Chain as a Biomarker in Neurology.},
journal = {European neurology},
volume = {},
number = {},
pages = {1-18},
doi = {10.1159/000552933},
pmid = {42424231},
issn = {1421-9913},
abstract = {Neurofilament light chain (NfL) has emerged as a highly sensitive biomarker of neuroaxonal injury across diverse neurological disorders. This review synthesizes current evidence regarding its diagnostic, prognostic, and therapeutic-monitoring utility, while outlining major clinical limitations and emphasizing the complementary role of glial fibrillary acidic protein (GFAP). NfL concentrations increase following axonal damage and correlate with inflammatory activity, lesion burden, and long-term disability progression in multiple sclerosis. Elevated levels also reflect neurodegeneration in Alzheimer's disease, predict disease severity and survival in amyotrophic lateral sclerosis, and are associated with motor and cognitive decline in Parkinson's disease and multiple system atrophy. In acute neurological conditions, including traumatic brain injury and stroke, NfL serves as a robust indicator of the extent of neuronal injury. Interpretation is constrained, however, by substantial physiological variability related to age, renal function, body mass index, and comorbidities, limiting the utility of absolute cut-off values. GFAP provides complementary information by capturing astrocytic damage, and the GFAP/NfL ratio may aid in differentiating multiple sclerosis from neuromyelitis optica spectrum disorder. Integration of NfL with multimodal biomarkers- such as GFAP, tau proteins, proteomic and metabolomic signatures, and advanced neuroimaging-may enhance diagnostic specificity and prognostic accuracy. Future research priorities include establishing age-adjusted reference intervals, validating longitudinal thresholds, and incorporating NfL into therapeutic monitoring frameworks. Advances in these areas are expected to improve diagnostic precision and support broader clinical implementation of NfL.},
}

@article {pmid42424238,
year = {2026},
author = {Tshimbombu, TN and Thurmann, KE and Decourt, B and Nyalundja, AD and Shardow, SB and Amoako, ME and Iragi, GM and Mwambali, JA and Sabbagh, MN},
title = {Autophagy in Alzheimer's disease: mechanisms, clinical trials, and horizons.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-21},
doi = {10.1159/000553506},
pmid = {42424238},
issn = {1660-2862},
abstract = {BACKGROUND: Alzheimer's disease (AD) is an incurable progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain. Recent findings have identified dysregulation of autophagy, a cellular mechanism for degradation and recycling, as a crucial contributor to the pathogenesis of AD. This narrative review examines the role of autophagy in the metabolism of Aβ and tau and evaluates current therapeutic strategies aimed at modulating autophagic pathways.

SUMMARY: Autophagy is governed by the key molecular regulators mammalian target of rapamycin, adenosine monophosphate-activated protein kinase, Beclin-1, and transcription factor EB, which collectively control the clearance of protein recycling, including aggregates, inside cells. Pharmacological agents such as rapamycin, resveratrol, and trehalose, alongside sigma-1 receptor agonists and gene therapy approaches, have demonstrated potential in modulating autophagy in preclinical and clinical studies. Despite these advances, significant challenges persist; namely, neuronal heterogeneity, optimal timing for therapeutic intervention, and the absence of reliable biomarkers to monitor autophagic activity and treatment efficacy.

KEY MESSAGES: Targeting autophagy offers a promising and potentially safe avenue for slowing AD progression. Future investigations should prioritize the development of selective autophagy modulators and personalized treatment strategies to restore autophagic flux and enhance clinical outcomes in patients with AD.},
}

@article {pmid42424274,
year = {2026},
author = {Nasir, AB and Kilani, Y and Aldiabat, M and Abdelghany, O and Hafez, Y and Desai, N and Madi, MY and Wade, FG and Qureshi, K and Frey, LJ and Farmer, AD and Syn, WK},
title = {Metabolic risk and metabolic dysfunction-associated steatotic liver disease and steatohepatitis in cognitive decline: A retrospective cohort study.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0353160},
doi = {10.1371/journal.pone.0353160},
pmid = {42424274},
issn = {1932-6203},
mesh = {Humans ; Female ; Retrospective Studies ; Male ; Middle Aged ; *Cognitive Dysfunction/epidemiology/metabolism/complications ; Aged ; Risk Factors ; *Fatty Liver/complications/metabolism/epidemiology ; *Alzheimer Disease/epidemiology/metabolism ; *Dementia, Vascular/epidemiology/metabolism ; },
abstract = {OBJECTIVE: To determine whether metabolic risk factors (MRFs), metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are associated with incident mild cognitive impairment (MCI), vascular dementia (VD), and Alzheimer disease (AD).

DESIGN: Retrospective cohort study using TriNetX (2003-2023) with Propensity score matching.

SETTING: Multicenter, population-based sample from 69 U.S. healthcare organizations in the TriNetX electronic health record.

PARTICIPANTS: Adults aged ≥50 years with ≥1 outpatient visit and sufficient clinical/laboratory data. Individuals with prior diagnoses of cognitive impairment, cerebrovascular disease, advanced liver disease, malignancy, schizophrenia, or substance use disorders were excluded. Two matched cohorts were constructed: one with 3,546,833 individuals with MRFs and 3,546,833 healthy controls, and another with 525,844 individuals with MASLD/MASH and 525,844 with MRFs only. Matching was based on age, sex, race, and ethnicity.

Incident MCI, VD, and AD, identified using ICD-10 codes, assessed at 5-20-year intervals. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression. Outcomes were prespecified.

RESULTS: Among 7,818,146 participants (mean [SD] age, 64.9 [8.8] years; 52.0% female), individuals with MRFs had higher odds of VD (OR, 1.65; 95% CI, 1.63-1.67), MCI (OR, 1.45; 95% CI, 1.42-1.48), and AD (OR, 1.21; 95% CI, 1.19-1.24) vs healthy controls. Compared to the MRF group, individuals with MASLD/MASH had lower odds of VD (OR, 0.86; 95% CI, 0.83-0.89) and AD (OR, 0.83; 95% CI, 0.78-0.88), but higher odds of MCI (OR, 1.37; 95% CI, 1.30-1.44); all p < .001.

CONCLUSIONS: In this large, propensity-matched retrospective cohort study, MRFs were independently associated with significantly increased long-term odds of MCI, VD, and AD. MASLD/MASH demonstrated a divergent cognitive risk profile relative to MRFs alone-characterized by higher odds of MCI but paradoxically lower odds of VD and AD, a pattern that warrants cautious interpretation given potential competing mortality risk, survivor bias, and residual confounding. These findings suggest that MASLD/MASH is associated with a distinct cognitive trajectory, highlighting the importance of early cognitive surveillance in this population.},
}

Humans
Female
Retrospective Studies
Male
Middle Aged
*Cognitive Dysfunction/epidemiology/metabolism/complications
Aged
Risk Factors
*Fatty Liver/complications/metabolism/epidemiology
*Alzheimer Disease/epidemiology/metabolism
*Dementia, Vascular/epidemiology/metabolism

@article {pmid42424329,
year = {2026},
author = {O'Shea, DM and Chang, LC and Chowdhury, M and Cook, DJ and Cresswell, K and Minor, BD and Mitsova, D and Tourelle, MS and Galvin, JE and Besser, LM},
title = {The heat exposure, aging trajectories, and Alzheimer's disease (HEAT-AD) study protocol.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0350611},
doi = {10.1371/journal.pone.0350611},
pmid = {42424329},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/etiology/blood/epidemiology/physiopathology ; *Aging ; *Hot Temperature/adverse effects ; Aged ; Biomarkers/blood ; Male ; Female ; Middle Aged ; Risk Factors ; Cognitive Dysfunction ; Brain/diagnostic imaging ; Cognition ; Magnetic Resonance Imaging ; },
abstract = {Urban heat islands (UHIs) are areas of elevated surface temperature caused by limited vegetation and dense development. Extreme heat disproportionately affects older adults and may increase risk for Alzheimer's disease (AD) and related dementias (ADRD), but few studies have examined whether cumulative neighborhood-level heat exposure is associated with cognitive decline or ADRD biomarkers. This study will investigate whether recent UHI exposure is associated with cognitive function; determine whether cumulative UHI exposure is associated with cognitive decline, plasma ADRD biomarkers, and brain imaging biomarkers; and evaluate whether UHI exposure is associated with ADRD risk factors, including physical inactivity, social isolation, and inflammation, and whether tree canopy mitigates heat-ADRD associations. The study includes 500 adults aged ≥50 years from the Healthy Brain Initiative cohort in South Florida. Geocoded residential addresses will be linked to satellite-derived land surface temperature data to quantify recent exposure at the baseline cognitive visit and cumulative exposure during the month before, and 1 and 5 years before baseline. Participants complete annual clinical and neuropsychological assessments, brain MRI, and blood collection for ADRD biomarkers. A sub-sample of 200 participants will wear smartwatches during two 3-week periods to capture GPS-based heat exposure, physical activity, and daily cognitive testing. Analyses will be replicated using the nationally representative Health and Retirement Study. Primary outcomes include cognitive domain scores, brain imaging measures, and preclinical AD status determined from plasma biomarkers. This study will provide comprehensive data on cumulative UHI exposure and ADRD risk by integrating cognitive assessment, neuroimaging, and biomarkers. Findings will clarify whether neighborhood heat represents a modifiable ADRD risk factor and inform urban greening and brain health promotion strategies.},
}

Humans
*Alzheimer Disease/etiology/blood/epidemiology/physiopathology
*Aging
*Hot Temperature/adverse effects
Aged
Biomarkers/blood
Male
Female
Middle Aged
Risk Factors
Cognitive Dysfunction
Brain/diagnostic imaging
Cognition
Magnetic Resonance Imaging

@article {pmid42424440,
year = {2026},
author = {Dans, MG and Awalt, JK and Nguyen, N and Palandri, J and Ngo, A and Jarman, KE and Jeon, JH and Yeo, T and Park, H and Uhlemann, AC and Mao, EY and Gancheva, MR and Wilson, DW and Mukherjee, P and Chakraborty, A and Kristan, M and Stewart, L and Sutherland, CJ and Baud, D and Brand, S and Fidock, DA and Jackson, PF and Cowman, AF and Sleebs, BE},
title = {2-Amino-3,4-Dihydroquinazolines Exhibit Potent Antimalarial Activity by Targeting Plasmepsin X.},
journal = {ACS infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsinfecdis.6c00258},
pmid = {42424440},
issn = {2373-8227},
abstract = {The emergence of resistance to most clinically used antimalarials necessitates the discovery of new chemotypes. A phenotypic screen against asexual Plasmodium falciparum identified the 2-amino-3,4-dihydroquinazoline scaffold, previously developed as a β-secretase 1 inhibitor for Alzheimer's disease. Evaluation of hit analogues against malarial aspartyl proteases revealed potent inhibition of plasmepsin X. Structure-activity analysis showed that key motifs on the hit scaffold are required for driving biochemical and antimalarial but are associated with poor selectivity against human aspartyl proteases and low metabolic stability. Plasmepsin X was validated as the molecular target through forward genetics, activity against mutant parasites, and inhibition of plasmepsin X substrate processing. 2-Amino-3,4-dihydroquinazoline analogs exhibit moderate asexual killing rates, low-to-moderate resistance risk, no cross-resistance with multidrug-resistant strains, and transmission-blocking activity. Further optimization of potency and metabolic stability will be required to achieve in vivo efficacy and realize the potential of this antimalarial class.},
}

@article {pmid42424464,
year = {2026},
author = {Crowley, G and Kim, M and O'Neill, N and Turkes, E and Ghasemi, F and Giudice, L and De Schepper, S and Tan, BJY and Maffei, B and S S Ferreira, L and Rebejac, J and Rueda-Carrasco, J and Toneva, M and Fajardo, JC and Ge, JZ and Yang, ZG and Korhonen, P and Muckett, P and Bennett, D and Paoletti, C and Sow, TTM and Posner, DA and Sierksma, A and Sokolova, D and Konstantellos, V and Ali, L and Movahedi, K and MacAskill, AF and Tybulewicz, VLJ and Malm, T and Lignani, G and Clatworthy, MR and Hong, S},
title = {C1q and immunoglobulins mediate activity-dependent synapse loss in the adult brain.},
journal = {Science (New York, N.Y.)},
volume = {393},
number = {6807},
pages = {eadv1219},
doi = {10.1126/science.adv1219},
pmid = {42424464},
issn = {1095-9203},
mesh = {Animals ; *Complement C1q/metabolism/genetics/immunology/physiology ; *Synapses/pathology/immunology ; Mice ; *Alzheimer Disease/pathology/immunology ; Amyloid beta-Peptides/metabolism ; *Hippocampus/pathology/immunology ; Disease Models, Animal ; B-Lymphocytes/immunology ; *Immunoglobulins/metabolism ; Chemogenetics ; Neurons ; },
abstract = {Complement component 1q (C1q), the initiator of the classical complement cascade, mediates synaptic elimination in development and disease, yet the triggers for its deposition on synapses remain unclear. Using in vivo chemogenetics, we demonstrate that neuronal hyperactivity induces region-specific, C1q-dependent synapse loss in the adult hippocampus. Suppressing perforant pathway hyperactivity in a mouse model of Alzheimer's disease reduced local amyloid-β amounts and C1q deposition and partially rescued synapse loss. Combining spatial transcriptomics, live cell tracking, and super-resolution microscopy, we identified association of antibody-secreting B-lineage cells in the adult hippocampus with activity-dependent, C1q-mediated synapse loss under physiological conditions. Together, these findings link neuronal hyperactivity to C1q-mediated synapse loss in the adult brain and implicate immunoglobulins as players in this process.},
}

Animals
*Complement C1q/metabolism/genetics/immunology/physiology
*Synapses/pathology/immunology
Mice
*Alzheimer Disease/pathology/immunology
Amyloid beta-Peptides/metabolism
*Hippocampus/pathology/immunology
Disease Models, Animal
B-Lymphocytes/immunology
*Immunoglobulins/metabolism
Chemogenetics
Neurons

@article {pmid42424747,
year = {2026},
author = {Galler, JA and Yang, L and Wu, CY and Young, C and Guzmán-Vélez, E and Cropp, KW and Bannon, AW and Dodge, HH and Gerber, JA and Arnold, SE},
title = {MIND GamePack: A novel digital health technology for assessment of participants with and without cognitive impairment.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100642},
doi = {10.1016/j.tjpad.2026.100642},
pmid = {42424747},
issn = {2426-0266},
abstract = {BACKGROUND: Digital biomarkers offer promising avenues for enhancing the identification, prognosis, and phenotyping of Alzheimer's Disease (AD). This study evaluates the feasibility and utility of the MIND GamePack©, a digital game platform designed to measure leisure cognitive activity over time.

METHODS: Gameplay data were collected from 60 participants across two cohorts over 3-6 months: Cohort I (no cognitive complaints) and Cohort II (subjective complaints, mild cognitive impairment, mild dementia). Analyses focused on compliance, correlation with validated neuropsychological instruments (Montreal Cognitive Assessment [MoCA], Repeatable Battery for the Assessment of Neuropsychological Status [RBANS], and Trail Making Test [TMT]), test-retest reliability, and known groups comparison.

RESULTS: The MIND GamePack© displayed high compliance and excellent test-retest reliability within 1 week (ICC=0.81-0.95) for most selected features. Several game features displayed moderate to strong correlations with standardized neuropsychological test performance. Features related to memory tasks across select games (Normalized Accuracy and Normalized Redundant Move Variability of Memory Match and Word Repetition Rate of Word Scramble) exhibited significant associations with RBANS Sum of Index Score, TMT Part A, and MoCA, respectively. Participants without cognitive impairment exhibited improvement in features over 3 months compared to those with cognitive impairment. Baseline game features differentiated cognitively normal [CN] from cognitively impaired [CI] participants across nearly all domains after controlling for age, sex, and education (p<.01).

CONCLUSIONS: The MIND GamePack© offers a sensitive, engaging approach to cognitive monitoring and screening, with potential use for dense tracking in longitudinal research and interventional clinical trials.},
}

@article {pmid42424917,
year = {2026},
author = {Lapmanee, S and Thonapan, N and Sriwong, S and Bhubhanil, S and Wongchitrat, P and Charoenphon, N and Ngernsutivorakul, T and Hooncharoen, K and Bunwatcharaphansakun, P and Khongkow, M and Namdee, K},
title = {RGD-functionalized cannabidiol lipid nanoparticles improve brain delivery and alleviate cognitive and metabolic dysfunction via gut-brain axis modulation in an Alzheimer's disease model.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {201},
number = {},
pages = {119724},
doi = {10.1016/j.biopha.2026.119724},
pmid = {42424917},
issn = {1950-6007},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss. Evidence links gut-brain axis dysfunction and metabolic disturbances to AD. Although cannabidiol (CBD) has neuroprotective effects, its use is limited by poor bioavailability and brain delivery.

METHODS: Arginylglycylaspartic acid (RGD)-functionalized, CBD-loaded lipid nanoparticles (CBD/LNP-RGD) were developed to enhance targeted delivery across the blood-brain barrier (BBB) via integrin αvβ3-mediated transcytosis. Cellular uptake and BBB permeability were evaluated in vitro. Anti-inflammatory and antioxidant effects were assessed in Aβ/LPS-induced models. In vivo efficacy was examined using cognitive-behavioral tests, including the novel object recognition and the Morris water maze. Metabolic parameters, histopathology, synaptic protein expression, and gut barrier integrity were also evaluated.

RESULTS: CBD/LNP-RGD demonstrated a 3-fold increase in cellular uptake and a 65% enhancement in BBB transport compared to non-targeted formulations. Treatment significantly reduced pro-inflammatory cytokines (i.e., IL-6 and TNF-α, p < 0.001) and intracellular reactive oxygen species (p < 0.001). In vivo, CBD/LNP-RGD improved cognitive performance comparable to Donepezil (p < 0.001). Additionally, it normalized glycemic control, insulin resistance, and triglyceride levels without hepatic or renal toxicity. At the tissue level, CBD/LNP-RGD reduced Aβ and tau pathology, restored short-chain fatty acids, preserved hippocampal neuronal integrity, and upregulated synaptophysin and PSD-95 proteins. Enhanced intestinal barrier function was evidenced by increased expression of tight junction proteins ZO-1 and occludin.

CONCLUSIONS: CBD/LNP-RGD represents a multifunctional nanotherapeutic platform that improves brain delivery and exerts neuroprotective, anti-inflammatory, antioxidant, and metabolic regulatory effects. Its ability to modulate both central pathology and the gut-brain axis highlights its potential as a disease-modifying strategy for Alzheimer's disease.},
}

@article {pmid42413380,
year = {2026},
author = {Sivalingam, AM},
title = {β-sitosterol and next-generation neuroprotection for multi-target strategies and the gut-brain axis in neurodegenerative diseases.},
journal = {The Journal of steroid biochemistry and molecular biology},
volume = {264},
number = {},
pages = {107080},
doi = {10.1016/j.jsbmb.2026.107080},
pmid = {42413380},
issn = {1879-1220},
abstract = {Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases arise from complex interactions among oxidative stress, neuroinflammation, metabolic dysfunction, and dysregulated signaling networks. This review aim of the synthesize mechanistic evidence on β-sitosterol as a multi-target phytochemical and clarify how its actions connect to gut-brain axis modulation in neurodegeneration. The integrated mechanistic framework linking β-sitosterol's effects on cholesterol homeostasis, neuroinflammation, mitochondrial function, cholinergic signaling, and microbiota-barrier integrity to cognitive outcomes. Scope: preclinical and early translational evidence on β-sitosterol alone and with complementary phytochemicals, including nano-delivery strategies. Increasing evidence highlights phytochemicals as promising multi-target therapeutic agents capable of modulating these interconnected pathological processes. β-Sitosterol exhibits broad activity by regulating cholesterol metabolism, suppressing neuroinflammation, restoring redox balance, preserving mitochondrial function, and inhibiting important Alzheimer's diseases targets, including acetylcholinesterase and butyrylcholinesterase. The mechanisms action of β-sitosterol may (i) dampen microglial activation via TLR4/NF-κB signaling, (ii) activate Nrf2-dependent antioxidant responses (Nrf2/HO-1), (iii) support mitochondrial function and reduce ROS, (iv) stabilize membrane cholesterol and modulate amyloidogenic processing, and (v) inhibit acetylcholinesterase/butyrylcholinesterase to restore cholinergic tone. Complementary showing a neuroprotective effect actions of other phytochemicals such as curcumin, resveratrol, sulforaphane, and sinapic acid further enhance neuroprotection by modulating pathways like Nrf2/HO-1, TLR4/NF-κB, PI3K/Akt, and autophagy. Collectively, preclinical studies demonstrate that diverse botanical extracts significantly improve cognitive performance, reduce amyloid burden, restore cholinergic function, and attenuate neuroinflammation and oxidative damage. Emerging preclinical evidence suggests in rodent models of amyloid pathology, β-sitosterol (5-50 mg/kg) has been reported to improve memory in behavioral tests and reduce markers of neuroinflammation and oxidative stress; gut-brain effects include microbiota remodeling and enhanced barrier integrity, which correlate with reduced neuroimmune activation. Advances in nano-delivery systems and functional food formulations substantially improve phytochemical stability, bioavailability, and brain targeting. Available evidence is chiefly preclinical; clinical translation will require standardized dosing, pharmacokinetic and blood-brain barrier penetration studies, and randomized trials with microbiome and cognitive endpoints. Collectively, these findings position phytochemicals as promising candidates for multi-target disease modification and the development of next-generation neurotherapeutic strategies.},
}

@article {pmid42413499,
year = {2026},
author = {Vear, A and Olsen, SA and Lange, ECH and Müller, MA and Svendsen, C and Clemmensen, C},
title = {Preventative semaglutide and tirzepatide treatment does not alter disease progression in the 5xFAD mouse model of Alzheimer's disease.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102906},
doi = {10.1016/j.xcrm.2026.102906},
pmid = {42413499},
issn = {2666-3791},
abstract = {There is growing evidence that long-acting mimetics of the gut-derived incretin hormones GLP-1 and GIP act as disease-modifying therapies for Alzheimer's disease (AD). Here, we temporally characterize the efficacy of the approved incretin receptor agonists semaglutide, a GLP-1R agonist, and tirzepatide, a GLP-1R/GIPR co-agonist, in preventing AD progression. In 5xFAD mice treated for 2 or 4 months, both incretin therapies lower body weight and improve glucose tolerance, yet neither compound produces measurable effects on memory or learning tasks, amyloid-β plaque deposition, or glial cell activation. In a non-amyloidogenic model, 3 days of incretin pre-treatment does not alter microglial activation or the expression of inflammatory markers following lipopolysaccharide (LPS) administration in mice. Our findings indicate that chronic semaglutide or tirzepatide treatment, even when initiated before overt pathology and delivered for a prolonged period, does not slow neuropathological progression in 5xFAD or LPS-treated mice.},
}

@article {pmid42413698,
year = {2026},
author = {Huynh, AL and Wrigley, S and Ward, D and Andrews, JS and Burrell, LM and Yates, PA},
title = {Assessing the relationships between frailty, sarcopenia and Alzheimer's disease biomarkers: a scoping review.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103246},
doi = {10.1016/j.arr.2026.103246},
pmid = {42413698},
issn = {1872-9649},
abstract = {INTRODUCTION: While both frailty and sarcopenia have been linked with the Alzheimer's disease (AD) clinical phenotype, their association with AD pathophysiology is unclear. This review aimed to identify current evidence of relationships between frailty, sarcopenia and AD biomarkers.

METHODS: Four databases (Ovid MEDLINE, Embase, PsycINFO, Web of Science) were searched for articles that explored relationships between frailty or sarcopenia and AD biomarkers. AD biomarkers (fluid, tissue, neuroimaging) were defined by the 2024 criteria for diagnosis and staging of AD: Alzheimer's Association Workgroup. Assessment of frailty and sarcopenia were by use of a method/tool defined by the authors of the study.

RESULTS: 8187 articles were screened, with 49 studies included (31 frailty, 22 sarcopenia, 4 both). For frailty, the main AD biomarkers evaluated were hippocampal volume (35%) and beta-amyloid [Aβ] positron electron tomography (PET) (29%). For sarcopenia, the most common AD biomarkers evaluated were hippocampal volume (36%) and Aβ PET (55%). The findings were limited by the heterogeneity of the available evidence, in particular, the variability in frailty/sarcopenia definitions, AD biomarker assessments and the predominance of cross-sectional studies. Potential associations were identified across some studies, but these associations were not consistent across all studies.

CONCLUSIONS: Conclusions are limited by substantial heterogeneity in the assessment of frailty, sarcopenia, AD biomarkers, and a lack of longitudinal data. Future studies are needed that include longitudinal analyses, consensus in AD biomarker, frailty and sarcopenia assessments, and incorporation of novel AD biomarkers, in particular tau and neuroinflammation, to help clarify these relationships.},
}

@article {pmid42413719,
year = {2026},
author = {Alameen, AAM and Al-Kuraishy, HM and Abdelaziz, AM and Al-Gareeb, AI and Albuhadily, AK and Batiha, GE},
title = {Targeting PARP1-dependent parthanatos in Alzheimer's disease: Mechanisms and therapeutic opportunities.},
journal = {Life sciences},
volume = {402},
number = {},
pages = {124578},
doi = {10.1016/j.lfs.2026.124578},
pmid = {42413719},
issn = {1879-0631},
abstract = {Alzheimer's disease (AD) is the predominant cause of dementia globally. This review clarifies the dual function of poly(ADP-ribose) polymerase 1 (PARP1) in AD pathogenesis, emphasizing its role in mediating parthanatos, a unique caspase-independent cell death mechanism. We analyze contemporary literature regarding PARP1 expression, parthanatos signaling, and pharmaceutical treatments in AD models. In addition, PARP1 exhibits context-dependent duality: its physiological nuclear expression in hippocampus neurons is essential for memory consolidation and decreases early in cognitive impairment, suggesting a correlative association with synaptic malfunction. In contrast, overactivity of PARP1 resulting from Aβ-induced oxidative stress and DNA damage induces neurodegeneration via multiple pathways, including NAD+/ATP exhaustion leading to metabolism collapse, creation of the AIF-MIF complex promoting parthanatos, NF-κB-induced neuroinflammation, dysregulation of mitophagy, and disruption of the neuroprotective SIRT1 signaling pathway. The overactivity contributes to a positive feedback loop, where PARP1 intensifies Aβ and tau protein accumulation while simultaneously disrupting the BBB. In preclinical models of AD, genetic knockout, pharmacologic agents such as PJ34 and MC2050, or precursors of NAD[+] such as nicotinamide and NMN attenuate Aβ deposition, normalize metabolism, and ameliorate cognitive decline. The PARP1/parthanatos pathway is at the center of the confluence of oxidative stress, DNA damage, metabolism disorder, and neuroinflammation in AD. Metformin and other PARP1 inhibitors offer intriguing treatment options. PARP1's cell-type- and intracellular location-dependent activity necessitates careful consideration of context, dose, and disease stage while developing therapies. The present understanding in this review could inform future research on PARP1 regulation in AD clinical practice.},
}

@article {pmid42413720,
year = {2026},
author = {Jiang, L and Zhang, Z and Luo, X and Wu, H and Huang, Z and Wu, W and Xu, S and Pan, J and Tan, Z},
title = {Steroidal alkaloid H89712 ameliorates neuroinflammation and memory deficits: Enhancing cerebral oxidative phosphorylation in APP/PS1 mice.},
journal = {Life sciences},
volume = {},
number = {},
pages = {124583},
doi = {10.1016/j.lfs.2026.124583},
pmid = {42413720},
issn = {1879-0631},
abstract = {AIMS: Alzheimer's disease (AD) poses a major health challenge with limited therapeutic options. This study aimed to investigate the anti-AD potential and underlying mechanism of a novel steroidal alkaloid, H89.

MATERIALS AND METHODS: In vitro, Aβ25-35-exposed HT-22 hippocampal neurons and LPS-stimulated BV2 microglia were used to assess H89 neuroprotection and anti-inflammatory activity. In vivo, 6-month-old APP/PS1 mice were orally administered H89 for 2 months. Spatial memory was assessed by Y-maze (YM) and Morris water maze (MWM). Hippocampal morphology, neuronal apoptosis (TUNEL/NeuN), Aβ deposition (IHC), microglial activation (IBA-1), inflammatory cytokines (ELISA), and oxidative phosphorylation (RNA-seq, qRT-PCR, Western blot) were examined. Brain malondialdehyde (MDA), ATP, and cellular ROS were quantified.

KEY FINDINGS: H89 (10 and 50 nM) significantly protected HT-22 cells against Aβ25-35-induced injury and attenuated LPS-induced TNF-α, IL-1β, and IL-6 secretion while elevating IL-10 in BV2 cells. In APP/PS1 mice, H89 increased novel arm exploration in the YM and target quadrant residence in the MWM, indicating improved spatial learning and memory. H89 ameliorated hippocampal neuronal morphology, reduced apoptosis, attenuated Aβ plaques and microglial activation (IBA-1), decreased TNF-α, IL-6 and MDA, and elevated IL-10 and cerebral ATP. Transcriptomic and molecular analyses confirmed that H89 upregulated oxidative phosphorylation-related genes and proteins (ATP5E, ATP5J2, NDUFA13, NDUFB3, COX7C, COX11). Cerebral ATP positively correlated with spatial memory but negatively correlated with neuroinflammation and oxidative stress.

SIGNIFICANCE: H89 exerts neuroprotective effects by enhancing mitochondrial oxidative phosphorylation and brain energy supply, concurrently suppressing neuroinflammation, oxidative stress, and neuronal apoptosis, suggesting its potential as a therapeutic candidate for AD.},
}

@article {pmid42413776,
year = {2026},
author = {Zafar, SA and Qin, W and Chengliang, L and Khan, AA and Faisal, MS},
title = {Thymus-derived myeloid programs track microglial tolerance states across human cohorts.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106221},
doi = {10.1016/j.neuint.2026.106221},
pmid = {42413776},
issn = {1872-9754},
abstract = {INTRODUCTION: Microglial functional positioning varies across individuals and disease contexts, yet conserved biological axes supporting reproducible cross-cohort inference remain poorly defined. Intrathymic T cell development offers a paradigm in which chemokines, extracellular matrix (ECM)/adhesion factors, and axon guidance cues jointly govern immune cell migration and selection. We asked whether thymus-derived transcriptional programs provide a transferable basis for quantifying microglial tolerance-like positioning across independent human cohorts.

METHODS: We applied consensus non-negative matrix factorization to Tabula Sapiens thymus single-cell transcriptomes to derive eight Myeloid Education Signatures (MES); under formal enrichment testing, two were significantly enriched for ECM/adhesion biology and the rest were treated as data-driven programs without a dominant axis. MES scores were projected into four independent microglia cohorts (SEA-AD, Olah, Tuddenham, multiple sclerosis; >100 donors) and related to a donor-level tolerance score (homeostatic minus activation gene-set activity). Glucocorticoid receptor (GR) activity, calibrated from an external perturbation dataset, was evaluated as a moderator. Cross-cohort synthesis used random-effects meta-analysis with sensitivity analyses and multiple testing control.

RESULTS: Seven of eight MES modules were inversely associated with tolerance positioning; the eighth (MES08, defined by CCL2/CXCL2 chemokine genes) showed the most heterogeneous coupling across cohorts. The association strengthened monotonically with microglial purity in three of four cohorts, was recapitulated in Visium spatial transcriptomics, and was robust to covariate adjustment, housekeeping-gene removal, and leave-one-dataset-out sensitivity. This coupling was preferential to thymus-derived modules: modules built identically from six other tissues (blood, spleen, liver, lung, bone marrow, lymph node) coupled 1.2 to 2.9 fold less strongly, across module-number and feature-selection choices. Under a formal per-module interaction model, GR activity did not moderate the association, a well-powered null reproduced with a canonical GR panel and an external cohort. Irisin pathway (five-gene FNDC5/PPARGC1A module) associations were modest and largely non-significant after correction.

CONCLUSIONS: Thymus-derived myeloid programs constitute a transferable, tissue-preferential axis inversely coupled to microglial tolerance-like positioning, without detectable glucocorticoid moderation.},
}

@article {pmid42413810,
year = {2026},
author = {Lv, Y and Jia, Y and Xu, B and Zhao, C and Fu, W and Zhang, Y and Li, B and Li, X},
title = {Atrazine induces Alzheimer's disease-like neurotoxicity by targeting SDHB and disrupting synaptic function: An integrated bioinformatic and in vivo study.},
journal = {Chemico-biological interactions},
volume = {437},
number = {},
pages = {112249},
doi = {10.1016/j.cbi.2026.112249},
pmid = {42413810},
issn = {1872-7786},
abstract = {Atrazine (ATR) is a globally prevalent herbicide linked to increased risks of cognitive impairment and neurodegeneration, but its molecular mechanism remains unclear. This study integrates bioinformatics, machine learning, and experimental validation to elucidate ATR induced Alzheimer's disease (AD)-like pathology. We combined predicted ATR targets with AD brain transcriptomics, identifying 32 shared genes enriched in neurodegeneration and synaptic signaling pathways. We constructed a diagnostic model using 14 machine learning algorithms; the ensemble model achieved an improved AUC of 0.891 in the training set, with external validation AUCs of 0.833, 0.869, and 0.900. SHAP interpretability analysis identified SDHB as the most important key risk factor. Molecular docking validated the stable binding between ATR and core target proteins, with binding energies ranging from -4.9 to -5.9 kcal/mol. Single-cell sequencing and in silico gene knockdown confirmed that SDHB deficiency primarily disrupts neuronal synaptic signaling pathways. In vivo experiments demonstrated that ATR exposure induces anxiety-like behavior and memory deficits, suppressed hippocampal SDHB, and elevated Aβ and p-tau levels. ATR also reduced synaptic markers PSD95 and SYP in a dose dependent manner, confirming SDHB suppression leads to synaptic damage. Based on these findings, we established the first standardized adverse outcome pathway (AOP) framework delineating the cascade of events from ATR-induced SDHB inhibition to cognitive impairment. This study demonstrates that ATR targets SDHB to induce synaptic dysfunction and AD-like neuropathology, offering a new mechanistic basis for environmental risk assessment.},
}

@article {pmid42413887,
year = {2026},
author = {Vallejo-Azar, MN and Freccero, P and Postillone, MB and Princich, JP and Solis, P and Medel, N and Lisso, J and Irureta, N and Morganti, S and Fernández, J and Collavini, S and Bendersky, M and Ramírez, A and Bernal, V and Kochen, S and Dalmasso, MC and Gonzalez, PN},
title = {GeNED.ar cohort: Neuroimaging Resource for Aging Studies in an Admixed Population from Argentina.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122117},
doi = {10.1016/j.neuroimage.2026.122117},
pmid = {42413887},
issn = {1095-9572},
abstract = {Well-characterized cohorts are essential for advancing neuroimaging biomarkers and refining models of brain aging and dementia across diverse populations. Despite growing neuroimaging research in Latin America, additional multimodal cohorts integrating imaging, genomic, and environmental data are needed to capture population diversity. We present GeNED.ar (Genetics and Neuroimaging of Aging and Dementia in Argentina), a multimodal cohort established in the Metropolitan Area of Buenos Aires to investigate brain aging in a population with genetic admixture and socioeconomic heterogeneity. The dataset combines two complementary recruitment strategies, community-based healthy participants and Memory Clinic attendees, including 3T MRI, genome-wide genotyping, and detailed sociodemographic data from 367 individuals aged 18-94 years. Participants comprise healthy individuals (n=235) and Memory Clinic attendees classified as cognitively unimpaired (n=65), mild cognitive impairment (n=37), Alzheimer's or mixed dementia (n=24), and vascular dementia (n=6). Genetic ancestry analysis (n=191) indicated a predominantly admixed population (65% European, 28.3% Native American) with significant differences across recruitment sources. Brain age gap (BAG), estimated from T1-weighted MRI, increased progressively along the clinical continuum, where people with dementia exhibited older-appearing brains relative to cognitively unimpaired participants, and intermediate values were observed in mild cognitive impairment. No independent associations were observed between BAG and individual genetic or environmental risk factors. By integrating multimodal MRI and genomic data across complementary recruitment settings, GeNED.ar provides a unique regional resource to evaluate neuroimaging biomarkers, facilitate cross-cohort validation, and strengthen the generalizability of aging and dementia models in genetically and socially diverse populations.},
}

@article {pmid42413935,
year = {2026},
author = {Lee, S and Kao, CY and Li, Z and Dan, T and Wu, G and Hao, W},
title = {Optimal control for anti-abeta treatment in Alzheimer's disease using a reaction-diffusion model.},
journal = {Journal of the Royal Society, Interface},
volume = {23},
number = {240},
pages = {},
doi = {10.1098/rsif.2025.1158},
pmid = {42413935},
issn = {1742-5662},
support = {1R35GM146894/GF/NIH HHS/United States ; DMS-2533995//NSF/ ; DMS 2208373//NSF/ ; DMS 2513176//NSF/ ; //Huck Chair in AI Mathematical Modeling from Penn State University's Huck Institutes of the Life Sciences/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy ; Humans ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Models, Biological ; Positron-Emission Tomography ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely impairs survival and quality of life. While anti-amyloid beta (Aβ) therapies can slow disease progression, their efficacy depends on personalized dosing that maximizes benefits and minimizes risks, such as amyloid-related imaging abnormalities (ARIA). Mathematical modelling offers a powerful tool for understanding AD dynamics and optimizing treatment, yet most models focus solely on temporal behaviour, overlooking spatial heterogeneity within the brain. In this study, we propose a spatially explicit reaction-diffusion model to describe Aβ plaque dynamics. We formulate an optimal control problem to minimize plaque concentration while balancing therapeutic efficacy and treatment risk. Under reasonable assumptions, we establish well-posedness and uniqueness of the optimal solution. A finite element method (FEM)-based numerical framework is developed to compute personalized treatment strategies. Our model is calibrated using longitudinal Aβ positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), enabling estimation of patient-specific parameters, such as growth rate and effective diffusivity. Results show that optimized treatment strategies consistently outperform constant dosing regimens across patient groups, achieving substantial reductions in cumulative amyloid burden while minimizing side effects. This integrated, data-driven framework advances personalized, spatially informed therapeutic optimization for AD.},
}

*Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy
Humans
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Models, Biological
Positron-Emission Tomography

@article {pmid42414168,
year = {2026},
author = {Lee, DR and Endo, AS and Kalbasi, TR and Turner, M and Jimenez, IA and Serrano, KS and Centeno, A and Reuben, DB},
title = {Psychiatric Hospitalization Precipitants and Outcomes in a Comprehensive Dementia Care Program.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.06.002},
pmid = {42414168},
issn = {1545-7214},
abstract = {OBJECTIVES: Characterize the precipitants and outcomes of psychiatric hospitalizations among patients enrolled in a comprehensive dementia care program and identify factors associated with discharge to higher-level residential setting.

DESIGN: Retrospective cohort study.

SETTING: UCLA Alzheimer's and Dementia Care Program.

PARTICIPANTS: Patients hospitalized at the UCLA Resnick Neuropsychiatric Hospital (NPH).

MEASUREMENTS: Precipitating reasons for hospitalization, patient demographic and clinical characteristics, hospitalization-level characteristics, and caregiver relationship. Discharge to higher-level residential settings (e.g., assisted living, nursing home). Change in scheduled Central Nervous System (CNS)-active medications (antipsychotics, antidepressants, and sedative/hypnotics).

RESULTS: There were 180 psychiatric hospitalizations among 150 patients, with a median age of 79 years (IQR, 73-85) at admission and MMSE score of 17 (IQR, 12-24) at first hospitalization. Agitation was the most common precipitating reason for hospitalization (n = 127, 71%). Median length of stay was 14 days (IQR, 9-26); 54 (30%) resulted in discharge to a higher-level residential setting. Agitation as the precipitant for hospitalization (aOR, 4.7; 95% CI, 1.7-12.9, p = 0.003) and male sex (aOR, 2.3; 95% CI, 1.0-5.5, p = 0.049) were associated with higher odds of discharge to a higher-level setting. Most hospitalizations resulted in no change in the number of scheduled CNS-active medications (e.g., 69% had no change in the number of scheduled antipsychotics), while escalation occurred in 19%-28%, depending on medication class.

CONCLUSION: Psychiatric hospitalization precipitated by agitation or involving male patients was often followed by transition to higher-level residential care. Future studies should evaluate whether earlier outpatient psychiatry involvement and proactive placement planning can reduce hospitalization and subsequent placement changes.},
}

@article {pmid42414260,
year = {2026},
author = {Sulatsky, MI and Stepanenko, OV and Kayda, AA and Stepanenko, OV and Mikhailova, EV and Sulatskaya, AI},
title = {Spontaneous aging of mature amyloids alters structural stability, cytotoxicity, and susceptibility to biological clearance.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03245-1},
pmid = {42414260},
issn = {2058-7716},
support = {23-74-10092//Russian Science Foundation (RSF)/ ; },
abstract = {Accumulation of amyloid fibrils is a key factor in the pathogenesis of progressive diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's disease, as well as systemic amyloidosis. Although amyloid deposits are known to persist in vivo for years or even decades, it remains unclear how the structure and biological properties of mature fibrils evolve during prolonged post-assembly residence. Here, we addressed this question using a simplified cell-free aqueous model designed to isolate the intrinsic time-dependent behavior of mature amyloid aggregates from the complexity of the biological milieu. Specifically, we investigated the long-term evolution of two polymorphs of lysozyme amyloid fibrils as model systems with distinct clustering propensities that mimic the diversity of amyloid deposits. We challenge the assumption of amyloid stability by demonstrating their spontaneous degradation over 16 months at physiological temperature, a process we define as amyloid "aging". This process is characterized by aggregate declustering, fibril shortening, and progressive depolymerization into monomeric subunits, accompanied by a pronounced reduction in intrinsic toxicity across multiple human cell lines. Notably, "aged" fibrils were disassembled and degraded more efficiently than freshly prepared aggregates by the molecular chaperone α-B-crystallin and immune-associated proteases, including matrix metalloproteinase-9 and cathepsins B and D. However, this enhanced degradation revealed a paradox: accelerated processing of "aged" amyloids did not always reduce cytotoxicity and, in some cases, even exacerbated it, consistent with the generation of biologically active fibril-derived species rather than their complete conversion into non-toxic monomers. We provide the first systematic evidence that mature amyloids are dynamic structures undergoing spontaneous degradation that fundamentally alters their cytotoxicity and susceptibility to biological clearance. Our results introduce amyloid aging as a previously underappreciated dimension of amyloid biology and emphasize the need to account for fibril "age" when evaluating pathogenic potential and developing anti-amyloid therapeutic strategies.Spontaneous "aging" of amyloid fibrils leads to suprastructural remodeling: declustering, fibril shortening, and attenuated cytotoxicity. While "aged" aggregates are degraded more efficiently by immune-associated proteases and α-B-crystallin than "fresh" fibrils, this enhanced degradation does not reduce cytotoxicity and, in some cases, exacerbates it, highlighting the complex interplay between aggregate maturity and biological outcomes.},
}

@article {pmid42414290,
year = {2026},
author = {Li, H and Pan, W and Rajendran, S and Zang, C and Wang, F},
title = {Empowering clinical trial design with agentic intelligence and real-world data.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42414290},
issn = {2041-1723},
mesh = {Humans ; Electronic Health Records ; *Clinical Trials as Topic/methods ; *Research Design ; Machine Learning ; *Artificial Intelligence ; },
abstract = {Clinical trial design (CTD) is a time-consuming process that requires substantial domain expertise. Large-scale real-world data (RWD), such as electronic health records (EHR), encodes practice-based evidence that is of tremendous value to CTD. In recent years, many machine learning methods have been developed to extract such real-world evidence (RWE) from the RWD to inform CTD, but they still need to be communicated with the domain experts extensively in an iterative manner to be further refined and ultimately useful. In this paper, we introduce EmulatRx, an agentic framework that derives RWE for helping with CTD. Through the iterative conversation and analysis across agents with different roles, EmulatRx can autonomously refine trial protocols and finally generate a robust report containing insights that inform better CTD. We applied EmulatRx on the CTD process for both acute diseases (e.g., septic shock, acute heart failure, acute pulmonary edema, and acute kidney injury) using the MIMIC-IV data and chronic diseases (e.g., Alzheimer's disease and Parkinson's disease) using the INSIGHT Network across five New York City health systems. The results demonstrate EmulatRx's capabilities in facilitating and accelerating the CTD process.},
}

Humans
Electronic Health Records
*Clinical Trials as Topic/methods
*Research Design
Machine Learning
*Artificial Intelligence

@article {pmid42414687,
year = {2026},
author = {Pearson, H},
title = {How to avoid dementia - what the science really says.},
journal = {Nature},
volume = {655},
number = {8122},
pages = {294-297},
pmid = {42414687},
issn = {1476-4687},
}

@article {pmid42414714,
year = {2026},
author = {Álvarez-Rodríguez, L and Vázquez, C and Cordón, B and Garcia-Martin, E and de Moura, J and Novo, J and Ortega, M},
title = {3D OCT-Based Retinal Biomarker Analysis for Automatic Regional-Wise Characterization of Neurodegenerative Diseases.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10278-026-02098-5},
pmid = {42414714},
issn = {2948-2933},
support = {PI17/01726//Instituto de Salud Carlos III/ ; PI20/00437//Instituto de Salud Carlos III/ ; PI23/00935//Instituto de Salud Carlos III/ ; RD21/0007/0022//Instituto de Salud Carlos III/ ; FORT23/00010//Instituto de Salud Carlos III/ ; PID2023-148913OB-I00//Ministerio de Ciencia e Innovación/ ; ED431C 2024/33//Xunta de Galicia/ ; B23_23R//Gobierno de Aragón/ ; B50_24//Gobierno de Aragón/ ; },
abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), essential tremor (ET), multiple sclerosis (MS), and Parkinson's disease (PD) are complex disorders that often exhibit overlapping symptoms, leading to diagnostic challenges. Given the increasing interest in retinal imaging as a non-invasive biomarker for neurodegeneration, this study proposes a fully automated machine learning pipeline for disease characterization using optical coherence tomography (OCT). We analyze macular thickness patterns across three key and relevant retinal elements: retinal nerve fibre layer (RNFL), ganglion cell layer to Bruch's membrane (GCL-BM), and the total retina. These are processed by two complementary regional layouts: the standard ETDRS scheme and a custom 3 × 3 quadrant grid. These measurements are used to train multiple classifiers to distinguish between healthy controls and NDDs either collectively or individually. The proposed method processes 34,375 OCT B-scans from 353 subjects and highlights disease-specific thickness patterns with a pathological distinction score ranging up to 0.71 depending on the retinal region, disease, and classifier. Sector-based grids generally outperform quadrant-based ones, revealing highly localized pathological signatures. Our findings demonstrate that each disease manifests distinct retinal alterations, aligning with current clinical literature while offering novel insights for ET and PD. The study reinforces the potential of grid-based OCT analysis as a discriminative and fully automatic screening tool, paving the way for improved early diagnosis and differential analysis of NDDs through retinal biomarkers.},
}

@article {pmid42415081,
year = {2026},
author = {Perez-Toro, PA and Almizel, M and Nöth, E and Maier, A and Arias-Vergara, T},
title = {Generating Alzheimer's narratives using large language models.},
journal = {BMC medical informatics and decision making},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12911-026-03653-4},
pmid = {42415081},
issn = {1472-6947},
abstract = {BACKGROUND: Analyzing semi-spontaneous speech is a promising direction for supporting Alzheimer's disease (AD) assessment, yet progress is limited by the scarcity of annotated clinical data. Large Language Models (LLMs) offer new opportunities to generate synthetic narratives that may resemble speech patterns of both patients with AD and healthy controls during cognitive evaluation tasks such as the Cookie Theft Picture description.

METHODS: This study evaluates whether models including GPT, T5/Flan-T5, LLaMA, Mistral, and Qwen can generate clinically plausible picture-description narratives under two configurations: Human-to-Bot, where an LLM responds directly to real interviewer prompts, and Bot-to-Bot, where two LLMs simulate both interviewer and participant roles. Models were fine-tuned on transcripts from the DementiaBank Pitt Corpus and assessed using lexical and semantic metrics, as well as human expert ratings. Generated narratives were further used to augment training data for an AD vs. healthy control classifier based on BERT embeddings and an MLP architecture.

RESULTS: LLMs differed substantially in their ability to reproduce clinically meaningful and semantically coherent narratives of patient-interviewer interactions. Mistral, LLaMA, and Qwen achieved the strongest automatic evaluation metrics, e.g., BERTScores above 0.90 in the Human-to-Bot condition-and produced narratives rated by human experts as fluent, plausible, and diagnostically informative. When combining real and synthetic narratives for classifier training, the highest F1-score reached 0.84, outperforming models trained on real data alone (F1 = 0.74). Synthetic data generated in Human-to-Bot settings contributed most to diagnostic improvements, whereas Bot-to-Bot interactions exhibited greater variability and reduced clinical realism.

CONCLUSION: LLMs can generate high-quality synthetic narratives that enhance downstream AD classification and show promising clinical plausibility in cognitive assessment contexts. Incorporating LLM-generated data provides a scalable strategy for mitigating data scarcity in dementia research. Future work should focus on improving fully synthetic dialogue quality, expanding multilingual capabilities, and refining evaluation frameworks to better capture clinically relevant linguistic features.},
}

@article {pmid42415114,
year = {2026},
author = {Strickland, MR and Holtzman, DM},
title = {ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer's disease and related disorders.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00970-0},
pmid = {42415114},
issn = {1750-1326},
support = {T32AG058518/NH/NIH HHS/United States ; RF1NS090934/NH/NIH HHS/United States ; },
abstract = {Apolipoprotein E (ApoE) is highly expressed in the central nervous system (CNS) where it plays a critical role in lipid homeostasis and in the etiology of Alzheimer's disease (AD) and related diseases. ApoE associates with lipids to form discoidal and spherical lipoproteins that carry lipid and protein cargo throughout the brain. In this review, we focus on the significance of ApoE as a lipoprotein and how this impacts the function of ApoE in homeostasis and disease. In the CNS, ApoE is primarily secreted by astrocytes, though other cells, including microglia, secrete ApoE under certain conditions. ApoE lipoproteins (LpE) secreted by different cell types carry unique lipids and proteins which alter its function. The lipidation state of ApoE alters its conformation and binding to different receptors and, consequently, its ultimate impact on AD pathology. Most dramatically, nonlipidated ApoE has minimal binding to the low density lipoprotein receptor (LDLR), while lipidation of ApoE restores high affinity binding to LDLR. Furthermore, the degree of ApoE lipidation also impacts ApoE receptor binding through changes in protein conformation and stoichiometry of ApoE molecules per lipoprotein. The lipidation state of ApoE also alters its interaction with amyloid-β and tau, the proteins involved in forming amyloid plaques and neurofibrillary tangles, the pathological hallmarks of AD. LpE also carry lipids and proteins that alter the function of ApoE. Understanding how the lipid and protein content of LpE interacts with the conformational changes that occur with lipidation and maturation are essential to mechanistically understanding the role of ApoE in homeostasis and disease pathogenesis. In this review, we highlight the current understanding of LpE biology in the CNS and delineate important areas of future research.},
}

@article {pmid42415176,
year = {2026},
author = {Eom, JW and Kim, KR and Kim, DH and Song, JG and Han, C and Kim, HW and Ha, S and Song, WJ and Kim, YH},
title = {Zinc-mediated lysosomal activation by 1H10 enhances autophagy and attenuates tau pathology in Alzheimer's disease models.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01328-9},
pmid = {42415176},
issn = {1756-6606},
support = {NRF-2020R1I1A1A01061724//National Research Foundation of Korea/ ; RS-2023-NF001356//National Research Foundation of Korea/ ; 2025-RISE-01-019-04//The seoul RISE centor/ ; },
abstract = {Impaired autophagic flux and lysosomal dysfunction contribute critically to the accumulation of pathological protein aggregates in Alzheimer's disease (AD). Emerging evidence suggests that intracellular zinc dynamics regulate lysosomal function by modulating processes such as acidification and lysosomal biogenesis. We previously identified 1H10 as an AMP-activated protein kinase (AMPK) inhibitor and subsequently demonstrated its zinc-binding capacity and ability to regulate intracellular zinc homeostasis. Building on our prior findings that intra-lysosomal zinc promotes acidification and activates transcription factor EB (TFEB), we investigated whether 1H10 enhances lysosomal function through zinc mobilization in neurons, thereby improving autophagy and reducing pathological protein accumulation. In primary cortical neurons, 1H10 increased lysosomal abundance and enhanced lysosomal degradative capacity in a zinc-dependent manner, as demonstrated by increased cathepsin B activity and DQ-BSA degradation. It alleviated lysosomal dysfunction induced by v-ATPase inhibition and promoted autophagic flux, leading to reduced accumulation of amyloid-β (Aβ) and tau in neuronal models. In 5XFAD mice, 1H10 treatment showed trends toward improved spatial learning in the Morris water maze, reduced tau phosphorylation at Thr205 and Ser214, normalized LC3-II levels, and restored autophagic-lysosomal homeostasis, without significant changes in extracellular amyloid plaque burden. These findings indicate that zinc-mediated lysosomal activation by 1H10 enhances the autophagy-lysosomal pathway and attenuates tau pathology in AD models, suggesting that targeting lysosomal function may represent a potential therapeutic strategy for neurodegenerative disorders characterized by impaired proteostasis.},
}

@article {pmid42415281,
year = {2026},
author = {Aldana, BI and Freude, K},
title = {Chemokines in Alzheimer's Disease: Early Defence, Late Damage and the Impact of Sex and Infection.},
journal = {Basic & clinical pharmacology & toxicology},
volume = {139},
number = {2},
pages = {e70273},
doi = {10.1111/bcpt.70273},
pmid = {42415281},
issn = {1742-7843},
support = {R434-2023-242//Lundbeck Foundation/ ; N/A//Alzheimersfonden/ ; },
mesh = {Humans ; *Alzheimer Disease/immunology/metabolism ; *Chemokines/metabolism/immunology ; Animals ; Female ; Male ; Sex Factors ; Signal Transduction ; Virus Diseases/immunology ; Neuroinflammatory Diseases/immunology ; COVID-19/immunology ; Receptors, Chemokine/metabolism ; Brain/immunology/metabolism ; Sex Characteristics ; },
abstract = {Chemokines constitute a versatile signalling network maintaining homeostasis and glia-neuron communication in the healthy brain but become progressively dysregulated during aging and Alzheimer's disease (AD). This review examines how chemokine systems transition from tightly regulated homeostatic signals to drivers of chronic neuroinflammation in AD. We describe the major chemokine families (CC, CXC, CX3C) and their dominant central nervous system (CNS) receptors (CCR2, CXCR3, CX3CR1), which activate canonical inflammatory pathways including NF-κB, JAK/STAT and PI3K-AKT. In AD, chemokine dysregulation occurs in a coordinated manner across multiple functional modules, including recruitment-associated (CCL2, CXCL1), interferon-inducible (CXCL10), loss-of-restraint (CX3CL1) and vascular-associated chemokines. These alterations shift the network from regulated immune communication to self-sustaining inflammatory circuits perpetuating chronic neuroinflammation. These networks reprogram microglia and astrocytes into disease-associated phenotypes, amplify peripheral immune cell infiltration and destabilise synaptic function. Biological sex profoundly influences neuroinflammatory trajectories, with females exhibiting enhanced microglial senescence and interferon signalling, while males show accelerated complement activation. Viral pathogens, particularly neurotropic viruses (HSV-1, HHV-6, VZV) and SARS-CoV-2, actively reprogram chemokine networks, linking infection to amyloid-β accumulation, tau pathology and neurodegeneration. Therapeutically, chemokine axes represent precision targets requiring stage-matched, sex-stratified interventions rather than broad anti-inflammatory approaches. Understanding chemokine network dynamics offers mechanistic insights into AD pathogenesis and could provide pointers for therapeutic strategies.},
}

Humans
*Alzheimer Disease/immunology/metabolism
*Chemokines/metabolism/immunology
Animals
Female
Male
Sex Factors
Signal Transduction
Virus Diseases/immunology
Neuroinflammatory Diseases/immunology
COVID-19/immunology
Receptors, Chemokine/metabolism
Brain/immunology/metabolism
Sex Characteristics

@article {pmid42415306,
year = {2026},
author = {Gaetani, L and Nardi, G and Parnetti, L},
title = {Can the integration of blood-based biomarkers into Alzheimer's disease diagnosis revolutionize the field?.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/14737175.2026.2700246},
pmid = {42415306},
issn = {1744-8360},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a clinical-biological entity in which pathophysiological changes precede symptoms by years. Biomarkers are essential for early and accurate diagnosis, particularly in the era of disease-modifying therapies requiring biological confirmation. Cerebrospinal fluid (CSF) and amyloid positron emission tomography (amyloid-PET) are the reference standards, but increasing attention is devoted to blood-based biomarkers (BBMs) due to their scalability and cost-effectiveness.

AREAS COVERED: In this critical perspective, the authors critically appraise the current evidence supporting plasma phosphorylated tau at threonine 217 (p-tau217) as the leading BBM for AD. They also discuss its analytical performance, biological rationale, and diagnostic accuracy across the AD continuum, its relationship with established CSF, PET, and neuropathological biomarkers, its potential role in identifying patients eligible for disease-modifying therapies, and the main clinical and biological factors influencing its interpretation. Finally, they highlight current limitations, unresolved challenges, and give their future perspectives for the integration of plasma biomarkers into routine clinical practice.

EXPERT OPINION: BBMs are expected to reshape AD diagnostics. A stepwise approach, using plasma biomarkers as first-line tests followed by confirmatory CSF or PET, is currently the most feasible strategy. Ultimately, highly specific, brain-derived tau biomarkers may enable BBMs to replace CSF biomarkers.},
}

@article {pmid42415348,
year = {2026},
author = {Sohn, C and Pardo, S and Molleur, D and Paduri, SR and Lambert, M and Uttke, Z and Sohn, EJ and Thomas, MG and Weintraub, ST and Frost, B},
title = {Elevation of the mechanically-sensitive e protein emerin links nuclear mechanotransduction to tau-induced cytoskeletal remodeling in neurons.},
journal = {Nucleus (Austin, Tex.)},
volume = {17},
number = {1},
pages = {2697135},
doi = {10.1080/19491034.2026.2697135},
pmid = {42415348},
issn = {1949-1042},
mesh = {*Neurons/metabolism/pathology ; *Nuclear Proteins/metabolism/genetics ; Humans ; *Mechanotransduction, Cellular ; *tau Proteins/metabolism/genetics ; *Cytoskeleton/metabolism ; *Membrane Proteins/metabolism/genetics ; *Cell Nucleus/metabolism ; Animals ; Actins/metabolism ; },
abstract = {Neurodegenerative tauopathies, including Alzheimer's disease, are neuropathologically defined by pathological tau deposition. While tau drives neurotoxicity by disrupting cytoskeletal, nucleoskeletal, and genomic architecture, cellular mechanisms mediating tau-induced dysfunction of the cytoskeleton and nucleoskeleton are incompletely understood. Here, we identify proteins with differing abundance in a cellular tauopathy model, iTau. Building upon previous findings that pathogenic tau reduces nuclear tension, we find elevated levels of emerin, a central regulator of nuclear mechanotransduction, in iTau neurons and tau mutant iPSC-derived neurons. Neuronal emerin overexpression drives neurotoxicity, increases filamentous actin (F-actin), and induces nuclear invagination, mimicking cellular phenotypes of tauopathy. Alterations in emerin binding partners reflect its cytosolic relocalization in iTau neurons, suggesting that pathogenic tau may impact nuclear mechanotransduction by altering emerin levels and localization. Overall, we identify emerin as a potential mediator of cytoskeletal and nucleoskeletal remodeling in tauopathy and provide a foundation for future studies of emerin function in neurons.},
}

*Neurons/metabolism/pathology
*Nuclear Proteins/metabolism/genetics
Humans
*Mechanotransduction, Cellular
*tau Proteins/metabolism/genetics
*Cytoskeleton/metabolism
*Membrane Proteins/metabolism/genetics
*Cell Nucleus/metabolism
Animals
Actins/metabolism

@article {pmid42415414,
year = {2026},
author = {Nguyen, DD and Paine, M and Lee, S and Fazlollahi, A and Wang, BB and O'Sullivan, JD and Nestor, PJ},
title = {Global Rather Than Vertical-Selective Saccadic Abnormalities in Progressive Supranuclear Palsy.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70480},
pmid = {42415414},
issn = {2328-9503},
support = {//Mater Foundation/ ; 2023/GNT2030157//NHMRC Ideas/ ; },
abstract = {OBJECTIVE: To test whether vertical saccades are preferentially affected in Progressive Supranuclear Palsy (PSP).

METHODS: PSP patients (n = 24) were compared to age-matched controls (n = 94) and two degenerative groups (Alzheimer's disease, n = 20; Lewy body disease, n = 50). Video-oculography (sampling rate: 1000 Hz) was used to measure visually guided saccades (15.3° amplitude) in vertical and horizontal planes. Traditional corrected velocity alongside novel metrics of velocity interruption, vacillation, and directional instability were compared across diagnostic groups.

RESULTS: Vertical saccades were slower than horizontal in all groups including controls. Velocities were significantly slowed in PSP; however, the magnitude of slowing was comparable in vertical and horizontal directions. Similarly, vertical and horizontal velocities were strongly correlated in PSP (r = 0.77, p < 0.001), as they were in all other groups. Likewise, velocity interruption, vacillation, and directional instability were more disordered in the vertical compared to the horizontal axis in both controls and PSP (p < 0.05). Z-scores of all metrics in PSP were abnormal but with no predilection for vertical saccades. Vacillation was a predictor of saccade velocity.

INTERPRETATION: Contrary to conventional belief, vertical saccades were not selectively impaired in PSP. Instead, the findings indicated a more global disruption of the saccadic system. The clinical observation of impaired vertical saccades in PSP appears to be because vertical saccades are slower and more disordered than horizontal in the general population; thus, when abnormalities of saccades develop in all directions, it first reaches a threshold to be noticeable at the bedside in the vertical plane.},
}

@article {pmid42415688,
year = {2026},
author = {Hill, N and AlMuallim, HYO and Maddock, E and Hobbs, C and Clarke, E and Goncalves, MB and Corcoran, JPT},
title = {Treatment with KCL-286, a first-in-class retinoic acid receptor-β (RARβ) agonist, ameliorates neuronal DNA damage and inflammation in a mouse model of Alzheimer's disease.},
journal = {FEBS open bio},
volume = {},
number = {},
pages = {},
doi = {10.1002/2211-5463.70284},
pmid = {42415688},
issn = {2211-5463},
support = {110047/Z/15/Z/WT/WT_/Wellcome Trust/United Kingdom ; MR/R006466/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder for which effective disease-modifying therapies remain limited. Accumulation of neuronal DNA double-strand breaks (DSBs) is an early pathological event that contributes to genomic instability and neuronal vulnerability in AD. Therapeutic strategies that enhance DNA repair may therefore be of considerable interest. Here, using the Tg2576 mouse model of AD, we show that treatment with KCL-286, a selective retinoic acid receptor-β (RARβ) agonist, reduces neuronal DNA damage. KCL-286 enhances DSB repair in neurons, in part through upregulation of the DNA repair factor BRCA1, while also attenuating neuroinflammatory activation. In addition, KCL-286 normalises microglial and astrocytic morphology, consistent with reduced pathological glial activation. Together, these findings demonstrate that selective RARβ activation ameliorates neuronal DNA damage and neuroinflammation in a mouse model of AD, supporting further investigation as a potential disease-modifying therapeutic strategy.},
}

@article {pmid42415907,
year = {2026},
author = {Li, J and Chen, B and Jiang, J and Feng, Y and Zhang, R and Li, D and Wang, R and Long, Z and Ge, L and Guo, Y and Zhou, Z and Zou, W and Zhong, C and Liao, L},
title = {Efficacy of antioxidants as a therapy for Alzheimer's disease: a meta-analysis.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1878597},
pmid = {42415907},
issn = {2296-861X},
abstract = {BACKGROUND: Oxidative stress plays a central role in the pathogenesis of Alzheimer's disease (AD), contributing to neuronal damage, amyloid-beta aggregation, tau hyperphosphorylation, and neuroinflammation. Although antioxidants have been proposed as potential therapeutic agents, clinical trials have yielded inconsistent results.

OBJECTIVE: To systematically evaluate the efficacy of various antioxidants-including vitamins, polyphenols, and other antioxidant preparations-on cognitive function, oxidative stress biomarkers, neuropsychiatric symptoms, and disease progression in patients with AD.

METHODS: We conducted a systematic search of PubMed, Embase, and Web of Science from inception to October 2, 2025, for randomized controlled trials (RCTs) evaluating antioxidant interventions in AD patients. Study selection, data extraction, and quality assessment were performed independently by multiple reviewers. Meta-analyses were conducted using random-effects models where significant heterogeneity was present (I[2] > 50%). Outcomes included cognitive function scales (e.g., ADAS-Cog, MMSE), oxidative stress markers, neuropsychiatric symptoms, daily living abilities, neuroimaging measures, and fluid biomarkers.

RESULTS: A total of 23 RCTs comprising 10,537 participants were included. Antioxidants showed mixed effects across outcomes. While certain oxidative stress markers (urinary 8-iso-prostaglandin F2α: SMD 0.75, 95% CI 0.12-1.38) and neuropsychiatric symptoms (NPI: SMD -0.85, 95% CI -1.13 to -0.57) improved significantly, core cognitive endpoints such as ADAS-Cog (SMD 0.01, 95% CI -0.21 to 0.23) and MMSE (SMD 0.19, 95% CI -0.17 to 0.56) showed no significant benefit. Fluid biomarkers including Aβ42, p-tau, and t-tau remained unchanged. High heterogeneity was observed across multiple outcomes, reflecting variability in antioxidant types, dosages, and patient populations.

CONCLUSION: Antioxidants may improve certain oxidative stress markers and neuropsychiatric symptoms in AD patients but do not consistently enhance core cognitive function or alter AD-specific pathology. Current evidence does not support antioxidants as disease-modifying therapies, though they may serve as adjunctive interventions to improve quality of life and behavioral symptoms. Well-designed RCTs with longer follow-up and standardized protocols are warranted.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420261321660, identifier: CRD420261321660.},
}

@article {pmid42415930,
year = {2026},
author = {Wang, PJ and Yang, XY and Ji, L and Shi, JJ and Cai, XM and Sun, P and Liu, HX and Jiang, F and Yang, F},
title = {Peripheral metabolomic profiling reveals lipid and amino acid alterations associated with immuno-inflammatory responses in treatment-naïve late-onset Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1858299},
pmid = {42415930},
issn = {1663-4365},
abstract = {BACKGROUND: Immuno-metabolic dysregulation contributes to Alzheimer's disease (AD) pathogenesis, yet the peripheral metabolic landscape and its interplay with neuroinflammation remain poorly characterized in treatment-naïve, late-stage patients. This study aimed to delineate plasma metabolic alterations and immuno-metabolic interactions in Chinese first-time outpatients with late-onset AD (CFTO-LOAD).

METHODS: Untargeted metabolomics and ELISA were applied to plasma from 35 CFTO-LOAD patients and 35 sex-matched cognitively healthy controls (CHCs) to quantify metabolites, cytokines (TNF-α, IL-17, IL-9), and soluble Aβ/Tau markers.

RESULTS: A total of 875 differentially abundant metabolites (DAMs) were identified in CFTO-LOAD, comprising 227 upregulated and 648 downregulated species (P < 0.05), predominantly lipids, fatty acids (e.g., dodecanoic acid, arachidonic acid), and amino acids (e.g., L-arginine, L-leucine). KEGG analysis revealed enrichment in fatty acid and amino acid metabolism, GABAergic synapse, and intestinal immune network pathways. CFTO-LOAD patients exhibited elevated pro-inflammatory cytokines TNF-α and IL-17 (P adj < 0.05), reduced IL-9 (P adj < 0.001), increased soluble p-Tau, p-Tau181, and p-Tau217 (P adj < 0.01), and decreased Aβ42/Aβ40 ratio (P adj < 0.001). Linear regression identified significant correlations between differential metabolites and immune/pathological markers, including positive associations of dodecanoic acid with TNF-α (r = 0.34, P adj < 0.05) and arachidonic acid with Aβ42/Aβ40 ratio (r = 0.30, P adj < 0.05), and negative associations of arachidonic acid with p-Tau217 (r = -0.43, P adj < 0.01) and sphinganine 1-phosphate with TNF-α (r = -0.28, P adj < 0.05).

CONCLUSION: These findings characterize the peripheral immuno-metabolic landscape in treatment-naïve late-onset AD, identifying metabolic mediators that may mechanistically link neuroinflammation to Aβ and Tau pathology. This provides a foundation for biomarker development and therapeutic targeting in late-stage disease, pending independent validation.},
}

@article {pmid42415934,
year = {2026},
author = {Li, Q and Gu, M and Li, W},
title = {Exercise and neural circuit stability in early Alzheimer's disease: evidence across memory, executive, cholinergic, and circadian systems.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1863929},
pmid = {42415934},
issn = {1663-4365},
abstract = {Early Alzheimer's disease (AD) is increasingly understood as a phase in which neural circuit dysfunction emerges alongside molecular pathology and local neuronal injury. Although physical exercise has been linked to a deceleration in cognitive decline and beneficial cognitive and neural outcomes, most mechanistic explanations have predominantly focused on molecular or cellular pathways, with less emphasis on circuit-level interpretations. This narrative review integrates evidence from four neural systems that exhibit early vulnerability in AD and are pertinent to exercise-responsive cognitive or behavioral domains: the entorhinal cortex-dentate gyrus (EC-DG) circuit, the ventral hippocampus-medial prefrontal cortex (vHPC-mPFC) pathway, the medial septum/vertical diagonal band-hippocampal (MS/VDB-hippocampal) cholinergic circuit, and the suprachiasmatic nucleus-paraventricular nucleus (SCN-PVN) circadian axis. Across these systems, the evidence remains inconsistent. Direct circuit-level findings, including electrophysiological and functional-connectivity measurements, indicate circuit disruption in specific domains, whereas many exercise-related effects are inferred from molecular, structural, neurochemical, behavioral, or clinical-proxy outcomes. We therefore propose a multicircuit framework in which exercise may ameliorate AD-related cognitive and behavioral dysfunction through convergent but circuit-specific routes: EC-DG excitability and plasticity, vHPC-mPFC communication substrates, MS/VDB-hippocampal cholinergic modulation, and SCN-PVN circadian-neuroendocrine timing. This framework clarifies the evidence boundaries of exercise-related circuit modulation in early AD and identifies direct circuit-level measurements as a priority for future translational studies.},
}

@article {pmid42416049,
year = {2026},
author = {Yang, M and Liang, Z},
title = {GLP-1 receptor agonists in neurological diseases: mechanisms and therapeutic prospects from metabolism to neuroprotection.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1839620},
pmid = {42416049},
issn = {1664-3224},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; *Neuroprotection/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used metabolic therapies for type 2 diabetes and obesity, with well-established cardiovascular benefits. Beyond glycemic control, accumulating experimental and clinical evidence suggests that GLP-1RAs exert pleiotropic actions relevant to neurological diseases. Metabolic dysfunction, chronic inflammation, oxidative stress, mitochondrial impairment, and neurovascular injury represent convergent mechanisms that contribute to neurodegeneration, cerebrovascular pathology, and metabolism-related brain disorders. Notably, these processes overlap with pathways modulated by GLP-1 signaling across systemic and central compartments. GLP-1 receptors are expressed in neurons, glial cells, and components of the neurovascular unit, providing a biological basis for possible neurological effects. Preclinical studies suggest that GLP-1RAs can reduce neuroinflammation and oxidative stress, support mitochondrial function, and help maintain blood-brain barrier integrity. Clinical findings, however, remain inconsistent. Studies in Parkinson's disease have reported encouraging signals, but biomarker evidence for disease modification is still limited. In Alzheimer's disease, clinical trials have produced mixed or negative results. These differences may reflect disease stage, patient selection, drug-specific pharmacology, central nervous system exposure, endpoint sensitivity, and treatment duration. Overall, GLP-1RAs may influence neurological disease through metabolic, inflammatory, and vascular pathways, but their clinical role remains unsettled. Future studies should use biomarker-informed designs, prespecified neurological endpoints, appropriate drug selection, and sufficiently long follow-up to determine which patients and disease stages are most likely to benefit.},
}

Humans
*Glucagon-Like Peptide-1 Receptor Agonists
Animals
*Neuroprotective Agents/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy/metabolism
Glucagon-Like Peptide-1 Receptor/metabolism
*Neuroprotection/drug effects
Oxidative Stress/drug effects

@article {pmid42416144,
year = {2026},
author = {Huang, F and Guo, M and Yang, Y and Wang, Z},
title = {Aloe emodin attenuates Aβ1-42-Induced neurotoxicity in SH-SY5Y cells via downregulation of PPM1K.},
journal = {Open medicine (Warsaw, Poland)},
volume = {21},
number = {1},
pages = {20261473},
pmid = {42416144},
issn = {2391-5463},
abstract = {OBJECTIVES: To study the role and underlying mechanism of aloe emodin, a natural anthraquinone compound known for antioxidant, and anti-inflammatory activities, in Alzheimer's disease (AD).

METHODS: Aβ1-42-induced injury model was established using SH-SY5Y cells. A combination of CCK-8 assay, flow cytometry, ELISA, ROS fluorescence probe, RT-qPCR, and western blot assay was employed to systematically evaluate the effects of aloe emodin on cell viability, apoptosis, inflammation, and oxidative stress. Potential molecular targets were identified through bioinformatics analysis. The regulatory role of PPM1K in aloe emodin-mediated neuroprotection was further validated using PPM1K overexpression experiments.

RESULTS: Bioinformatics analysis revealed that PPM1K is significantly upregulated in AD and showed predicted in silico binding with aloe emodin. Aloe emodin markedly improved the viability of Aβ1-42-treated SH-SY5Y cells, suppressed apoptosis, reduced the release of pro-inflammatory cytokines, and attenuated ROS generation, accompanied by the downregulation of PPM1K expression. In contrast, overexpression of PPM1K significantly weakened the neuroprotective effects of aloe emodin, as evidenced by decreased cell viability and increased levels of apoptosis and oxidative stress.

CONCLUSIONS: Aloe emodin alleviates Aβ1-42-induced neuronal injury by targeting and downregulating PPM1K expression, suggesting that PPM1K is a critical mediator of the neuroprotective effects of aloe emodin.},
}

@article {pmid42416176,
year = {2026},
author = {Kim, DJ and Kim, YC and Jeong, BH},
title = {Association of SPHK1 polymorphisms with Alzheimer's disease susceptibility: Functional impact of the rs2247856 SNP on transcriptional efficiency.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70288},
pmid = {42416176},
issn = {2352-8737},
abstract = {INTRODUCTION: Sphingosine kinase 1 (SPHK1) has been implicated in the regulation of pro-resolving lipid mediators relevant to neuroinflammation in Alzheimer's disease (AD). However, no studies have evaluated the genetic association between SPHK1 polymorphisms and AD susceptibility.

METHODS: We analyzed genotype and allele frequencies of polymorphisms in the SPHK1 gene between patients with AD and healthy controls. In addition, transcription factor binding sites were evaluated. Furthermore, promoter activities associated with rs2247856 single nucleotide polymorphism (SNP) were assessed using a luciferase reporter assay.

RESULTS: Among the identified SNPs, the genotype distribution of rs2247856 showed a significant association with AD. Haplotype analysis revealed that haplotype 3 (CAGTACGG) was significantly more frequent in patients with AD than in controls. Profiler of Multi-Omics Data (PROMO) analysis suggested that the rs2247856 A allele disrupts the activating transcription factor 3 transcription factor binding site. Luciferase assays demonstrated significantly reduced promoter activity in constructs containing the A allele compared to the G allele (p < 0.001), indicating allele-specific regulation of SPHK1 transcription.

DISCUSSION: Our findings identify rs2247856 as a functional regulatory SNP in the SPHK1 gene associated with AD susceptibility. The reduced transcriptional activity of the A allele may impair SPHK1-mediated anti-inflammatory signaling, potentially contributing to AD pathogenesis.},
}

@article {pmid42416267,
year = {2026},
author = {de Leon, J and Allen, IE and Miller, Z and Dronkers, N and Henry, M and Gorno-Tempini, ML and Grasso, S},
title = {Reported symptoms and patterns of language impairment in bilingual speakers with primary progressive aphasia: a retrospective study.},
journal = {Aphasiology},
volume = {},
number = {},
pages = {},
pmid = {42416267},
issn = {0268-7038},
abstract = {BACKGROUND: The relative scarcity of studies of bilingual speakers with primary progressive aphasia (PPA) leads to knowledge gaps regarding their symptoms and patterns of language impairment. It is unknown if PPA symptoms in bilingual speakers differ from those of monolingual speakers. In addition, it remains unclear if one of a bilingual speaker's languages is more vulnerable to the onset of symptoms and/or is better preserved. Furthermore, bilingualism factors (e.g. order/age of language acquisition (L1/L2) and language dominance) may explain patterns of impairment both within and across the variants of PPA.

AIMS: To characterize the bilingualism factors, speech and language symptoms, and patterns of language impairment in a retrospective cohort of bilingual speakers with PPA.

METHODS: In a large cohort (N = 69) of bilingual speakers, we performed a chart review to extract information regarding self/caregiver-reported PPA symptoms, first language impacted by PPA at symptom onset, less preserved language at time of evaluation, and bilingual history factors (age/order of acquisition (L1/L2) and language dominance). We explored how emergence and presentation of symptoms associated with bilingualism factors.

RESULTS: The presenting symptoms were mostly consistent with current PPA diagnostic criteria, although symptoms unique to bilingual speakers were reported. The language reported to first be impacted by PPA, as well as the less preserved language at the time of evaluation, was generally reported to be the less dominant language, regardless of PPA variant. These measures did not associate as closely with age/order of acquisition (L1 versus L2).

CONCLUSION: Bilingual speakers with PPA may report additional symptoms that reflect their ability to speak more than one language. The less dominant language was most susceptible to the initial impact of PPA and also tended to the less preserved language at the time of evaluation. Future studies of bilingual speakers with neurodegenerative diseases should systematically consider bilingualism factors, which are likely to contribute to clinical presentation and disease progression.},
}

@article {pmid42416270,
year = {2026},
author = {Wang, A and Curel, T and Claeysen, S and Travers-Lesage, V and Cadot, M and Davis, A and Sopkova-de Oliveira Santos, J and Modeste, F and Brazzolotto, X and Nachon, F and Dallemagne, P and Since, M and Rochais, C},
title = {Combining β2-AR agonism with butyrylcholinesterase inhibition, a synergistic neuroprotective action against Alzheimer's disease.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42416270},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder for which the current treatments remain largely symptomatic. Pleiotropic prodrug strategies offer a promising approach to address this complexity, combining complementary pharmacological mechanisms within a single molecular entity. In this study, we report the design, synthesis, and biological evaluation of novel carbamate-based pleiotropic prodrugs that combine butyrylcholinesterase (BuChE) inhibition and β2-adrenergic receptor (β2-AR) agonism. Seven salmeterol-derived carbamates were synthesized and evaluated for their cholinesterase inhibitory activity, β2-AR activity, and neuroprotective potential. Several derivatives exhibited potent and selective inhibition of human BuChE in the nanomolar range, revealing a clear structure-activity relationship driven by carbamate substitution and amine protection. Kinetics and LC-MS analyses demonstrated a pseudo-irreversible covalent inhibition mechanism associated with rapid enzyme reactivation, thereby enabling controlled salmeterol release. While carbamates behaved as inactive prodrugs at the β2-AR level, selected compounds displayed significant neuroprotective effects in a cellular model of amyloid-β-induced toxicity. Collectively, these findings validate salmeterol-derivated carbamates as innovative pleiotropic prodrugs and support the potential of combining BuChE inhibition and β2-AR agonism as a disease-modifying strategy for Alzheimer's disease.},
}

@article {pmid42416335,
year = {2026},
author = {Wang, XT and Wang, J and Zhao, XJ},
title = {Exercise training promotes neurogenesis in the adult hippocampus with a particular focus on cell cycle regulation.},
journal = {Frontiers in sports and active living},
volume = {8},
number = {},
pages = {1770350},
pmid = {42416335},
issn = {2624-9367},
abstract = {Adult neurogenesis is predominantly restricted to two neurogenic regions in the mammalian brain: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) within the hippocampus. The hippocampus serves as a critical brain structure involved in learning and memory processes, and the continuous generation of new neurons contributes to enhanced synaptic plasticity. Accumulating evidence has demonstrated that impaired hippocampal neurogenesis is closely associated with various neuropsychiatric disorders, including Alzheimer's disease, epilepsy, and traumatic brain injury. Although the precise molecular and cellular mechanisms underlying adult neurogenesis remain incompletely elucidated, extensive research over the past several decades has identified numerous endogenous, exogenous, and environmental factors that modulate this process. Notably, exercise training, as a key exogenous stimulus, has been shown to promote adult hippocampal neurogenesis by influencing the neurochemical environment and functional integration of newly generated neurons. This review aims to summarize the relationship between cell cycle dynamics and adult hippocampal neurogenesis, with a particular emphasis on how physical exercise regulates the cell cycle to activate and promote the proliferation of neural stem cells (NSCs) in the DG, thereby facilitating the differentiation and lineage progression of neural progenitor cells. A deeper understanding of the regulatory mechanisms by which exercise enhances adult hippocampal neurogenesis may provide novel insights into the development of therapeutic strategies for neurological and psychiatric disorders.},
}

@article {pmid42416382,
year = {2026},
author = {Cabán, M and Abraído-Lanza, AF and Brown-Bradley, C and Meng, A and Tran, E and Lee, J and Wetmore, JB and Ottman, R and Siegel, K},
title = {The use of religion, prayer, and faith to cope with the receipt of Alzheimer's disease risk information in a research context: A qualitative study of Latinos in NYC.},
journal = {SSM. Qualitative research in health},
volume = {9},
number = {},
pages = {},
pmid = {42416382},
issn = {2667-3215},
abstract = {People commonly turn to religion when confronted with threatening events including illness. However, limited research has investigated the use of religious coping to manage distress associated with knowledge of one's risk for serious illnesses such as Alzheimer's disease (AD). To examine how they coped with receiving information about their risk for late-onset AD, semi-structured interviews were conducted with a sample of Latinos (ages 40-64) living in Northern Manhattan approximately 6 weeks, 9 and 15 months after receiving a numerical risk estimate (expressed as a percentage) of their chances of developing AD by age 85. Some also were told their APOE genotype, including whether it increased their susceptibility to late onset AD. Of 202 participants interviewed, 43 mentioned using religion to cope with the implications of receiving their AD risk information and the emotions it evoked and are the focus of this report. Five themes emerged from the data: 1) Praying to be protected from AD; 2) Praying to help manage emotions; 3) Giving control over to God; 4) Accepting AD as part of God's plan; and 5) Praying for the strength to accept one's fate and deal with whatever it brings. To our knowledge this is the first report describing how individuals use religion/spirituality to cope with the perceived implications of and the emotions elicited by receiving their AD risk information. This information can inform the development of culturally tailored support resources for those who choose to learn their risk status.},
}

@article {pmid42416856,
year = {2026},
author = {Ameenudeen, S and Srinivasan, H},
title = {Network pharmacology-based identification of hub genes targeted by ayurvedic formulation Triphala in controlling Alzheimer's disease by polypharmacological mechanisms.},
journal = {In silico pharmacology},
volume = {14},
number = {2},
pages = {186},
pmid = {42416856},
issn = {2193-9616},
abstract = {UNLABELLED: The multifactorial neurodegenerative disease known as Alzheimer's disease (AD) is typified by amyloid-β aggregation, tau hyperphosphorylation, neuroinflammation, and synaptic dysfunction, as well as progressive cognitive decline. Due to the limited effectiveness of conventional therapeutic approaches, multi-target agents must be investigated. A traditional Ayurvedic polyherbal formulation, Triphala contains a wide range of bioactive phytochemicals that have been shown to have neuroprotective effects. The molecular targets of Triphala phytocompounds related to AD pathology were clarified in the current study using a network pharmacology approach. BindingDB and SwissTargetPrediction were used to predict the putative protein targets of 18 phytocompounds, yielding 54 distinct targets. The STRING database was used to build a protein-protein interaction (PPI) network, which Cytoscape was then used to analyse. The following 7 important hub genes were identified using topological parameters (degree, betweenness, closeness centrality): BCL2, CASP3, MMP9, JUN, NFKB1, PTGS2, and ESR1. Potential mechanistic overlap was highlighted by the significant involvement of 20 genes in AD-related pathways and 30 genes in the lipid and atherosclerosis pathway, according to gene enrichment analysis using KEGG. Synaptic plasticity, oxidative stress response, neuroinflammatory signalling, and apoptosis regulation are the main functions of these genes. The integrative analysis highlights Triphala's polypharmacology mechanism and raises the possibility that it could be used as a multi-target therapeutic candidate for AD. This study offers a logical foundation for additional in vitro and in vivo validation of Triphala-derived neurotherapeutics as well as a systems-level framework for comprehending herb-compound-gene-disease interactions.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00704-6.},
}

@article {pmid42416912,
year = {2026},
author = {Zou, Z and Liu, H and Lei, D and Jian, X and Li, X},
title = {Dynamic changes of gut microbiota during progression of three Alzheimer's disease mice models.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1849896},
pmid = {42416912},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder characterized by cognitive impairment and irreversible neuronal degeneration, affecting approximately 55 million individuals worldwide. Despite extensive research efforts, the underlying pathogenic mechanisms of AD remain incompletely understood, and effective therapeutic strategies for preventing or delaying disease progression are still lacking. Increasing evidence suggests that the microbiota-gut-brain axis plays an important role in neurodegenerative diseases, including AD. However, the dynamic alterations of gut microbiota during AD progression across different transgenic mouse models remain poorly characterized.

METHODS: In the present study, we investigated age-dependent changes in gut microbiota composition in three commonly used AD mouse models, including APP/PS1, 3xTg, and 5xFAD mice, using 16S rRNA gene sequencing. Fecal samples were collected longitudinally at 2, 4, 6, and 8 months of age to evaluate microbial diversity, community structure, and differential bacterial taxa during aging and disease progression.

RESULTS: Our results demonstrated distinct and model-dependent alterations in gut microbiota composition across different stages of AD progression. Significant changes in microbial diversity and bacterial community structure were observed among the three AD mouse models and wild-type controls. In particular, dynamic alterations in Verrucomicrobiota, Proteobacteria, and Actinobacteriota were consistently identified during aging in AD mice. In addition, β-diversity, Linear discriminant analysis effect size (LEfSe), and correlation network analyses further revealed differential microbial signatures associated with different AD mouse models and age stages.

DISCUSSION: Overall, our findings provide additional evidence that gut microbiota composition undergoes dynamic alterations during aging in multiple AD mouse models and may be associated with AD-related progression. This study may contribute to a better understanding of microbiota-associated changes during AD development and provide a basis for future mechanistic studies targeting the microbiota-gutbrain axis in AD.},
}

@article {pmid42417039,
year = {2026},
author = {Feng, L and Jin, X and Li, X and Qu, T and Guo, H and Wang, Z and Quan, Y and Chen, L and Wang, L and Wang, Y},
title = {One-month early time-restricted eating enhances long-term memory by modulating brain fluid dynamics in males with metabolic syndrome: Evidence from perivascular diffusion and global blood-oxygen-level-dependent-cerebrospinal fluid coupling.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261465674},
doi = {10.1177/13872877261465674},
pmid = {42417039},
issn = {1875-8908},
abstract = {BackgroundMetabolic syndrome (MetS) serves as a precursor to Alzheimer's disease, a condition characterized by initial memory impairment and driven by dysregulated brain fluid dynamics. While time-restricted eating (TRE) improves memory in MetS, the mechanistic role of brain fluid dynamics in this process remains unclear.ObjectiveTo investigate whether a 1-month early TRE (eTRE) intervention enhances memory performance by improving brain fluid dynamics in individuals with MetS.MethodsTwenty-eight men with MetS and 30 matched healthy male controls underwent MRI scans. Brain fluid dynamics was assessed using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index and global blood-oxygen-level-dependent-cerebrospinal fluid (gBOLD-CSF) coupling. In the MetS group, metabolic risk factors, cognitive and psychological status, and memory performance were evaluated pre- and post-eTRE. Relationships between imaging indices and memory scores were examined by correlation analysis.ResultsAt baseline, men with MetS exhibited a lower DTI-ALPS index and higher gBOLD-CSF coupling than healthy controls (p < 0.05). After 1-month eTRE, the DTI-ALPS index increased (p < 0.001), while gBOLD-CSF coupling decreased (p = 0.027), approaching healthy control levels. Metabolic parameters and long-term memory performance also improved significantly (all p < 0.05). Changes in DTI-ALPS were positively correlated with delayed recall (r = 0.445, p < 0.05), whereas changes in gBOLD-CSF coupling were negatively correlated (r = -0.550, p < 0.05).ConclusionsA 1-month eTRE intervention improved long-term memory and brain fluid dynamics in males with MetS, providing a promising non-pharmacological strategy to counteract metabolic-driven neurodegenerative diseases.Trial registrationNational Medical Research Registration and Filing Information System (https://www.medicalresearch.org.cn/), MR-61-24-042065.},
}

@article {pmid42417046,
year = {2026},
author = {Weiss, JN and Eber, D and Cole, R},
title = {Dynamic light scattering spectroscopy and the Centiloid scale.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467030},
doi = {10.1177/13872877261467030},
pmid = {42417046},
issn = {1875-8908},
abstract = {Dynamic light scattering (DLS) spectroscopy measures the Brownian movement of particles. Fifteen patients underwent DLS measurement and positron emission tomography amyloid imaging. The DLS measurement is noninvasive, quantitative, and inexpensive, with immediate results. We report a significant correlation between DLS measurements and Centiloid values.},
}

@article {pmid42417051,
year = {2026},
author = {Agüero-Rabes, P and Roa-Escobar, J and Téllez, R and Mañanes, V and Gómez-Tortosa, E},
title = {Eligibility for lecanemab therapy in a biomarker defined memory clinic cohort: A five-year analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261466695},
doi = {10.1177/13872877261466695},
pmid = {42417051},
issn = {1875-8908},
abstract = {We assessed cross-sectional lecanemab eligibility (January 2026) in 479 patients with mild cognitive impairment or dementia who underwent Alzheimer's disease (AD) biomarker testing at a tertiary memory clinic (2021-2025). Overall eligibility was 16%, with exclusions due to negative biomarkers (41%), advanced disease stage (31%), APOE ε4/ε4 homozygosity (6%), and other safety reasons (6%). In the 2025 subgroup (n = 100), eligibility increased to 32%, reflecting fewer exclusions for disease progression and a targeted evaluation of patients likely to meet criteria. These findings highlight a narrow post-diagnosis therapeutic window and suggest an upper eligibility limit under the current appropriate use recommendations for anti-amyloid therapies.},
}

@article {pmid42417056,
year = {2026},
author = {Dimas-Harms, LJ and Moser, VA},
title = {The arsenic-Alzheimer's disease link: Emerging evidence and unanswered questions.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467042},
doi = {10.1177/13872877261467042},
pmid = {42417056},
issn = {1875-8908},
abstract = {Arsenic is a toxic heavy metal that reaches humans primarily through contaminated groundwater, presenting a persistent global public health concern. Chronic exposure, even at concentrations lower than current safety standards, disturbs brain development and function, raising concern that arsenic may contribute to Alzheimer's disease (AD). Wei et al. investigate early-life arsenic exposure and AD using Swedish national registries and geographic variation in groundwater arsenic. This work represents a critical step toward understanding whether historical environmental exposures in northern Europe have increased late-life neurodegenerative risk and underscores the importance of treating arsenic as a potentially modifiable environmental risk factor for AD.},
}

@article {pmid42417147,
year = {2026},
author = {Wang, Y and Nan, B and Gillen, DL and Corrada, MM},
title = {Statistical analysis of disease onset during lifespan with left truncation.},
journal = {Biometrics},
volume = {82},
number = {3},
pages = {},
doi = {10.1093/biomtc/ujag118},
pmid = {42417147},
issn = {1541-0420},
support = {R01 AG056764/NH/NIH HHS/United States ; RF1 AG075107/NH/NIH HHS/United States ; R01 AG021055/NH/NIH HHS/United States ; P30 AG066519/NH/NIH HHS/United States ; DMS 2412746//National Science Foundation/ ; },
mesh = {Computer Simulation ; Humans ; *Models, Statistical ; Data Interpretation, Statistical ; Dementia/mortality/epidemiology ; Alzheimer Disease/mortality ; *Age of Onset ; Statistics, Nonparametric ; },
abstract = {We consider a new nonparametric method for analyzing the onset of a chronic condition, e.g., dementia, when death occurs frequently in the study population. In contrast to the commonly used semi-competing risks or illness-death model, we study the distribution of the disease onset time conditional on the death time, which consists of two components that provide straightforward interpretations of the disease onset during the lifespan. Without imposing any model assumption, we propose a kernel-weighted product-limit estimator that properly handles the left-truncation, a common issue in aging studies. The estimator is asymptotically normal and its variance can be estimated by a Greenwood-type variance estimator. We use the integrated Brier score for the bandwidth selection and illustrate the proposed method with simulation studies, an analysis of The 90+ Study, and an analysis of the UC Health Data Warehouse.},
}

Computer Simulation
Humans
*Models, Statistical
Data Interpretation, Statistical
Dementia/mortality/epidemiology
Alzheimer Disease/mortality
*Age of Onset
Statistics, Nonparametric