@article {pmid42448384,
year = {2026},
author = {Mani, LY and Unwin, RJ},
title = {Relationship between cognitive impairment and chronic kidney disease.},
journal = {Practical neurology},
volume = {26},
number = {4},
pages = {313-318},
doi = {10.1136/pn-2025-004837},
pmid = {42448384},
issn = {1474-7766},
mesh = {Humans ; *Renal Insufficiency, Chronic/complications/epidemiology/psychology ; *Cognitive Dysfunction/epidemiology/etiology/diagnosis ; *Cognition Disorders ; },
abstract = {Cognitive impairment is an under-recognised but clinically significant complication of chronic kidney disease (CKD). The global prevalence of CKD is approximately 10%, and it frequently affects neurological function, and particularly executive and language domains. This article encourages neurologists and neuropsychiatrists to consider CKD as a potential contributor to cognitive decline. By recognising the characteristic cognitive profile associated with CKD, and distinguishing it from coexisting neurodegenerative pathology, clinicians can implement early interventions that improve outcomes. We outline mechanisms that link CKD to cognitive dysfunction, present diagnostic approaches and offer multidisciplinary strategies for assessment and management.},
}

Humans
*Renal Insufficiency, Chronic/complications/epidemiology/psychology
*Cognitive Dysfunction/epidemiology/etiology/diagnosis
*Cognition Disorders

@article {pmid42448407,
year = {2026},
author = {Rangappa, N and Upadhyay, R and Lakshman, N and Ramasamy, S and Sevanan, M and Justin, A and Chinnathambi, S},
title = {Small molecular therapeutic targets for neurodegenerative diseases.},
journal = {Advances in protein chemistry and structural biology},
volume = {153},
number = {},
pages = {135-167},
doi = {10.1016/bs.apcsb.2025.10.012},
pmid = {42448407},
issn = {1876-1631},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology/genetics ; Animals ; *Molecular Targeted Therapy ; },
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis disease are characterized by progressive neuronal loss, protein aggregation, and synaptic dysfunction. These diseases share common pathological mechanisms including oxidative stress, mitochondrial impairment, chronic neuroinflammation, protein misfolding, and epigenetic dysregulation. Current therapies offer only symptomatic relief and fail to halt disease progression. Recent advances in transcriptomics and proteomics have enabled the identification of shared molecular pathways and druggable targets across multiple neurodegenerative diseases. The key targets, such as BDNF-TrkB, TREM2, SIRT1, PINK1-Parkin, GSK-3β, NLRP3, and mTOR have shown promise in preclinical models, offering opportunities for broad-spectrum therapeutic development. Importantly, blood-brain barrier disruption and neuroinflammatory crosstalk exacerbate disease pathology and hinder drug delivery. Innovative strategies involving nanocarriers, gene therapy, and epigenetic modulation are emerging to overcome these barriers. This review highlights the convergence of disease mechanisms, discusses common molecular signatures and therapeutic vulnerabilities, and explores novel small molecular interventions targeting shared pathways mainly in AD and PD. A deeper understanding of aging-associated molecular dysfunction is essential to design sustainable, disease-modifying therapeutics with cross-disease relevance.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism/pathology/genetics
Animals
*Molecular Targeted Therapy

@article {pmid42448408,
year = {2026},
author = {Velmurugan, G and Krishnan, D and Upadhyay, R and Sivasamy, R and Sevanan, M and Chinnathambi, S},
title = {Signaling cascades of microtubule-associated protein Tau in Alzheimer's disease.},
journal = {Advances in protein chemistry and structural biology},
volume = {153},
number = {},
pages = {169-190},
doi = {10.1016/bs.apcsb.2025.10.013},
pmid = {42448408},
issn = {1876-1631},
mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/metabolism/pathology ; *Signal Transduction ; Mitochondria/metabolism/pathology ; Protein Processing, Post-Translational ; Animals ; Phosphorylation ; Neurons/metabolism/pathology ; },
abstract = {Accumulation of neurofibrillary tangles (NFTs) in the neuronal cells is the predominant features of Alzheimer's diseases (AD) and other Tauopathies. Studies on molecular mechanism of human neurodegenerative disease shows that the substantial posttranslational modifications (PTMs) of Tau is essential for the conversion of monomeric soluble form into the aberrant insoluble aggregates in pathological condition. During pathogenesis of AD, Tau phosphorylation state is altered by the activation of various kinases and phosphates and eventually Tau become hyperphosphorylated. Hyperphosphorylated Tau detach from microtubules and aggregate intracellularly in affected neurons. This pathological Tau invades the subcellular organelles including mitochondria and leads to degeneration and cell death. Ageing is the crucial factor causing alteration in brain including, structural and functional role of Tau. Pathological Tau disrupts signaling cascades of mitochondria, energy-associated mechanism and this causes the elevation of oxidative stress in the neurons. Furthermore, hyperphosphorylated Tau also inhibits the mitophagy and autophagy-lysosomal pathway, resulting in the buildup of dysfunctional mitochondria in the affected neurons. This review highlights the major signaling cascades involved in Tau PTMs and its interlinked role in mitochondrial damage in aging population in AD.},
}

Humans
*tau Proteins/metabolism
*Alzheimer Disease/metabolism/pathology
*Signal Transduction
Mitochondria/metabolism/pathology
Protein Processing, Post-Translational
Animals
Phosphorylation
Neurons/metabolism/pathology

@article {pmid42448409,
year = {2026},
author = {Upadhyay, R and Velmurugan, G and Krishnan, D and Sivasamy, R and Sevanan, M and Chinnathambi, S},
title = {Understanding molecular role of lipids for Alzheimer's disease.},
journal = {Advances in protein chemistry and structural biology},
volume = {153},
number = {},
pages = {191-210},
doi = {10.1016/bs.apcsb.2025.10.011},
pmid = {42448409},
issn = {1876-1631},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Lipid Metabolism ; Animals ; Membrane Microdomains/metabolism/pathology ; Oxidative Stress ; *Lipids ; Neurons/metabolism/pathology ; },
abstract = {Human health and neurological functions are significantly impacted by lipids, the fundamental building block of cell membranes. The central nervous system is rich in lipids, and they are evidently disturbed in neurological conditions and neurodegenerative diseases like Alzheimer's disease (AD). Alteration in lipid profile is highly linked with aging. During early onset of AD, there is a noted lipid peroxidation and modifications of fatty acids at the level of lipid rafts in the neuronal cells. AD is an age-linked neurodegenerative condition with multifaceted etiology, with combining genetic and environmental risk factors, which lacks disease-modifying therapies. While the aberrant deposition of lipids was shown in the initial studies of AD neuropathology. Clinically, lipidomic and metabolomic research have constantly exposed the changes in the levels of various lipid classes emerging in early onset of AD individuals. Also, decades of investigations have discovered multifactorial link between lipid metabolism and key AD pathogenic pathway such as amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, and myelin degeneration. Herewith, we highlighted the features that impact lipid composition in neuronal cells, and the association of different lipids with known aspects of AD pathogenesis, and potential therapeutics that aim lipid crossroads.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*Lipid Metabolism
Animals
Membrane Microdomains/metabolism/pathology
Oxidative Stress
*Lipids
Neurons/metabolism/pathology

@article {pmid42448482,
year = {2026},
author = {Wang, T and Lin, S and Xu, C and Chen, Y and Sui, Y and Sun, J and Wang, R and Chen, H and Lian, J and Wang, W},
title = {Multimodal MRI Reveals Stage-Specific Reorganization of Structure-Function Coupling from Compensatory to Decoupled States in Cerebral Small Vessel Disease.},
journal = {Academic radiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.acra.2026.06.044},
pmid = {42448482},
issn = {1878-4046},
abstract = {RATIONALE AND OBJECTIVES: Cerebral small vessel disease (CSVD) affects white matter integrity and can alter the brain's network architecture. However, the relationship between structural and functional connectivity in CSVD remains underexplored. This study aims to investigate the differences in topological properties of structural and functional brain networks across CSVD burden groups.

MATERIALS AND METHODS: This cross-sectional study utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu), concentrating on participants who had both DTI and resting-state fMRI data. Participants were classified into non-CSVD (CSVD-n), mild CSVD (CSVD-m), or severe CSVD (CSVD-s) groups based on a CSVD burden score ranging from zero to four. Structural networks were reconstructed from DTI data using deterministic tractography, while functional networks were derived from resting-state fMRI data through Pearson's correlation of regional time series. Graph theoretical analyses were conducted using GRETNA in MATLAB to calculate global and nodal metrics, as well as structure-function coupling indices. Group comparisons were performed using one-way ANOVA (one-way analysis of variance), with age, sex, and education as covariates. Statistical significance was assessed at a two-tailed p < 0.05, adjusted for multiple comparisons across nodes and networks using false discovery rate (FDR) correction.

RESULTS: The study included 280 participants (mean 75.0±7.9y, median 76y; 49.6% female). The participants were divided into groups: CSVD‑n (118, 42.1%), CSVD‑m (80, 28.6%), and CSVD‑s (82, 29.3%). Analysis of structural networks revealed that CSVD‑s exhibited reduced global/local efficiency (7.42±2.63 vs. 8.42±2.75, p = 0.03; 16.00±4.77 vs. 17.83±5.16, p = 0.02) and increased path length (0.15±0.04 vs. 0.13±0.04, p = 0.003). Nodal damage was observed in the left hippocampus in CSVD‑m (p = 0.0008) and was widespread in CSVD‑s (all p < 0.001). In terms of functional networks, no global differences were found (all p > 0.05); however, CSVD‑s exhibited nodal changes in the cingulate/Heschl gyrus (p < 0.001). Regarding coupling, CSVD‑m showed increased coupling in the insula/orbitofrontal regions (p = 0.002-0.041) and decreased coupling in the pallidum (p = 0.026). Conversely, CSVD‑s demonstrated increased coupling in the olfactory/occipital/temporal regions (p = 0.001-0.023) and decreased coupling in the rolandic operculum (p = 0.019) and hippocampus (compared to CSVD‑m, p = 0.009). Furthermore, left insular coupling was correlated with MoCA (r=-0.245, p = 0.015).

CONCLUSION: In the mild CSVD group, researchers observed increased coupling in regions such as the insula and orbitofrontal cortex. In contrast, the severe CSVD group exhibited widespread structural network differences, decreased coupling in the hippocampus and rolandic operculum, and functional nodal alterations. These cross-sectional comparisons among CSVD burden groups reveal a pattern of differences consistent with stage-like progression. However, causality cannot be inferred from this cross-sectional design.},
}

@article {pmid42448639,
year = {2026},
author = {Aktaş, E and Yurt, İ and Cerlet, YN and Hanağası, HA},
title = {Rethinking Alzheimer's Disease Therapy: From Amyloid-Centric Approaches to Multi-Target Phytochemical Strategies.},
journal = {Journal of neurochemistry},
volume = {170},
number = {7},
pages = {e70506},
doi = {10.1111/jnc.70506},
pmid = {42448639},
issn = {1471-4159},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Phytochemicals/therapeutic use/administration & dosage ; Animals ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Oxidative Stress/drug effects/physiology ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, characterized by irreversible neuronal loss and progressive cognitive decline. The disease is driven by complex and interconnected pathological processes, including amyloid-β plaque deposition and tau neurofibrillary tangle formation, which converge on neuroinflammation, oxidative stress, synaptic dysfunction, and widespread neuronal network failure. Although recently approved antibody-based therapies such as lecanemab and donanemab effectively reduce cerebral amyloid burden, their clinical benefits remain modest and are accompanied by significant safety concerns, including amyloid-related imaging abnormalities (ARIA). Current pharmacological strategies predominantly rely on single-target mechanisms, an approach increasingly recognized as insufficient to address the multifactorial neurobiology of AD. This review critically evaluates the limitations of conventional amyloid-centric therapeutic strategies and contrasts them with emerging multi-target approaches based on phytochemicals. We synthesize current experimental and translational evidence to present a mechanistic framework illustrating how plant-derived bioactive compounds, including flavonoids and polyphenols, function as systems-level modulators of AD pathology rather than purely symptomatic agents. Particular emphasis is placed on their coordinated actions on amyloid processing via BACE1 inhibition, restoration of tau homeostasis through GSK-3β/PP2A regulation, attenuation of neuroinflammatory signaling, enhancement of endogenous antioxidant defenses through Nrf2 activation, and preservation of synaptic integrity. When considered collectively, the available evidence supports the concept that multi-target phytochemical strategies represent a biologically congruent and neurologically relevant paradigm for Alzheimer's disease therapy. Future progress will likely depend on integrating these compounds into broader polypharmacological and multidomain intervention frameworks, together with lifestyle-based strategies, repurposed drugs, anti-amyloid therapies, and rigorous translational validation.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Phytochemicals/therapeutic use/administration & dosage
Animals
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
Oxidative Stress/drug effects/physiology
tau Proteins/metabolism

@article {pmid42448663,
year = {2026},
author = {Xu, X and Fan, SS and Wu, H and Du, Y and Bo, Y and He, J and He, Y and Cheng, N and Meng, XY},
title = {Integrative multi-omics reveals MHC class II-mediated neuroinflammation and systemic metabolic dysregulation as transdiagnostic drivers in major brain disorders.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04280-3},
pmid = {42448663},
issn = {2158-3188},
support = {62402006//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82303057//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Psychiatric, neurodevelopmental, and neurodegenerative disorders, including Alzheimer's disease (AD), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BIP), major depressive disorder (MDD), and schizophrenia (SCZ), exhibit complex etiologies driven by immune and metabolic dysregulation. While distinct in their clinical onset, these conditions share overlapping molecular vulnerabilities. This study pioneers an integrative multi-omics framework, combining multi-tissue TWAS, cross-disorder pleiotropy analyses, Mendelian Randomization (MR), predictive machine learning, and BV2 microglial profiling. Crucially, our analysis uncovered a robust "Dual-Axis" etiological architecture. First, a systemic metabolic axis emerged as a primary driver, particularly involving FADS2-mediated lipid dysregulation and gut-brain axis interactions. This axis shares mechanisms between bipolar disorder and schizophrenia, with Multi-tissue TWAS revealing peripheral contributions (e.g., liver, colon) to CNS pathology. Second, MHC Class II-mediated pathways, driven by HLA-DRA, HLA-DRB1, HLA-DQB1, and HLA-DQA1, emerged as a transdiagnostic neuroinflammatory nexus across AD, BIP, MDD, and SCZ, orchestrating antigen presentation to CD4[+] T-helper cells. To bridge these genomic findings with cellular function, BV2 microglial profiling was performed to provide a cellular-context reference specifically for the identified immune risk component. This cellular model confirmed that the immunogenetic risk burden maps to a specific proinflammatory activation state characterized by upregulated neurotoxins (Lcn2, Nos2, Ccl2) and suppressed lipid transport/phagocytosis (Apoe, Cd68). Machine learning models leveraging these signatures achieved robust predictive performance, particularly for BIP and MDD. MR analyses uncovered causal roles of immune, lipid, and microbial pathways, with shared metabolic signatures (e.g., N-acetylarginine) across disorders. Integration with traditional medicine databases linked lipid metabolism to Artemisia argyi, suggesting novel therapeutic avenues. This integrative approach redefines the molecular framework of these disorders by highlighting systemic metabolic dysregulation and strongly implicating MHC Class II-mediated neuroinflammation as two convergent drivers, advancing precision psychiatry through targeted immunotherapies and metabolic modulators.},
}

@article {pmid42448676,
year = {2026},
author = {Luu, D and Twisselmann, AM and Tennant, VR and Hall, BJ and Mahajan, A and Kim, A and Terner, J and Davison, ML and Wheeler, K and Ching, CRK and Hall, J and Borzage, MT and Johnson, L and Toga, AW and O'Bryant, SE and Yaffe, K and Braskie, MN and , },
title = {Depression and hippocampal subfield volume in older adults.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04223-y},
pmid = {42448676},
issn = {2158-3188},
support = {U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG054073//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG058533//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG070862//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P41EB015922//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19AG078109//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; S10OD032285//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
abstract = {Depression is associated with a higher risk for developing Alzheimer's Disease (AD) [1], but the mechanisms that underlie the complex relationship between depression and AD remain largely elusive. The hippocampus is a region of the brain that is commonly affected by both AD and depression and serves as a focal point for our study. We aim to understand the relationship of 1) depression and antidepressant medications to hippocampal subfield volume during normal aging, and 2) whether AD risk, as measured by amyloid and tau pathology and APOE4 status, impacts these relationships. We studied 2009 ethno-racially diverse cognitively unimpaired older adults aged 50 to 90 years who either had depression (n = 630) or were not depressed (n = 1379). Participants with depression were further stratified by antidepressant medication usage. High-resolution MRI scans were used to calculate hippocampal subfield volumes that included the CA1, the subiculum, and a composite region that included the CA2, CA3, and the dentate gyrus (CA23DG). Having depression was associated with a smaller CA23DG, independent of amyloid and tau pathology in the brain. Within the subgroup of participants with depression, those who used antidepressant medications had smaller CA1 and CA23DG volumes than those who did not use these medications.},
}

@article {pmid42448798,
year = {2026},
author = {Radhakrishnan, K and Zhang, Y and Mustapha, O and Weigel, TK and Upchurch, CM and Tian, X and Herbert, F and Huang, W and Leitinger, N and Eyo, UB and Ai, H and Ferris, HA},
title = {7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in a mouse model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61753-7},
pmid = {42448798},
issn = {2045-2322},
support = {T32GM139787/NH/NIH HHS/United States ; R01AL168194/NH/NIH HHS/United States ; RF1AG077773/NH/NIH HHS/United States ; RF1AG077773/NH/NIH HHS/United States ; },
abstract = {Oxidative stress is a prominent feature of Alzheimer's disease (AD). Within this context, cholesterol undergoes oxidation, producing the pro-inflammatory product 7-ketocholesterol (7-KC). In this study, we observe elevated levels of 7-KC in the brains of the 3xTg mouse model of AD. To further understand the contribution of 7-KC on the oxidative environment, we developed a method to express a genetically encoded fluorescent hydrogen peroxide (H2O2) sensor in astrocytes, the primary source of cholesterol in the brain. With this sensor, we showed that 7-KC increases H2O2 levels in astrocytes in vivo, but not when directly applied to astrocytes in vitro. When 7-KC was applied to a microglia cell line alone or mixed astrocyte and microglia cultures, it resulted in microglia activation and increased oxidative stress in astrocytes. Depletion of microglia from 3xTg mice resulted in reduced 7-KC and reduced reactive oxygen species in astrocytes. Taken together, these findings suggest that 7-KC, via microglia activation, contributes to increased astrocyte oxidative stress in the 3xTg mouse model of AD. This study contributes to understanding one of the drivers of the vicious cycle of oxidative stress seen in mouse models of AD whereby increased reactive oxygen species drive cholesterol oxidation, resulting in additional oxidative stress.},
}

@article {pmid42448890,
year = {2026},
author = {Aumont, E and Trudel, L and Hall, BJ and Chan, T and Hosseini, SA and Macedo, AC and Therriault, J and Arias, JF and Lebrun, A and Oliva-Lopez, D and Rahmouni, N and Bezgin, G and Stevenson, J and Servaes, S and Fonov, V and Hsiao, C and Hopewell, R and Vitali, P and Klostranec, J and Montembeault, M and Iturria-Medina, Y and Baker, SL and Gauthier, S and Rosa-Neto, P},
title = {Using CA1 rather than the whole hippocampus to capture tau-PET Braak stage II.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42448890},
issn = {1619-7089},
support = {2020-VICO-279314//Fonds de Recherche du Québec - Santé/ ; 2024 VICO-356138//Fonds de Recherche du Québec - Santé/ ; CFI Project 34874//Fondation Brain Canada/ ; 33397//Fondation Brain Canada/ ; 152985//Institute of Aging/ ; 159815//Institute of Aging/ ; 162303//Institute of Aging/ ; Postdoctoral fellowship//Institute of Aging/ ; MOP-11-51-31//Consortium canadien en neurodégénérescence associée au vieillissement/ ; NIRG-12-92090/ALZ/Alzheimer's Association/United States ; NIRP-12-259245/ALZ/Alzheimer's Association/United States ; },
abstract = {PURPOSE: Tau-PET enables in-vivo staging of Alzheimer disease (AD) pathology, including early Braak stage II involvement of the hippocampus. Conventional whole-hippocampus definitions combine heterogeneous subfields and are susceptible to off-target signal that varies across tracers, limiting sensitivity, specificity, and longitudinal interpretability of early tau accumulation.

METHODS: Cross-sectional and longitudinal analyses were conducted in the TRIAD (N = 456) and the ADNI (N = 497) observational cohorts with tau-PET with [[18]F]MK-6240 or [[18]F]flortaucipir and structural MRI. A CA1-specific Braak stage II region of interest was compared with a whole-hippocampus approach. Outcomes included Braak stage concordance, longitudinal stability, tau-PET progression, and biological plausibility assessed by amyloid-PET burden and extrahippocampal tau signal.

RESULTS: Spatial analyses localised early hippocampal tau-PET signal predominantly to the anterior CA1. Whole-hippocampus measures were more frequently influenced by off-target signal consistent with choroid plexus contamination. Participants classified as CA1-based Braak stage II showed higher amyloid-PET burden, more consistent tau accumulation in the Braak stage III region, and more stable longitudinal progression. CA1-based staging yielded fewer discordant classifications and fewer stage regressions at follow-up.

CONCLUSION: CA1-specific tau-PET quantification improves biological plausibility and longitudinal consistency of Braak stage II classification by targeting the hippocampal subfield most vulnerable to early tau pathology and mitigating off-target contamination. CA1-based Braak stage II participants showed greater coherence with the biological framework of AD than those staged using the whole hippocampus. Applicable to available PET resolution, this approach may enhance characterisation of early AD and support participant selection in trials targeting preclinical tau accumulation.},
}

@article {pmid42448968,
year = {2026},
author = {Costa, AP and Acquarone, E and Lazarian, A and Herman, M and Wartchow, KM and Bartelo, N and Dartora, WJ and Krumsiek, J and Li, XL and Baskin, JM and Arancio, O and Hussaini, SA and McIntire, LB},
title = {Temporal and spatial control of phosphatidylinositides using optogenetics ameliorates behavioral deficits in an Alzheimer's disease mouse model.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-026-10517-0},
pmid = {42448968},
issn = {2399-3642},
support = {W81XWH-19-1-0817/GRANT12727289//U.S. Department of Defense (United States Department of Defense)/ ; GRANT13369767/GRANT13710486//U.S. Department of Defense (United States Department of Defense)/ ; 1R56AG072794/1R01AG072794//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; TL1TR001875/UL1TR001873//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; R01GM151682//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1R01NS110024//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {Deficits in levels of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] mediate Alzheimer's disease (AD) pathogenesis and etiology. The depletion of PI(4,5)P2 has been reported in AD in both human brain and animal models. Repletion of the synaptic pool of PI(4,5)P2, through haploinsufficiency of the degrading enzyme, Synaptojanin 1, ameliorated behavioral deficits in a mouse model of AD, in spite of accumulating amyloid. In order to refine the contribution of PI(4,5)P2 to AD, we used optogenetic translocation of the PI(4,5)P2-synthesizing enzyme, phosphoinositide phosphate 4 kinase2A (PIP4K2A) to the plasma membrane using light inducible dimerizable cryptochrome 2 (CRY-2) and the transcription factor CRY2-binding domain (CIBN) fused to the plasma membrane-targeting motif (CAAX). Spatiotemporally controlled production of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] at the plasma membrane induced amelioration of behavioral deficits in a mouse model of AD. Imaging mass spectrometry confirmed alteration of specific PI(4,5)P2 acyl species, di-oleate, indicating that precise PI(4,5)P2 species may ultimately be leveraged for therapeutic intervention.},
}

@article {pmid42449057,
year = {2026},
author = {Bukar, AM and Che Mohd Nassir, CMN and Ayuba, M and Manoharan, SD and Usman, AS and Umar, BI and Hein, ZM and Mohd Moklas, MA and Mehat, MZ and Abdul Hamid, H},
title = {Ficus deltoidea Preserves Hippocampal Neuronal Integrity and Redox Balance in Oxidative Stress-Driven Alzheimer's Disease-Like Rat Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42449057},
issn = {1559-1182},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Alzheimer Disease/pathology/drug therapy/metabolism ; Male ; Rats, Wistar ; *Ficus/chemistry ; *Hippocampus/pathology/drug effects/metabolism ; Disease Models, Animal ; *Neurons/drug effects/metabolism/pathology/ultrastructure ; Oxidation-Reduction/drug effects ; Aluminum Chloride ; *Plant Extracts/pharmacology/therapeutic use ; Galactose ; Neuroprotective Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology ; Rats ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide, with oxidative stress playing a central role in its pathogenesis. Ficus deltoidea (FD), a medicinal plant rich in flavonoids vitexin and isovitexin, possesses potent antioxidant and anti-inflammatory properties, yet its neuroprotective efficacy in AD remains incompletely characterized. This study investigated the protective effects of FD in a D-galactose- and aluminum chloride (AlCl3)-induced oxidative stress-driven AD-like rat model using behavioral, histological, ultrastructural, and biochemical approaches. Fifty-four male Wistar rats were assigned to six groups: control, AD-like model, donepezil (1 mg/kg), and FD-treated groups (50, 100, and 200 mg/kg) for 10 weeks. Anxiety-like behavior and spatial working memory were assessed using the elevated plus maze (EPM) and T-maze tests, respectively. Hippocampal neuronal integrity was evaluated by hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM), while oxidative stress biomarkers (MDA, CAT, T-SOD, CuZn-SOD, and HO-1) were quantified using ELISA. FD treatment, particularly at 200 mg/kg, significantly improved spatial working memory and normalized anxiety-related behavior, with treatment responses approaching those observed in the donepezil-treated group. Histological analyses revealed preservation of pyramidal neurons across CA1, CA2, CA3, and dentate gyrus subregions, while ultrastructural studies demonstrated marked protection of mitochondrial integrity, myelin sheath organization, and smooth endoplasmic reticulum morphology. Biochemically, FD significantly reduced lipid peroxidation and enhanced endogenous antioxidant defenses. In conclusion, FD exerted significant neuroprotective effects characterized by preservation of hippocampal structure, maintenance of neuronal ultrastructure, and restoration of redox homeostasis in an oxidative stress-driven AD-like model. These findings demonstrate that FD mitigates oxidative stress-associated neuronal injury and cognitive impairment in a D-galactose and AlCl3-induced AD-like rat model, supporting its potential as a phytotherapeutic candidate for oxidative stress-related neurodegeneration. However, further studies are required to determine its effects on canonical Alzheimer's disease pathologies, including amyloid and tau abnormalities.},
}

Animals
*Oxidative Stress/drug effects
*Alzheimer Disease/pathology/drug therapy/metabolism
Male
Rats, Wistar
*Ficus/chemistry
*Hippocampus/pathology/drug effects/metabolism
Disease Models, Animal
*Neurons/drug effects/metabolism/pathology/ultrastructure
Oxidation-Reduction/drug effects
Aluminum Chloride
*Plant Extracts/pharmacology/therapeutic use
Galactose
Neuroprotective Agents/pharmacology/therapeutic use
Antioxidants/pharmacology
Rats
Maze Learning/drug effects

@article {pmid42449130,
year = {2026},
author = {Macedo, AC and Trudel, L and Therriault, J and Rahmouni, N and Aumont, É and Bezgin, G and Hosseini, SA and Tissot, C and Chan, T and Servaes, S and Hall, B and Wang, YT and Quispialaya-Socualaya, K and Woo, MS and Fernandez-Arias, J and Stevenson, J and Zheng, Y and Gonçalves, MP and Lussier, FZ and Ferrari-Souza, JP and Ferreira, PCL and Bellaver, B and Povala, G and Amaral, LSD and Massarweh, G and Soucy, JP and Meeker, KL and Braskie, MN and Betthauser, TJ and Christian, BT and Rea Reyes, RE and Caldwell, JK and Ashton, NJ and Karikari, TK and Zetterberg, H and Blennow, K and Zimmer, ER and Benedet, AL and Johnson, SC and Pascoal, TA and Rosa-Neto, P and , },
title = {Spatiotemporal dynamics of tau extent and load increase in Alzheimer's disease across four longitudinal cohorts.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {42449130},
issn = {2662-8465},
support = {F225864C02; M159875C51//McGill University (McGill)/ ; },
abstract = {This longitudinal study including four independent cohorts assessed the spatiotemporal dynamics of tau extent and load changes in Alzheimer's disease using tau positron emission tomography data from 2,459 participants, including 898 followed for up to 7 years. Regional standardized uptake value ratios indexed tau load, whereas the spatial extent of tauopathy (SEOT) (proportion of abnormal voxels) measured tau extent. We observed burden-dependent longitudinal dynamics of tau progression: SEOT showed greater sensitivity to increases over time in regions with low baseline tau burden, whereas the standardized uptake value ratio was more informative for tracking accumulation once regional burden was established. This pattern was consistent across Braak regions and cohorts and was reflected in differential associations with other Alzheimer's disease severity markers. These findings refine models of tau propagation by suggesting that tau positron emission tomography changes may be differentially captured by extent-based and load-based metrics at different stages of disease progression, highlighting SEOT as a promising surrogate outcome for trials.},
}

@article {pmid42449162,
year = {2026},
author = {Zhang, F and Petersen, M and Mapstone, M and Hall, J and Handen, B and Christian, B and Head, E and Rosas, HD and Lai, F and Lee, JH and Krinsky-McHale, SJ and Schmitt, FA and Harp, J and Hom, C and Lott, IT and Hartley, S and Zaman, S and Ances, BM and Ptomey, L and Burns, JM and Cohen, AD and Brickman, AM and Bryant, SEO and , },
title = {Blood biomarkers predict conversion from cognitively stable to mild cognitive impairment or Alzheimer's disease in Down syndrome at 16-month follow-up in ABC-DS.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71659},
doi = {10.1002/alz.71659},
pmid = {42449162},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; //National Institute for Child Health/ ; U01 AG051406/AG/NIA NIH HHS/United States ; U01 AG051412/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; AG016573//NIH Programs/ ; P50 AG005133/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; //Eunice Kennedy Shriver Intellectual and Developmental Disabilities/ ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; UL1 TR002366/TR/NCATS NIH HHS/United States ; U24 AG21886/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *Down Syndrome/blood/complications ; *Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; Female ; Male ; *Cognitive Dysfunction/blood/diagnosis ; Disease Progression ; Longitudinal Studies ; Follow-Up Studies ; Middle Aged ; Support Vector Machine ; Sensitivity and Specificity ; },
abstract = {INTRODUCTION: Individuals with Down syndrome (DS) face high risk for Alzheimer's disease (AD), yet presymptomatic detection of cognitive decline is hindered by lifelong intellectual disability.

METHODS: Using data from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS), blood samples from 246 participants were analyzed, yielding 404 longitudinal observations (45 Converters, 359 Stable) collected at 0, 16, and 32 months were analyzed. A Support Vector Machine was trained on 25 plasma biomarkers spanning neurodegeneration, inflammation, and vascular health, along with demographic factors (age, sex, ethnicity, karyotype, apolipoprotein E [APOE ε4]). Batch-effect correction and feature selection were applied, resulting in 13 key markers.

RESULTS: The refined model achieved 92.4% sensitivity, 59.9% specificity, and an area under the curve (AUC) of 77.9%, accurately identifying individuals at risk of cognitive decline up to 16 months before clinical progression.

DISCUSSION: This multi-domain, blood-based machine learning approach demonstrates that plasma biomarkers are valuable non-invasive tools for early detection and risk stratification of cognitive decline in DS.},
}

Humans
*Down Syndrome/blood/complications
*Biomarkers/blood
*Alzheimer Disease/blood/diagnosis
Female
Male
*Cognitive Dysfunction/blood/diagnosis
Disease Progression
Longitudinal Studies
Follow-Up Studies
Middle Aged
Support Vector Machine
Sensitivity and Specificity

@article {pmid42449163,
year = {2026},
author = {Adefisan-Adeoye, AO and Oluwadamilare, H and Aisedion, M and Shittu, TS and Amangele, T and Adeoye, TD and Unuofin, JO and Orimolade, BM and Lebelo, SL and Adaramoye, OA},
title = {Neuromodulatory effects of berberine chloride against aluminum chloride/D-Galactose induced Alzheimer-like neurodegeneration model in rats.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-61600-9},
pmid = {42449163},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, neuroinflammation, and neuronal loss. This study evaluated the neuroprotective potential of berberine chloride (BC) against D-Galactose (D-Gal) and aluminum chloride (AlCl3)-induced Alzheimer-like neurodegeneration models in rats using donepezil as a standard drug. Animals were randomly assigned into four groups: control, AD-model (D-Gal 60 mg/kg/day, i.p.+AlCl3 200 mg/kg/day, orally), BC-treated (100 mg/kg/day), and donepezil-treated (2 mg/kg/day). The AD model exhibited significant cognitive deficits, evidenced by reduced spontaneous alternation (39%↓), prolonged escape latency (38%↑), and diminished locomotor activity. BC markedly enhanced endogenous antioxidant defense, elevating superoxide dismutase and catalase activities by 165% and 145% (p < 0.05), while reducing lipid peroxidation and nitric oxide levels in brain tissue (67%↓). BC also markedly suppressed advanced glycation end (AGEs) products by 37% (p < 0.05). Furthermore, BC improved cholinergic function by significantly lowering serum acetylcholinesterase activity (30%↓) and ameilorated hepatic and renal biochemical indices-AST (42%↓), ALT (55%↓), and urea (55%↓). Histopathological examination revealed preservation of hippocampal and cortical neuronal architecture, with reduced neurodegeneration and gliosis in BC-treated animals. Collectively, these findings demonstrate that BC exerts potent neuroprotective, antioxidant, anti-glycation, and anti-inflammatory effects, highlighting its promise as a multi-target candidate for cognitive impairment.},
}

@article {pmid42449182,
year = {2026},
author = {},
title = {Correction to "Systemic piezo1 activation improves cerebrovascular function in Alzheimer's disease".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71677},
doi = {10.1002/alz.71677},
pmid = {42449182},
issn = {1552-5279},
}

@article {pmid42449187,
year = {2026},
author = {Hansen, N and Sadlonova, M and Esselmann, H and Celano, CM and Derad, C and Asendorf, T and Hohberg, M and Chebbok, M and Heinemann, S and Morgado, B and Titsch, T and Packroß, K and Knopp, CM and Becker, MM and Günther, I and Krasiuk, I and Rediske, AI and Süttmann, NP and Itting, PT and Wirths, O and Kutschka, I and Baraki, H and von Arnim, CAF and Wiltfang, J and , },
title = {Early Alzheimer´s disease blood biomarkers are associated with a higher risk for postoperative long-term cognitive decline: Insights from the FINDERI study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71631},
doi = {10.1002/alz.71631},
pmid = {42449187},
issn = {1552-5279},
support = {#F/65/21//German Heart Foundation/German Foundation/ ; UIDB/04501/2020//iBiMED/ ; },
mesh = {Humans ; *Biomarkers/blood ; Female ; *Alzheimer Disease/blood ; Male ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; *Postoperative Cognitive Complications/blood ; Aged ; Risk Factors ; *Cardiac Surgical Procedures/adverse effects ; Peptide Fragments/blood ; *Cognitive Dysfunction/blood ; Apolipoprotein E4/blood ; Apolipoproteins E/blood ; *Postoperative Complications/blood ; Neuropsychological Tests ; },
abstract = {BACKGROUND: The study aim is to investigate whether blood biomarkers (BBMs) of Alzheimer's disease (AD) pathology are associated with postoperative cognitive dysfunction (POCD) after cardiac surgery.

METHODS: Cognitive performance was assessed before and 12 months postoperatively using the Montreal Cognitive Assessment (MoCA) and categorized into stages-minimal (1), notable (2), and substantial (3) decline-in the FIND DElirium RIsk factors (FINDERI) study of patients undergoing cardiac surgery. BBMs were measured preoperatively (amyloid beta [Aβ]1-42, Aβ1-40, phosphorylated tau 181 [p-tau181], p-tau217, apolipoprotein E ε4 [apoE4] and apoE).

RESULTS: A total of 394 patients completed follow-up investigations. POCD Stage 1 was observed in 105 (26.6%), POCD Stage 2 in 52 patients (13.2%), and POCD Stage 3 in 30 patients (7.6%). The AT[217]term (ratio Aβ1-40/1-42 * p-tau217) was significantly associated with POCD stages in multiple logistic regression.

DISCUSSION: Early Alzheimer's BBMs are associated with POCD in patients, suggesting that our exploratory findings assessing BBMs may support risk stratification, inform decision-making, and contribute to strategies aimed at preventing POCD.},
}

Humans
*Biomarkers/blood
Female
*Alzheimer Disease/blood
Male
tau Proteins/blood
Amyloid beta-Peptides/blood
*Postoperative Cognitive Complications/blood
Aged
Risk Factors
*Cardiac Surgical Procedures/adverse effects
Peptide Fragments/blood
*Cognitive Dysfunction/blood
Apolipoprotein E4/blood
Apolipoproteins E/blood
*Postoperative Complications/blood
Neuropsychological Tests

@article {pmid42449193,
year = {2026},
author = {Shaikh, M and Fletcher, P and Zaman, S and , and Brown, S},
title = {Structural MRI across lifespan reveals differential thalamic trajectories in Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71671},
doi = {10.1002/alz.71671},
pmid = {42449193},
issn = {1552-5279},
support = {ARUK-RF2021B-001//Alzheimer's Research UK/ ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; },
mesh = {Humans ; *Down Syndrome/pathology/diagnostic imaging/blood ; *Thalamus/pathology/diagnostic imaging ; Male ; Female ; *Magnetic Resonance Imaging ; Middle Aged ; Adult ; Biomarkers/blood ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Alzheimer Disease/pathology ; Neurofilament Proteins/blood ; },
abstract = {INTRODUCTION: Up to 90% of Down syndrome (DS) patients develop Alzheimer's disease (AD). Sleep disturbance, affecting over 75% of DS patients, is implicated in AD pathogenesis. The thalamus, central to sleep and arousal, shows early vulnerability in DS-related AD.

METHODS: Structural 3T MRI scans from 253 DS participants (119 males, mean age 43.0 ± 9.4 years) and 36 controls (30 males, mean age 43.1 ± 12.2 years) from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study were analyzed, alongside neurodegenerative plasma biomarker assays (phosphorylated tau [pTau]181, pTau217, neurofilament light chain [NfL], amyloid beta [Aβ]40, Aβ42).

RESULTS: In DS, intracranial volume-adjusted thalamic volume declined with age (t = -2.589, p = 0.00987), approximating 2.5% loss per decade. This was linear, gray matter involution-independent, and heterogeneous across nuclei, correlating negatively with pTau and NfL. Controls exhibited no significant volumetric changes.

DISCUSSION: Anteromedial and posterior thalamic shrinkage in DS AD mirrors sporadic AD. Associations with neurodegenerative biomarkers support thalamic atrophy as a sensitive marker of DS-related AD progression.},
}

Humans
*Down Syndrome/pathology/diagnostic imaging/blood
*Thalamus/pathology/diagnostic imaging
Male
Female
*Magnetic Resonance Imaging
Middle Aged
Adult
Biomarkers/blood
tau Proteins/blood
Amyloid beta-Peptides/blood
Alzheimer Disease/pathology
Neurofilament Proteins/blood

@article {pmid42449194,
year = {2026},
author = {Kennedy, JT and Wisch, JK and Handen, BL and Hartley, S and Brickman, AM and Lee, JH and Krinsky-McHale, S and Lai, F and Rosas, H and Head, E and Christian, B and Zaman, S and Lott, IT and Hom, C and Ptomey, LT and Burns, JM and Cohen, A and Tudorascu, D and Laymon, C and Lao, P and Petersen, M and Schmitt, F and Ances, BM},
title = {Age predicts Alzheimer's in Down syndrome better than MRI, plasma, or cognition.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71661},
doi = {10.1002/alz.71661},
pmid = {42449194},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; U01 AG051406/AG/NIA NIH HHS/United States ; U01 AG051412/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P50 AG16537//The Alzheimer's Disease Research Centers Program/ ; P50 AG005133/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; U54 HD090256/HD/NICHD NIH HHS/United States ; U54 HD087011/HD/NICHD NIH HHS/United States ; P50 HD105353/HD/NICHD NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; U24 AG21886//National Centralized Repository for Alzheimer Disease and Related Dementias/ ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; //NIHR Cambridge Biomedical Research Centre and the Windsor Research Unit, CPFT, Fulbourn Hospital Cambridge, UK/ ; },
mesh = {Humans ; *Down Syndrome/complications/blood/diagnostic imaging ; *Alzheimer Disease/diagnosis/blood/complications/diagnostic imaging ; Female ; Magnetic Resonance Imaging ; tau Proteins/blood ; Male ; Biomarkers/blood ; Middle Aged ; Cognitive Dysfunction/diagnosis ; Aged ; *Cognition/physiology ; *Aging ; Amyloid beta-Peptides/blood ; ROC Curve ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) dementia in Down syndrome (DS) occurs at predictable ages. It is unclear whether age can differentiate across AD stages (amyloid positivity, tau positivity, mild cognitive impairment [MCI], dementia).

METHODS: Using data from the Alzheimer's Biomarker Consortium-Down Syndrome, we analyzed how well age differentiated stage using receiver operating characteristic curves. We compared areas under the curve (AUC) for age to AUCs for imaging, biofluid, cognitive, motor, and behavioral variables.

RESULTS: Sample varied by stage and variable. Up to 148 variables and 461 participants were analyzed. Age effectively differentiated amyloid positivity, tau positivity, and MCI (AUCs > 0.85) but poorly discriminated MCI from dementia (0.588). No variable was better than age in distinguishing stages, except for MCI/dementia.

DISCUSSION: Our results show that age alone is effective at staging DS AD. Age is the most reliable correlate of amyloid, tau status, and cognitive impairment in DS and could screen for future clinical trials.},
}

Humans
*Down Syndrome/complications/blood/diagnostic imaging
*Alzheimer Disease/diagnosis/blood/complications/diagnostic imaging
Female
Magnetic Resonance Imaging
tau Proteins/blood
Male
Biomarkers/blood
Middle Aged
Cognitive Dysfunction/diagnosis
Aged
*Cognition/physiology
*Aging
Amyloid beta-Peptides/blood
ROC Curve
Neuropsychological Tests

@article {pmid42449255,
year = {2026},
author = {Okutucu, M and Arpa, M},
title = {Evaluation of serum semaphorin-3A and interleukin 6 levels in patients with neovascular age-related macular degeneration.},
journal = {BMC ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12886-026-05128-6},
pmid = {42449255},
issn = {1471-2415},
abstract = {PURPOSE: To determine whether serum semaphorin 3 A (Sema3A) and interleukin 6 (IL-6) play a role in the common etiopathogenesis of nAMD and nAMD-associated systemic diseases by evaluating these mediators levels.

METHODS: This prospective case-control study included 74 patients divided into nAMD (n = 33) and a control group (n = 41). Serum Sema3A and IL-6 levels were analyzed using the enzyme-linked immunosorbent assay.

RESULTS: The nAMD group had a statistically higher IL-6 level [5,9 (1-16,9) pg/mL], compared to the control group [1,5 (0,38 - 2,96) pg/mL] (p < 0.001). On the other hand, the Sema3A level of the nAMD group was lower at [26,3 (11,5-100) ng/mL] compared to the control group at [44,7 (16,8-100) ng/mL] (p < 0.001). The IL-6 level in the hypertension (+) group [2,5 (0,5-16,9) pg/ml] was significantly higher than that in the hypertension (-) group [1,7 (0,4-15,3) pg/ml] (p < 0.001). No significant difference was found between the hypertension (+) and hypertension (-) groups in terms of SEMA3A level. There was a negative correlation between serum SEMA3A and serum IL-6 levels of the whole participants (p < 0.001, r=-0.471).

CONCLUSIONS: Decreased levels of the anti-inflammatory and anti-angiogenic mediator Sema3A and increased levels of inflammatory mediator IL-6 detected in nAMD suggest that these molecules may play a role in systemic manifestations of this syndrome, such as inflammation, cardiovascular diseases, atrial fibrillation, and Alzheimer's disease.

CLINICAL TRIAL NUMBER: Not applicable.},
}

@article {pmid42449379,
year = {2026},
author = {Suksangkharn, Y and Schott, BH and Zeidman, P and Vockert, N and Lattmann, R and Schütze, H and Yakupov, R and Peters, O and Hellmann-Regen, J and Preis, L and Ersözlü, E and Priller, J and Spruth, EJ and Beckmann, J and Schneider, A and Fliessbach, K and Wiltfang, J and Bartels, C and Rostamzadeh, A and Glanz, W and Incesoy, EI and Teipel, S and Kilimann, I and Goerss, D and Laske, C and Spottke, A and Kronmüller, M and Brosseron, F and Lüsebrink, F and Schmid, M and Kleineidam, L and Stark, M and Hetzer, S and Dechent, P and Jessen, F and Maass, A and Düzel, E and Ziegler, G},
title = {Disruption of temporo-parietal network in Alzheimer's disease and its association with memory impairment.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02138-w},
pmid = {42449379},
issn = {1758-9193},
abstract = {Alzheimer's disease (AD) is characterised by the accumulation of β-amyloid (Aβ) and tau proteins, resulting in neurodegeneration and cognitive decline. Although Aβ and tau disrupt synaptic function, the association linking these molecular pathologies to network-level dysfunction and memory impairment remains poorly understood. Here, we investigated the effects of Aβ and tau pathology (CSF Aβ42/40 ratio and tau phosphorylated at position 181, p-tau-181, respectively) on effective connectivity related to memory encoding, which may provide a link between synaptic pathology and cognitive outcomes. Functional magnetic resonance imaging (fMRI) during visual memory encoding was acquired from 205 participants in the multicentric DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) across the AD spectrum. Effective connectivity was assessed using Dynamic Causal Modelling (DCM) of task-fMRI data, focusing on the parahippocampal place area (PPA), hippocampus (HC), and precuneus (PCU)-regions central to memory encoding. Disruptions in connectivity between temporal and parietal lobes were associated with both memory impairment and indices of AD pathology. Specifically, reduced positive effective connectivity from the PCU to the PPA and from the HC to the PCU were linked to higher p-tau-181 levels, with an amplification effect observed in the presence of amyloid accumulation for the latter connectivity. The disruption from the PCU to the PPA was found to be associated with decreased memory performance. Together, these findings indicate that temporo-parietal connectivity is associated with both AD molecular pathology and, for a subset of connections, with memory performance.},
}

@article {pmid42449394,
year = {2026},
author = {Hu, W and Zou, Y and Yin, J and Liu, L and Ding, Y and Gao, X and Li, Y and Kong, X},
title = {Unknotting the nexus of asthma and neuroinflammation: from brain network alterations to therapeutic implications.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03955-4},
pmid = {42449394},
issn = {1742-2094},
support = {2023059//Tianjin Municipal Health Commission Research Project/ ; 2024021//Tianjin Traditional Chinese Medicine Key Research Area Project/ ; 2023ZD036//Tianjin Municipal Education Commission Research Project/ ; ZR2024QH041//Natural Science Foundation of Shandong Province/ ; QDKY2023ZD02//Scientific Research Foundation of Qilu Hospital of Shandong University/ ; 2024-WJKY155//Medical and Health Scientific Research Project of Qingdao/ ; },
abstract = {Asthma is increasingly recognized as a systemic inflammatory syndrome that extends beyond the respiratory tract, with emerging evidence highlighting its relevance to neuroinflammation. The lung-brain axis-via interconnected inflammatory, vascular, metabolic, neural, and microbial pathways-provides a framework for understanding how chronic pulmonary disease may sustain or exacerbate neuroinflammatory processes. Mechanistically, asthma promotes blood-brain barrier disruption, systemic inflammation that seeds central neuroinflammation, oxidative stress, mitochondrial dysfunction, gut-lung-brain microbial crosstalk, and sleep fragmentation, all of which are biologically plausible drivers of sustained neuroinflammatory states and consequent neurodegenerative vulnerability. Epidemiological studies link asthma to increased risks of all-cause dementia and Alzheimer's disease, though cohort findings vary. Neuroimaging and biomarker evidence further support neuroinflammatory involvement, revealing altered hippocampal metabolism, white matter abnormalities, elevated plasma glial fibrillary acidic protein and neurofilament light chains, and cerebrospinal fluid markers of synaptic injury in severe or poorly controlled asthma-each reflecting neuroinflammatory or neurodegenerative sequelae. Links with Parkinson's disease and other neurodegenerative disorders remain more preliminary. Notably, asthma severity, phenotype, exacerbation frequency, and corticosteroid burden modulate neurological risk, suggesting that optimal disease control-potentially enhanced by biologic therapies-may confer neuroprotective benefits by dampening neuroinflammation. In conclusion, asthma should not be viewed solely as an airway disorder but as a potentially modifiable contributor to long-term brain vulnerability via neuroinflammatory pathways within the lung-brain axis. Future longitudinal studies integrating detailed phenotyping, biomarkers, and neuroimaging are needed to establish causality and guide anti-neuroinflammatory therapeutic strategies.},
}

@article {pmid42449395,
year = {2026},
author = {Jang, H and Kim, JW and Hwang, JW and Jeong, DW and Ka, J and Kang, DM and Suh, CH and Choi, Y and Oh, M and Kim, JS and Lim, JS and Lee, JH},
title = {Real-world safety and implementation challenges of lecanemab therapy for Alzheimer's disease in South Korea: a single-center experience.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02141-1},
pmid = {42449395},
issn = {1758-9193},
support = {RS-2022-KH125667//Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare and Ministry of science and ICT, Republic of Korea/ ; 2022-IF-0022//Asan Institute for Life Sciences/ ; },
abstract = {BACKGROUND: Lecanemab, an amyloid-targeting monoclonal antibody, was recently approved for early symptomatic Alzheimer's disease in South Korea. Asians were underrepresented in prior trials, and real-world data from Korea remain scarce, particularly regarding treatment settings, adverse events, and barriers to scalability. We assessed the feasibility and safety of lecanemab among Korean patients in a real-world tertiary hospital.

METHODS: A total of 112 patients initiated lecanemab treatment between December 2024 and October 2025 at Asan Medical Center. Prevalence of infusion-related reactions (IRRs), Amyloid-Related Imaging Abnormalities (ARIA), treatment discontinuation, and factors limiting implementation were evaluated.

RESULTS: Among 112 patients (mean age 71 years; 59% female), IRRs occurred in 41 (37%) and were generally mild or moderate under active surveillance. Among 105 at-risk patients who received at least four infusions and had at least one monitoring MRI, ARIA developed in 20 (19%): ARIA-E/H in 6 (5.7%) and isolated ARIA-H in 14 (13.3%). Only 1 patient with isolated ARIA-H presented with transient confusion. Patients with ARIA-E/H were younger, whereas those with ARIA-H were older and more likely to have baseline microhemorrhages. Eleven out of 105 were APOE ε4/ε4 homozygotes, of whom 5 developed ARIA. The rapid increase in treatment demand exceeded outpatient infusion capacity, resulting in progressively longer waiting times-up to 20 weeks 9 months after program initiation.

CONCLUSION: This single-center experience from a tertiary referral hospital in Korea demonstrates that lecanemab treatment was feasible and generally well-tolerated, with manageable adverse events including ARIA and IRRs; however, limited infusion capacity, lack of reimbursement, and patient concentration in tertiary centers highlight the need for referral networks and system-level strategies to improve nationwide accessibility.},
}

@article {pmid42449404,
year = {2026},
author = {Azami, H and Antonacci, Y and Blumberger, DM and Brooks, H and Faes, L and Fischer, CE and Flint, A and Herrmann, N and Kumar, S and Gallagher, D and Mah, L and Mulsant, BH and Schoer, N and Pollock, BG and Rajji, TK and , },
title = {Three-order interactions in the alpha band of default mode network EEGs based on O-information rate: insights from aging and Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02131-3},
pmid = {42449404},
issn = {1758-9193},
abstract = {BACKGROUND: Alpha-band default mode network (DMN) connectivity declines with aging and Alzheimer's disease (AD), yet most electroencephalography (EEG) connectivity studies used pairwise (two-order) measures, such as mutual information rate (MIR). We leveraged O-information rate (OIR) to quantify three-order interactions and to separate redundant from synergistic information processing across frontal, temporal, and parietal DMN regions. We hypothesized that, extending established findings of reduced pairwise connectivity, (i) OIR (and its components) would be reduced in older versus younger adults and in AD versus healthy controls (HC); (ii) combining MIR with OIR would improve classification compared with MIR alone; and (iii) OIR measures would correlate positively with global cognition (as assessed by the Montreal Cognitive Assessment (MoCA)).

METHODS: Resting-state EEG from two samples-healthy adult lifespan aging (95 younger; 93 older) and AD spectrum (44 HC; 84 amnestic mild cognitive impairment [aMCI]; 41 AD)-was source-localized using eLORETA to DMN regions. Alpha band (8-13 Hz) MIR and OIR were computed through multivariate spectral analysis. Group differences were tested using t-tests or analysis of covariance (ANCOVA) with multiple comparison correction. Classification (OIR, MIR, demographic, and combined feature sets) used cross-validated logistic-regression, linear-SVM, and random-forest models, with bootstrap 95% confidence intervals and DeLong tests for AUC comparisons.

RESULTS: OIR and its redundancy component were significantly reduced in older versus younger adults and in AD versus HC/aMCI, with no HC-aMCI differences. The synergy component showed no group differences. MIR decreased broadly with aging and fronto-parietally in AD. Regarding classification (AD spectrum dataset, cross-validated AUC), OIR-based metrics outperformed MIR (AD vs. HC: 0.93 vs. 0.73; AD vs. aMCI: 0.93 vs. 0.71; aMCI vs. HC: 0.48 vs. 0.46). Combining demographics with all information-theoretic features improved AD vs. HC (0.98; DeLong p = 0.023) but not AD vs. aMCI (0.93), where OIR alone was already at ceiling; no feature set exceeded chance for aMCI vs. HC. After correction, OIR and its redundancy component correlated positively with MoCA scores; MIR and the synergy component did not.

CONCLUSIONS: Alpha-band three-order DMN interactions-particularly redundant information processing-decline with aging and AD and provide additional information beyond two-order connectivity for diagnostic classification. OIR offers complementary measures to traditional metrics, and future studies should examine its value when combined with more established AD biomarkers.},
}

@article {pmid42449489,
year = {2026},
author = {Research International, B},
title = {RETRACTION: Effects of Phoenix dactylifera against Streptozotocin-Aluminium Chloride Induced Alzheimer's Rats and Their In Silico Study.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {e9797803},
doi = {10.1155/bmri/9797803},
pmid = {42449489},
issn = {2314-6141},
}

@article {pmid42449500,
year = {2026},
author = {Buckley, RF and Townsend, DL and Birkenbihl, CJ and Cuppels, M and Coughlan, GT and Seto, MT and Brown, JA and Properzi, MJ and Hönig, MC and Li, A and Schultz, AP and Chhatwal, J and Yang, HS and Arnold, S and Kivisäkk, P and James, BD and O'Bryant, S and Rissman, RA and Petersen, M and Caldwell, JZK and Betthauser, T and Oomens, JE and Carrigan, M and Healy, B and Condado, JG and Johnson, SC and Yau, WW and Langford, O and Farrell, M and Amariglio, RE and Rentz, DM and Papp, KV and Brookmeyer, R and Hohman, TJ and Donohue, M and Aisen, PS and Johnson, KA and Sperling, RA and , and , },
title = {Prognostic Value of Blood-Based P-Tau217 Levels for Progression to Cognitive Impairment.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.12556},
pmid = {42449500},
issn = {1538-3598},
abstract = {IMPORTANCE: Blood-based biomarkers for Alzheimer disease, particularly plasma phosphorylated tau 217 (p-tau217), accurately reflect early Alzheimer disease brain pathology in cognitively unimpaired individuals, but estimates of absolute risk of progression to cognitive impairment across multiple cohorts are needed.

OBJECTIVE: To estimate absolute risk of progression to cognitive impairment and rates of cognitive decline based on plasma p-tau217 across cognitively unimpaired older adults.

Longitudinal cohort study using harmonized data from 2684 cognitively unimpaired older adults (defined within cohort) across 6 observational and clinical trial cohorts based in North America, Japan, and Australia. The earliest enrollment was in 2004, with most recent follow-up in 2025.

EXPOSURE: Baseline plasma p-tau217.

MAIN OUTCOMES AND MEASURES: The primary outcome was time to progression to cognitive impairment (mild cognitive impairment, dementia, or 2 consecutive global Clinical Dementia Rating scores ≥0.5). The secondary outcome was longitudinal change on the latent Preclinical Alzheimer Cognitive Composite (PACC; higher values indicate better performance).

RESULTS: Among the 2684 participants (median [IQR] age, 69.6 [66.2-74.2] years; 1697 [63%] female), there were 478 events of progression to cognitive impairment over a median follow-up of 5.4 years (maximum follow-up of 13.5 years). Each 1-SD increase in baseline p-tau217 level was associated with an increased risk of progression to cognitive impairment (hazard ratio, 1.38 [95% CI, 1.30-1.46]), and the association remained significant after adjustment, including β-amyloid positron emission tomography scan Centiloids (hazard ratio, 1.32 [95% CI, 1.24-1.41]). Participants with high (1.1-2.4 SD) and very high (>2.5 SD) baseline p-tau217 had 24% (95% CI, 20%-28%) and 38% (95% CI, 33%-43%) absolute risk of progression over 5 years, respectively, and risk was markedly higher over 10 years, although longer-term estimates were constrained by limited data. Elevated p-tau217 was also associated with faster cognitive decline based on change in latent PACC score. Among the overall sample, baseline latent PACC scores ranged from -0.8 to 2.7. The 5-year annualized decline for the very high p-tau217 group was -0.07 latent PACC units/y (95% CI, -0.10 to -0.05), relative to 0.03 units/y (95% CI, 0.02-0.04) in the low p-tau217 group.

CONCLUSIONS AND RELEVANCE: In a pooled sample of multiple selected cohorts of cognitively unimpaired older adults, higher plasma p-tau217 levels were consistently associated with increased risk of clinical progression and accelerated cognitive decline. By providing time-specific absolute risk estimates, these findings support the potential of p-tau217 for prognostic model development, with direct implications for future trial design. Further validation in unselected populations is needed to inform individual prognosis and clinical decision-making in cognitively unimpaired individuals.},
}

@article {pmid42449502,
year = {2026},
author = {Schindler, SE and Wolk, DA},
title = {Predicting Risk of Cognitive Impairment With Alzheimer Disease Blood Biomarkers.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.13322},
pmid = {42449502},
issn = {1538-3598},
}

@article {pmid42449559,
year = {2026},
author = {Tsai, HY and Chang, CI and Yeh, YT and Tsai, PL and Lin, YL and Ho, CT and Chen, YK},
title = {An acetylated nobiletin derivative alleviates methylglyoxal-induced cognitive impairment and modulates gut microbiota.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70887},
pmid = {42449559},
issn = {1097-0010},
support = {//National Science and Technology Council/ ; },
abstract = {BACKGROUND: Nobiletin, a citrus polymethoxyflavone recognized as a functional food component with diverse health benefits, has been reported to exhibit antioxidant, anti-inflammatory and neuroprotective properties. Methylglyoxal (MG), a highly reactive dicarbonyl compound and precursor of advanced glycation end products, contributes to oxidative stress, tau hyperphosphorylation and amyloid-β (Aβ) accumulation, which are key events linking diabetes to Alzheimer's disease. In this study, an acetylated derivative of nobiletin, 5-acetoxy-6,7,8,3',4'-pentamethoxyflavone (5-AN), was evaluated for its neuroprotective and gut microbiota-modulating effects against MG-induced Alzheimer-like cognitive deficits in mice.

RESULTS: Oral administration of 5-AN (10 and 20 mg kg[-1] day[-1] for 13 weeks) improved behavioral performance in MG-treated mice, with the 20 mg kg[-1] group showing significant improvement in spatial learning, recognition memory and anxiety-like behavior. Immunohistochemical and Western blot analyses showed that 5-AN reduced hippocampal tau phosphorylation and Aβ accumulation at the same time as restoring phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β signaling, enhancing brain-derived neurotrophic factor expression and reducing cleaved caspase-3 expression. Gut microbiota analysis showed that MG exposure induced dysbiosis, characterized by reduced Bacteroides_H acidifaciens and increased MG-associated taxa such as Alistipes and Dysosmobacter, whereas 5-AN supplementation significantly reversed these alterations. Functional prediction analysis further indicated that MG-induced dysbiosis was associated with disruptions in neuroimmune-related pathways, including circadian entrainment, Th17 cell differentiation, interleukin-17 signaling and PI3K/Akt signaling, whereas 5-AN supplementation significantly restored these pathways.

CONCLUSION: These findings indicate that acetylated nobiletin may serve as a promising food-derived bioactive compound for mitigating cognitive impairment through coordinated modulation of neuronal function and gut microbiota. © 2026 Society of Chemical Industry.},
}

@article {pmid42449771,
year = {2026},
author = {Sotoudeh, H and Alizadeh, M},
title = {The Centiloid Scale in Amyloid PET Imaging: Current Role in Alzheimer's Disease Diagnosis, Treatment Planning, and Monitoring During Anti-Amyloid Therapy: A Clinical Perspective.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {13},
pages = {},
doi = {10.3390/diagnostics16131989},
pmid = {42449771},
issn = {2075-4418},
abstract = {Amyloid positron emission tomography (PET) has become a critical tool in the diagnosis and treatment of Alzheimer's disease (AD). The Centiloid (CL) scale, a tracer/scanner-independent, standardized quantification unit introduced in 2015, transforms tracer- and scanner-specific standardized uptake value ratios (SUVRs) into a common metric anchored at 0 CL in young cognitively unimpaired individuals and 100 CL in patients with mild-to-moderate AD. This review synthesizes current evidence on the clinical role of the CL scale across three domains: (1) diagnostic classification, with established thresholds of <10 CL for amyloid negativity and >30 CL for high-certainty amyloid positivity; (2) treatment eligibility, where a 2024 Alzheimer's Association Research Roundtable consensus of global experts recommended a 24-30 CL threshold for initiating lecanemab or donanemab therapy in patients with mild cognitive impairment (MCI) or mild AD dementia; and (3) longitudinal therapy monitoring, in which serial CL measurements provide objective evidence of amyloid clearance. We also review the emerging 'gray zone' (10-30 CL) as a distinct clinical entity with elevated progression risk, the critical role of CL quantification in complementing visual reads in borderline cases, technical limitations, and the future integration of CL in clinical practice. This review also critically addresses the ongoing debate on whether amyloid clearance represents a reliable surrogate for clinical benefit, strategies for managing discordant biomarker findings, and the practical feasibility of serial amyloid PET in routine care. With FDA approval of both lecanemab and donanemab, familiarity with the CL scale as a functional treatment biomarker is increasingly relevant for neuroradiologists and nuclear medicine physicians in the modern AD care pathway. As with all imaging modalities, the CL has physiologic and technical limitations. Although the CL scale was designed to reduce heterogeneity across tracers and scanner platforms, the impact of different commercial quantification software packages on CL output remains incompletely characterized. Consistent use of a single software platform for longitudinal monitoring in individual patients is therefore recommended.},
}

@article {pmid42449811,
year = {2026},
author = {Gasmi, K and Ammar, LB and Krichen, M and Alghuried, A},
title = {FLAME: Federated Learning and Aggregated Multi-Model Ensemble for Multi-Class Alzheimer's Disease Stage Classification from Structured Clinical Data.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {13},
pages = {},
doi = {10.3390/diagnostics16132029},
pmid = {42449811},
issn = {2075-4418},
support = {PSAU/2024/03/31787//Prince Sattam Bin Abdulaziz University/ ; },
abstract = {Background/Objectives: The precise identification of Alzheimer's disease (AD) stages through clinical data is crucial for early diagnosis and suitable therapy. This classification remains troublesome due to overlap in cognitive profiles across different phases of illness progression. This study presents a comprehensive and advanced diagnostic system, termed FLAME, featuring an enhanced federated learning architecture for privacy-preserving multi-institutional implementation. It provides a systematic review of machine learning (ML) and deep learning (DL) models for the classification of five stages of Alzheimer's disease (AD). The models include cognitively normal (CN), subjective memory complaints (SMC), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and Alzheimer's disease (AD). Methods: Sixteen traditional machine learning models and eleven deep learning architectures-including FT-Transformer and NODE-were evaluated using a structured clinical dataset comprising 362 features. A hybrid ensemble was created at the probability level by combining the two top-performing models, LightGBM and a five-layer DNN. The weights of this ensemble were automatically optimised using a Genetic Algorithm (GA) with Macro-F1 as the fitness criterion, confirmed stable across 30 independent runs (w★=0.5024±0.0001). A federated learning architecture was then established, deploying the DNN across non-IID clients while keeping LightGBM centralised. We examine four distinct aggregation algorithms: FedAvg, FedProx, FedNova, and SCAFFOLD. Results: Among all deep learning architectures, FT-Transformer achieved the highest standalone performance (accuracy = 0.7810, κ = 0.7081). The five-layer deep neural network (DNN) was selected as the DL representative for the hybrid ensemble. LightGBM attained superior machine learning performance (accuracy = 0.8156, κ = 0.7537), confirmed deterministic across 10 seeds. The LightGBM vs. XGBoost difference is not statistically significant (McNemar p=0.4227). The GA-optimised hybrid ensemble (w = 0.685) surpassed both individual baselines across all evaluation metrics. The FedNova hybrid design achieved superior overall performance in federated configurations, surpassing all centralised arrangements in accuracy (accuracy = 0.8213, κ 0.7614). Conclusions: Evolutionary ensemble optimisation combined with federated learning provides a robust, scalable, and privacy-preserving solution for AD stage classification, offering a clinically viable framework for real-world multi-institutional decision-support systems. However, the AD class remains severely under-recalled across all configurations (F1 ≤ 0.21), identifying this as the primary open challenge for clinical translation.},
}

@article {pmid42449815,
year = {2026},
author = {Camoni, L and Dondi, F and Pietrzak, A and Rinaldi, R and Tomasoni, F and Cossandi, M and Lucchini, S and Viganò, GL and Spiazzi, L and Bertagna, F},
title = {Technical Optimization Strategies for Amyloid PET Under Challenging Acquisition Conditions: A Comprehensive Narrative Review.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {13},
pages = {},
doi = {10.3390/diagnostics16132033},
pmid = {42449815},
issn = {2075-4418},
abstract = {Amyloid PET is increasingly used to confirm cerebral amyloid burden, but standard acquisition may be compromised by head motion, limited patient cooperation, reduced effective counts, premature scan termination, or non-repeatable imaging conditions. This comprehensive narrative review used a structured evidence-mapping approach in accordance with SANRA quality criteria. A structured literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science up to 15 March 2026. Eligible studies included clinical, phantom, or hybrid studies addressing acquisition-time reduction, injected-activity reduction or low-count imaging, motion correction, or artificial intelligence-based image enhancement. Findings were synthesized narratively because of substantial heterogeneity in tracers, scanners, protocols, reconstruction methods, populations, comparators, and endpoints. Sixteen studies were included. Moderate reductions in acquisition time or effective counts generally preserved semiquantitative performance, whereas visual interpretation became more vulnerable under more aggressive reductions, borderline amyloid status, or reduced image quality. Artificial intelligence-based restoration improved image-quality metrics and supported interpretation of short- or low-count acquisitions, but evidence remained model-specific. Motion correction was supported by one amyloid-specific [[18]F]flutemetamol PET/CT study and should be interpreted as a potentially useful but under-replicated strategy. Current evidence supports cautious, tracer-, scanner-, reconstruction-, and task-specific optimization under challenging acquisition conditions rather than universal protocol reduction or direct generalization to motion-prone, poorly cooperative, or non-repeatable acquisition scenario. Reduced protocols, artificial intelligence-based restoration, and motion correction should remain locally validated supportive strategies, not substitutes for standard acquisition.},
}

@article {pmid42449841,
year = {2026},
author = {Schlichtmann, B and Arslan, B and Johnson, K and Patzlaff, J and Unruh, D and Szabo, M and Holland, M and Todtleben, J and Salvati, M and Tan, K and Andreasson, U and Hinson, J and Levin, S and Zetterberg, H and Benedet, AL and Hill, HA},
title = {Analytical Performance and Evaluation in Clinical Cohorts of a Fully Automated Immunoassay for Plasma Glial Fibrillary Acidic Protein.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {13},
pages = {},
doi = {10.3390/diagnostics16132060},
pmid = {42449841},
issn = {2075-4418},
support = {2023-00356//Swedish Research Council/ ; },
abstract = {Background/Objectives: This study aimed to perform analytical validation and evaluation of the clinical performance of the Access Glial Fibrillary Acidic Protein (GFAP) research-use-only (RUO) immunoassay (Beckman Coulter) in plasma. Methods: A fully automated GFAP immunoassay was developed and evaluated for analytical validity and clinical performance. Analytical validation assessed precision, sensitivity, linearity, analytical specificity, and the stability of calibrators and samples. Evaluation of predefined clinical performance criteria included method comparison against the Quanterix Simoa GFAP Advantage Plus (RUO) assay and assessment of GFAP levels between participants with Alzheimer's disease (AD) and healthy controls. Results: The Access GFAP (RUO) immunoassay met all analytical criteria. Precision yielded coefficients of variation (CVs) < 10% across all concentration ranges. Sensitivity parameters included a lower limit of quantification (LLoQ) of 0.083 pg/mL and an analytical measurement range of 0.083-640 pg/mL. Linearity demonstrated <9% deviation across the measurement range. Interference testing showed <7% deviation for cross-reactants, common medications and AD-specific therapeutics. Plasma samples remained stable over 48 h at room temperature (<4% deviation) and five freeze-thaw cycles (<9% deviation). Method comparison demonstrated strong correlation with Simoa GFAP (R = 0.945) but systematic proportional bias, yielding 3% (slope = 0.030) of Simoa values. Samples from participants with AD exhibited significantly elevated GFAP levels (median 9.0 pg/mL, IQR: 5.3-19.1) versus controls (median 3.4 pg/mL, IQR: 1.5-6.5; p < 0.001). Conclusions: The high-throughput Access GFAP (RUO) immunoassay achieved all analytical performance criteria and demonstrated differences in GFAP levels between AD and healthy control sample cohorts. These findings support its use in research settings and as a foundation for future clinical implementation and may inform future studies evaluating cross-platform harmonization and potential clinical applications.},
}

@article {pmid42449859,
year = {2026},
author = {Syed, AH and Alhayyani, S},
title = {An Exploratory Six-Probe Blood RNA Signature for Predicting 12-Month Cognitive Decline Along the Alzheimer's Disease Continuum: An Interpretable Machine Learning Study.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {13},
pages = {},
doi = {10.3390/diagnostics16132078},
pmid = {42449859},
issn = {2075-4418},
support = {IPP: 569-830-2025//Deanship of Scientific Research (DSR) at King Abdulaziz University/ ; },
abstract = {Background/Objectives: Predicting how fast a patient with Alzheimer's disease will decline over the next year remains a challenge. Existing blood transcriptomic studies have not established whether probe selection is reproducible, whether the signal is transcriptional or reflects immune cell shifts, or whether they generalise across platforms. Methods: We applied five steps to 96 ADNI-GO whole-blood microarray samples (Affymetrix HG-U219; 12-month MMSE change): PyImpetus Markov Blanket selection, Elastic Net with leave-one-out cross-validation (LOOCV), SHAP attribution, MCP-counter cell-type deconvolution, and cross-platform mapping into AddNeuroMed (GSE63060, n = 329, Illumina). Feature selection preceded cross-validation without constituting data leakage. Results: The same six probes emerged across four independent runs (Jaccard J = 0.214, p = 0.03): AQP7, RPS5, CHD2, SNX5, ASS1, and an uncharacterised chr12q15 transcript. The panel achieved LOOCV MAE = 1.388 and R[2] = 0.247, outperforming the full-probe baseline by 14.9%. All probes survived immune cell correction with signs intact. SNX5 replicated in AddNeuroMed (r = -0.170, p = 0.002). Conclusions: The exploratory six-probe blood RNA panel predicts 12-month cognitive decline (LOOCV R[2] = 0.247) with transcriptional origin confirmed by cell-type deconvolution and cross-platform evidence for SNX5. External testing in ADNI-2 (n = 91, R[2] = -0.222) showed that generalisation depends on visit-timepoint matching, indicating clinical utility cannot yet be claimed and defining conditions for prospective validation. Code and a research prototype tool are publicly available.},
}

@article {pmid42449943,
year = {2026},
author = {Oloruntimehin, S and Malogolovkin, A},
title = {Trends in the Engineering of Adeno-Associated Virus (AAV) for Precision Gene Delivery to the Central Nervous System (CNS).},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135668},
pmid = {42449943},
issn = {1422-0067},
mesh = {Humans ; *Dependovirus/genetics ; *Genetic Therapy/methods ; Animals ; *Gene Transfer Techniques ; *Central Nervous System/metabolism ; *Genetic Vectors/genetics/administration & dosage ; Gene Therapy Agents ; Muscular Atrophy, Spinal/therapy/genetics ; *Central Nervous System Diseases/therapy/genetics ; },
abstract = {Rare genetic disorders of the central nervous system (CNS) remain some of the most complex and challenging diseases to treat for several reasons. Targeting the CNS, especially the brain, presents one of the greatest obstacles in gene therapy using adeno-associated virus (AAV) vectors. Although various AAVs have been identified for their ability to transduce different cells in the CNS, their effectiveness and efficiency are significantly limited by the presence of neutralising antibodies (NAbs) and restricted cargo capacity. Despite these challenges, our understanding of AAV structure and technological advances continue to enable researchers to develop innovative strategies that have resulted in groundbreaking, FDA-approved therapeutic products now available for Leber congenital amaurosis (LCA) (Luxturna[®]), spinal muscular atrophy (SMA) (Zolgensma[®]), and the two recent gene therapy products for aromatic L-amino acid decarboxylase (AADC) deficiency, Kebilidi[®] and Upstaza[®], which currently hold FDA and EMA approval, respectively. This review aims to highlight recent advances in the field of AAV gene therapy for neurological disorders, identify research gaps, and suggest areas for future investigation to enable potential breakthroughs particularly in neurodegenerative, neurodevelopmental, and neuromuscular disorders. We foresee that more tissue- and cell-specific AAV vectors designed using AI-powered platforms will emerge to precisely and efficiently target specific brain regions, transforming how CNS disorders are treated.},
}

Humans
*Dependovirus/genetics
*Genetic Therapy/methods
Animals
*Gene Transfer Techniques
*Central Nervous System/metabolism
*Genetic Vectors/genetics/administration & dosage
Gene Therapy Agents
Muscular Atrophy, Spinal/therapy/genetics
*Central Nervous System Diseases/therapy/genetics

@article {pmid42449980,
year = {2026},
author = {Li, Y and Zhao, H and Wu, J and Hu, Y and Pan, J and Frimpong, AO and Xie, B and Yang, W and Sun, M and Chen, W and Wang, P and Shao, C},
title = {Vitamin K2 Promotes Mitochondrial Structural and Functional Homeostasis to Ameliorate Alzheimer Pathology by Targeting the EGFR-Ras-ERK Signaling Axis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135708},
pmid = {42449980},
issn = {1422-0067},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Mitochondria/drug effects/metabolism/ultrastructure ; ErbB Receptors/metabolism ; Homeostasis/drug effects ; *Vitamin K 2/pharmacology ; Humans ; *MAP Kinase Signaling System/drug effects ; Drosophila melanogaster ; *ras Proteins/metabolism ; Signal Transduction/drug effects ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and a breakdown of mitochondrial homeostasis. Vitamin K2 (VK2) has emerged as a potential neuroprotective agent, yet the specific molecular cascades linking its intervention to the restoration of mitochondrial integrity remain poorly understood. This study utilizes an AD Drosophila model to investigate the efficacy of VK2 and elucidates its multidimensional regulatory mechanisms. Behavioral analysis showed that VK2 significantly rescued locomotor impairments, improving both vertical climbing and horizontal walking performance. Crucially, VK2 intervention achieved a systemic rescue of mitochondrial health: transmission electron microscopy (TEM) confirmed the preservation of mitochondrial ultrastructure and cristae density, while biochemical assays demonstrated a robust recovery of bioenergetic markers, including ATP levels and the NAD[+]/NADH ratio. Furthermore, VK2 treatment stabilized the mitochondrial membrane potential (MMP) and effectively attenuated the accumulation of reactive oxygen species (ROS). To identify the molecular drivers of this recovery, an unbiased integration of human clinical transcriptomic data and network pharmacology prioritized the EGFR-Ras-ERK signaling axis as a central hub. In vivo validation confirmed that VK2 suppresses the pathological overactivation of this cascade. VK2 reduced EGFR phosphorylation in parallel with the effects observed for the EGFR inhibitor Gefitinib. Collectively, our findings show that VK2 ameliorates locomotor deficits and mitochondrial dysfunction in Aβ42-expressing flies and that these effects are associated with suppression of the EGFR-Ras-ERK signaling axis. Further studies are required to establish direct target engagement and pathway causality.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/pathology
*Mitochondria/drug effects/metabolism/ultrastructure
ErbB Receptors/metabolism
Homeostasis/drug effects
*Vitamin K 2/pharmacology
Humans
*MAP Kinase Signaling System/drug effects
Drosophila melanogaster
*ras Proteins/metabolism
Signal Transduction/drug effects
Disease Models, Animal
Reactive Oxygen Species/metabolism
Membrane Potential, Mitochondrial/drug effects
Amyloid beta-Peptides/metabolism

@article {pmid42450002,
year = {2026},
author = {Kim, Y and Jung, YK},
title = {Proteasome Dysfunction and Aggregation-Prone Proteins in Neurodegenerative Diseases: From Mechanisms to Therapeutic Opportunities.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135730},
pmid = {42450002},
issn = {1422-0067},
support = {RS-2025-00519823//National Research Foundation of Korea/ ; RS-2024-00439842//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Proteasome Endopeptidase Complex/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology/drug therapy ; Animals ; Proteostasis ; *Protein Aggregation, Pathological/metabolism ; *Protein Aggregates ; Proteotoxic Stress ; Ubiquitin/metabolism ; Proteolysis ; Oxidative Stress ; },
abstract = {Neurodegenerative diseases are characterized by the accumulation of misfolded and aggregation-prone proteins, reflecting a failure of proteostasis. The ubiquitin-proteasome system (UPS), a major pathway for selective intracellular protein degradation, is essential for maintaining neuronal protein homeostasis. Proteasome dysfunction has been implicated in several major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), although its extent and mechanisms vary across disease contexts. In this review, we examine current evidence for proteasome dysfunction in neurodegeneration and discuss how disease-associated proteins impair proteasome function through direct inhibition, defective substrate processing, and sequestration into protein aggregates. We also address the contribution of oxidative stress, neuroinflammation, and aging to proteasome dysregulation. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function, including pharmacological activation, modulation of proteasome assembly and stability, and targeted protein degradation approaches. Understanding the context-dependent nature of proteasome dysfunction will be important for developing effective proteostasis-based therapies.},
}

Humans
*Proteasome Endopeptidase Complex/metabolism
*Neurodegenerative Diseases/metabolism/therapy/pathology/drug therapy
Animals
Proteostasis
*Protein Aggregation, Pathological/metabolism
*Protein Aggregates
Proteotoxic Stress
Ubiquitin/metabolism
Proteolysis
Oxidative Stress

@article {pmid42450004,
year = {2026},
author = {Petrov, W and Ślebioda, D and Kozińska, R and Kukla, K and Petrov, P and Sroka, M and Tesyna, J and Puźniak, G and Kudliński, M and Rejda, T and Skowron, I and Chłopaś-Konowałek, A},
title = {Analysis of the Efficacy of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer's Disease, Literature Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135733},
pmid = {42450004},
issn = {1422-0067},
mesh = {Humans ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Acetylcholinesterase/metabolism ; Rivastigmine/therapeutic use ; },
abstract = {The term 'dementia' encompasses a diverse group of progressive neurodegenerative disorders, the common feature of which is the deterioration of higher cortical functions. This process not only involves memory deficits and language communication disorders, but also executive dysfunction and loss of emotional control, which ultimately leads to a complete loss of the patient's independence. Within this group of disorders, Alzheimer's disease (AD) presents the most serious clinical challenge, characterized by a unique neuropathological triad: the presence of extracellular β-amyloid plaques, intracellular neurofibrillary tangles of tau protein, and widespread dysfunction of cholinergic transmission. The cholinergic hypothesis remains the cornerstone of the current understanding of cognitive impairment in AD. It posits that progressive dementia is caused by the selective degeneration of neurons in the anterior basal forebrain, resulting in a drastic reduction in acetylcholine (ACh) levels in the synaptic cleft. In the absence of a causal treatment, acetylcholinesterase inhibitors (AChEIs) remain the standard of care. Their pharmacological action is based on the inhibition of the AChE enzyme, which allows neurotransmission deficits to be compensated for by prolonging the half-life of acetylcholine at the synapse. This literature review presents a synthesis of the efficacy and safety of classic and novel AChEIs. A comprehensive search of the PubMed, Scopus, and Cochrane Library databases was conducted for clinical data published up to 2026. Evidence from key trials indicates that standard AChEIs induce significant cognitive stabilization compared to placebo, with rivastigmine maximizing daily living parameters via transdermal delivery. However, their therapeutic impact remains strictly symptomatic without arresting neurodegeneration. Conversely, emerging agents like huperzine A and the translation-blocker Posiphen demonstrate disease-modifying potential by modulating CSF biomarkers associated with amyloid and tau proteins. Clinically, while traditional regimens are limited by gastrointestinal toxicities, transitioning toward innovative multi-target structures represents a necessary shift to address both cognitive decline and neurodegeneration.},
}

Humans
*Cholinesterase Inhibitors/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism
Animals
Acetylcholinesterase/metabolism
Rivastigmine/therapeutic use

@article {pmid42450018,
year = {2026},
author = {Kang, H and Kim, H and Kim, WJ and French, L and Oh, H and An, SSA},
title = {Vitronectin Modulates Plasma Aβ Oligomerization Propensity Within Altered Albumin Interactome Networks in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135744},
pmid = {42450018},
issn = {1422-0067},
support = {S3355514//Ministry of SMEs and Startups/ ; },
mesh = {*Vitronectin/metabolism/blood ; *Alzheimer Disease/metabolism/blood/pathology ; *Amyloid beta-Peptides/blood/metabolism/chemistry ; Humans ; Protein Binding ; Protein Multimerization ; Proteomics/methods ; Protein Interaction Maps ; *Albumins/metabolism ; Biomarkers/blood ; },
abstract = {Amyloid beta (Aβ) oligomers are key mediators of synaptic dysfunction and neural circuit impairment in Alzheimer's disease (AD). While plasma Aβ oligomerization propensity (OAβ) correlates with cerebral amyloid pathology and cognitive decline, the systemic modulators of OAβ remain poorly understood. In this study, we identified the albumin interactome (albumin and its associated proteins) as a critical regulator of OAβ. Selective depletion of the albumin interactome from plasma eliminated the OAβ difference between amyloid PET (A-PET)- and A-PET+ individuals. Proteomic analysis revealed widespread network alterations within the albumin interactome of A-PET+ individuals. Notably, vitronectin (VTN) was identified as a key hub protein that was significantly reduced in A-PET+ individuals. Functional assays and in silico modeling demonstrated that VTN directly bound to Aβ and inhibited its oligomerization. Additionally, plasma VTN levels distinguished A-PET status. These findings suggest that systemic changes in the albumin interactome, particularly the reduction in VTN, are associated with dysregulated Aβ dynamics in plasma. Our results provide novel insights into systemic mechanisms underlying AD pathology and identify VTN as a potential peripheral modulator and biomarker of cerebral amyloid pathology.},
}

*Vitronectin/metabolism/blood
*Alzheimer Disease/metabolism/blood/pathology
*Amyloid beta-Peptides/blood/metabolism/chemistry
Humans
Protein Binding
Protein Multimerization
Proteomics/methods
Protein Interaction Maps
*Albumins/metabolism
Biomarkers/blood

@article {pmid42450021,
year = {2026},
author = {Kang, HY and Jang, BK and Yun, SH and Jeong, HY and Park, E and Oh, KI and Jeong, J and Jeong, SY},
title = {Aronia Bioactive Fraction-Alginic Acid Nanocomplex-Modulates Tau Phosphorylation and Aggregation in Cell Models of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135748},
pmid = {42450021},
issn = {1422-0067},
support = {RS-2022-KH130303//Ministry of Health and Welfare/ ; RS-2021-KH113820//Ministry of Health and Welfare/ ; RS-2025-25303051//Ministry of Health and Welfare/ ; },
mesh = {*tau Proteins/metabolism ; Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Phosphorylation/drug effects ; *Alginic Acid/pharmacology/chemistry ; HEK293 Cells ; Glycogen Synthase Kinase 3 beta/metabolism ; Protein Aggregates/drug effects ; Cell Line, Tumor ; *Plant Extracts/pharmacology/chemistry ; Proto-Oncogene Proteins c-akt/metabolism ; },
abstract = {Preventing or reversing Tau hyperphosphorylation and aggregation represent critical objectives in the development of effective therapies for Alzheimer's disease. The present study investigated the potential of a novel Aronia bioactive fraction-alginic acid nanocomplex (AANCP)-to simultaneously inhibit pathological features of Alzheimer's disease. Evaluations of Aronia bioactive fraction (ABF) and low-molecular-weight alginic acid (LAA), utilized both individually and as AANCP, were conducted in HEK293-TauP301L and SH-SY5Y-TauP301L cell models of Alzheimer's disease. Both ABF and LAA reduced the expression of total Tau and Tau phosphorylated at Ser396 in a concentration-dependent manner, with AANCP demonstrating significant synergistic activity of its components. Notably, the optimal AANCP ratio was 1:1 and 1:8 for inhibiting Tau phosphorylation and Tau aggregation, respectively. Mechanistically, AANCP inhibited Tau phosphorylation by upregulating p-Akt (phosphorylated protein kinase B) and p-GSK-3β (phosphorylated glycogen synthase kinase-3 beta), while also enhancing the activity of methylated PP2A, a key Tau phosphatase. Furthermore, AANCP exhibited superior efficacy in inhibiting heparin-induced Tau aggregation compared to the individual components. Analysis of autophagy markers indicated that the nanocomplex enhanced Tau clearance, as shown by increased LC3-II and Beclin-1 levels and reduced p62 levels. These results suggest AANCP as a promising therapeutic candidate that simultaneously reduces Tau phosphorylation and aggregation and facilitates autophagic Tau clearance, offering a potent, synergistic strategy for treating Alzheimer's disease.},
}

*tau Proteins/metabolism
Humans
*Alzheimer Disease/metabolism/drug therapy/pathology
Phosphorylation/drug effects
*Alginic Acid/pharmacology/chemistry
HEK293 Cells
Glycogen Synthase Kinase 3 beta/metabolism
Protein Aggregates/drug effects
Cell Line, Tumor
*Plant Extracts/pharmacology/chemistry
Proto-Oncogene Proteins c-akt/metabolism

@article {pmid42450026,
year = {2026},
author = {Stępnik, K},
title = {Curcumin in Alzheimer's Disease: From Mechanistic Insights to Translational Challenges and Emerging Curcuminoid Strategies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135754},
pmid = {42450026},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Curcumin/therapeutic use/pharmacology/analogs & derivatives/chemistry ; Animals ; Oxidative Stress/drug effects ; Diarylheptanoids/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by complex interactions between protein aggregation, oxidative stress, neuroinflammation, and cellular dysfunction. Among plant-derived compounds, curcumin has emerged as one of the most extensively studied polyphenols due to its broad spectrum of biological activities. This review provides a critical synthesis of the mechanistic, preclinical, and clinical evidence on curcumin in AD. Experimental studies consistently demonstrate that curcumin modulates key pathogenic processes, including neuroinflammatory signaling, oxidative stress, and amyloid-β aggregation, with more limited evidence for effects on tau pathology. While in vitro studies offer detailed mechanistic insights, in vivo models provide more integrated evidence, including improvements in cognitive performance and reductions in pathological markers. Despite this strong preclinical foundation, the clinical evidence remains limited and inconsistent. Randomized controlled trials have not demonstrated clear therapeutic efficacy, with outcomes strongly influenced by formulation, bioavailability, and study design. Poor solubility, rapid metabolism, and limited brain exposure remain key translational barriers. In response, increasing attention has been directed toward formulation strategies and structurally related compounds. Emerging curcuminoids, such as bisdemethoxycurcumin (BDMC), are discussed as potential next-generation candidates. Preliminary evidence suggests that BDMC may modulate oxidative stress, autophagy, astrocyte senescence, and amyloid-related processes, although the data remain largely preclinical. Overall, curcumin represents a mechanistically rich and preclinically promising multi-target compound but with unresolved translational limitations. Future research should prioritize pharmacokinetic optimization, formulation-dependent validation, and exploration of novel curcuminoid strategies to bridge the gap between experimental findings and clinical application in AD.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Curcumin/therapeutic use/pharmacology/analogs & derivatives/chemistry
Animals
Oxidative Stress/drug effects
Diarylheptanoids/therapeutic use/pharmacology
Amyloid beta-Peptides/metabolism

@article {pmid42450031,
year = {2026},
author = {Olegário, RL and Nóbrega, OT and Almeida, NR and Soto, DAS and Brito, CJ and Bispo, DDC and von Glehn, F and Páez, A and Dang-Vu, TT and Camargos, EF},
title = {Diffusion Tensor Imaging Along the Perivascular Space (DTI-ALPS) as a Neuroimaging Biomarker of Glymphatic Function in Neurodegenerative Diseases: A Systematic Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135758},
pmid = {42450031},
issn = {1422-0067},
support = {88887.841787/2023-00//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; 00193-00002602/2022-69//Foundation for Research Support of the Federal District/ ; 88881.218726/2025-01//Coordenação de Aperfeicoamento de Pessoal de Nível Superior/ ; },
mesh = {Humans ; *Glymphatic System/diagnostic imaging/metabolism ; *Diffusion Tensor Imaging/methods ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; Biomarkers/metabolism ; *Neuroimaging/methods ; Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {The glymphatic system has been proposed as a brain-wide pathway that promotes the exchange between cerebrospinal and interstitial fluids and facilitates the clearance of metabolic waste products, including amyloid-β and tau proteins. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) has emerged as a non-invasive magnetic resonance imaging technique proposed to indirectly assess glymphatic-related fluid dynamics. This systematic review evaluated the methodological consistency and clinical applicability of the ALPS index in neurodegenerative diseases. A structured search of PubMed (MEDLINE) and Web of Science identified human studies published up to January 2026 investigating DTI-ALPS in neurodegenerative conditions. Data regarding study populations, MRI acquisition parameters, image-processing methods, statistical approaches, and clinical associations were extracted and synthesized. Ten studies met the inclusion criteria. Across studies, lower ALPS index values were generally associated with cognitive impairment, amyloid burden, and disease severity, particularly in Alzheimer's disease. Several studies incorporated multimodal biomarkers, including amyloid positron emission tomography and cerebrospinal fluid markers, thereby improving the biological interpretation of DTI-ALPS findings. However, substantial methodological heterogeneity was identified across studies, including variability in region-of-interest placement, diffusion acquisition protocols, and image-processing pipelines. Furthermore, the interpretation of diffusivity metrics as direct measures of glymphatic flow remains controversial. Current evidence suggests that DTI-ALPS may represent a promising non-invasive imaging marker of glymphatic-related alterations; however, its biological specificity and clinical applicability remain insufficiently established. Standardized acquisition protocols, harmonized analytical pipelines, and longitudinal multicenter studies are required to clarify its role in neurodegenerative disease research.},
}

Humans
*Glymphatic System/diagnostic imaging/metabolism
*Diffusion Tensor Imaging/methods
*Neurodegenerative Diseases/diagnostic imaging/metabolism
Biomarkers/metabolism
*Neuroimaging/methods
Alzheimer Disease/diagnostic imaging
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid42450103,
year = {2026},
author = {Pluta, R and Ułamek-Kozioł, M and Kocki, J and Bogucka-Kocka, A and Czuczwar, SJ and Bogucki, J},
title = {LRP1 and RAGE Expression in the Frontal Cortex in the Alzheimer's Disease Ischemia Model During 2 Years of Follow-Up.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135831},
pmid = {42450103},
issn = {1422-0067},
mesh = {*Alzheimer Disease/metabolism/genetics/pathology ; *Receptor for Advanced Glycation End Products/genetics/metabolism ; *Low Density Lipoprotein Receptor-Related Protein-1/genetics/metabolism ; Animals ; *Frontal Lobe/metabolism/pathology ; *Brain Ischemia/metabolism/genetics/pathology ; Disease Models, Animal ; Male ; Humans ; Rats ; },
abstract = {Exploration of the gene-level changes that occur during post-ischemic neurodegeneration in the frontal cortex is crucial for understanding the development of dementia. An ischemic model of Alzheimer's disease was used to evaluate changes in the expression of the receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein 1 (LRP1), which are associated with amyloid and tau protein, in the frontal cortex after 10 min of cerebral ischemia, with survival at 2, 7, and 30 days and 0.5, 1, 1.5, and 2 years. LRP1 and RAGE expression was assessed by reverse transcription-quantitative polymerase chain reaction. After two days and 1.5 and 2 years post-ischemia, LRP1 expression was increased, after 7 days and 0.5 years it was decreased, and after 30 days and 1 year it oscillated around control values. The decrease in RAGE expression was statistically significant compared to the control group after 2 and 7 days and after 0.5 years, and after 30 days it oscillated around the control value, while after 1-2 years it increased significantly. RAGE and LRP1 expression showed the same pattern of changes from day 7 to year 2, peaking at 1 and 1.5 years, respectively. Another peak of RAGE overexpression was noted 2 years after ischemia. After 1, 1.5 and 2 years, overexpression of RAGE and LRP1 was observed after ischemia, with the dynamics of LRP1 changes being lower. Overall, the data showed a predominance of RAGE expression over LRP1 expression at 1-, 1.5-, and 2-years post-ischemia. The modification of LRP1 and RAGE after ischemia is useful in studying the molecular ischemic pathways involved in the development of Alzheimer's disease.},
}

*Alzheimer Disease/metabolism/genetics/pathology
*Receptor for Advanced Glycation End Products/genetics/metabolism
*Low Density Lipoprotein Receptor-Related Protein-1/genetics/metabolism
Animals
*Frontal Lobe/metabolism/pathology
*Brain Ischemia/metabolism/genetics/pathology
Disease Models, Animal
Male
Humans
Rats

@article {pmid42450155,
year = {2026},
author = {Untiveros, G and St Germain, R and Barrington, B and Kujawa, SA and Prakapenka, AV and Strizzi, L},
title = {Presenilin-1 Affects Melanoma Cell Behavior in an Amyloid Precursor Protein-Rich, Alzheimer's Disease-like, Microenvironment.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135885},
pmid = {42450155},
issn = {1422-0067},
mesh = {*Presenilin-1/metabolism/genetics ; Humans ; Animals ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Melanoma/metabolism/pathology ; *Tumor Microenvironment ; *Alzheimer Disease/metabolism/pathology ; Mice ; Cell Line, Tumor ; Amyloid beta-Peptides/metabolism ; Cell Movement ; },
abstract = {Recent studies report inverse relationships between the incidence of Alzheimer's Disease (AD) and certain malignancies, including melanoma. This has encouraged research into factor(s) in AD that can exert antitumor effects. Presenilin-1 (PS-1) is part of the enzymatic complex that cleaves amyloid precursor protein (APP) into amyloid-beta (Aβ) products that are linked to the neuronal damage seen in AD. PS-1 can also degrade β-catenin and reduce the effectiveness of the "wingless-related integration" (WNT) signaling pathway. Little is known about the relationship between the AD microenvironment, PS-1, and melanoma. We hypothesize that melanoma growth in AD depends on the degree of PS-1-dependent processing of APP into cytotoxic Aβ by melanoma cells. To determine how melanoma reacts to an APP-rich, AD-like microenvironment, PS-1-high (WM1552C) and PS-1-low (C8161) melanoma cells were treated with soluble recombinant human APP (rhAPP). We found that rhAPP treatment significantly reduced cellular activity in WM1552C but not in C8161 cells. Moreover, Aβ products were significantly higher in conditioned media from rhAPP-treated WM1552C compared to controls. Treatment with PS-1 inducing DAPT or PS-1 function inhibiting MRK-560 reversed the effects of rhAPP treatment, respectively in C8161 and WM1552C cells. Furthermore, we found that migration of WM1552C was significantly reduced in the presence of either soluble rhAPP or mouse AD brain tissue, compared to C8161, suggesting that in WM1552C the combination of PS-1 activity and the presence of APP/Aβ in the microenvironment interferes with cell migration. In summary, PS-1 function may predict how melanoma will grow in an APP/Aβ-rich microenvironment, such as AD.},
}

*Presenilin-1/metabolism/genetics
Humans
Animals
*Amyloid beta-Protein Precursor/metabolism/genetics
*Melanoma/metabolism/pathology
*Tumor Microenvironment
*Alzheimer Disease/metabolism/pathology
Mice
Cell Line, Tumor
Amyloid beta-Peptides/metabolism
Cell Movement

@article {pmid42450159,
year = {2026},
author = {Świątek, A and Kusiak, A and Maj, A},
title = {Salivary Biomarkers in Alzheimer's Disease: Emerging Diagnostic Tools and Their Association with Periodontal Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135888},
pmid = {42450159},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; *Biomarkers/metabolism/analysis ; *Saliva/metabolism/chemistry ; *Periodontal Diseases/metabolism/complications/diagnosis ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia worldwide. Current diagnostic methods, including cerebrospinal fluid analysis and neuroimaging, are often invasive, expensive, and not suitable for large-scale screening. Therefore, increasing attention has been directed toward the identification of non-invasive biomarkers. Saliva has emerged as a promising diagnostic biofluid containing proteins, metabolites, inflammatory mediators, exosomes, and nucleic acids potentially associated with neurodegenerative processes. This review aimed to summarize current evidence regarding salivary biomarkers in Alzheimer's disease and to discuss their diagnostic potential, limitations, and association with periodontal disease within the framework of the oral-brain axis. A literature search was conducted using PubMed, Scopus, and Google Scholar databases for studies published between 2018 and 2026. Relevant English-language articles focusing on salivary biomarkers, Alzheimer's disease, periodontitis, and oral-brain axis interactions were included. Current evidence suggests that salivary biomarkers such as amyloid-beta, tau protein, lactoferrin, exosomes, oxidative stress markers, metabolites, and nucleic acid-based biomarkers may reflect the pathological mechanisms associated with Alzheimer's disease. In addition, increasing evidence supports a relationship between chronic periodontal inflammation, oral pathogens, and neurodegenerative processes. However, substantial heterogeneity among studies, methodological variability, and a lack of standardized protocols currently limit the reproducibility and clinical applicability of saliva-based diagnostics. Salivary biomarkers represent a promising non-invasive approach for the early detection and monitoring of Alzheimer's disease. Nevertheless, further large-scale, longitudinal, and standardized studies are necessary to validate their diagnostic utility and support their implementation in routine clinical practice.},
}

Humans
*Alzheimer Disease/diagnosis/metabolism
*Biomarkers/metabolism/analysis
*Saliva/metabolism/chemistry
*Periodontal Diseases/metabolism/complications/diagnosis
Amyloid beta-Peptides/metabolism

@article {pmid42450256,
year = {2026},
author = {Shiyab, AS and Reed, EG},
title = {Peripheral and Central miRNA Signatures in Alzheimer's Disease: Tissue-Specific Variability, Sex-Associated Differences, and Implications for Blood-Based Biomarkers.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135990},
pmid = {42450256},
issn = {1422-0067},
support = {1R01AG075897-05/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics/blood/metabolism/diagnosis ; *MicroRNAs/genetics/blood/metabolism ; *Biomarkers/blood ; Brain/metabolism/pathology ; Animals ; Female ; Organ Specificity ; Male ; Gene Expression Profiling ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and significant neuropathological changes. Early and accurate diagnosis remains a major challenge, highlighting the need for reliable, minimally invasive biomarkers. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising candidates. Their expression is altered in the brains of AD patients, reflecting disease-specific pathological processes, and they are detectable in peripheral biofluids. However, discrepancies in miRNA profiles between the brain and the circulation, and between patient populations remain a significant limitation, raising questions about their origin, transport across the blood-brain barrier, and their reliability in reflecting central nervous system pathology. This review provides a comprehensive overview of current research comparing miRNA expression profiles in brain tissue and blood in AD, with a focus on their biological relevance, mechanisms of release and transport, and diagnostic potential. We also discuss the challenges associated with cross-tissue variability, methodological inconsistencies, and the need for standardized approaches. Finally, we highlight future directions, including multi-tissue analyses and integration with other noninvasive modalities, to improve the clinical utility of miRNA-based biomarkers in AD.},
}

Humans
*Alzheimer Disease/genetics/blood/metabolism/diagnosis
*MicroRNAs/genetics/blood/metabolism
*Biomarkers/blood
Brain/metabolism/pathology
Animals
Female
Organ Specificity
Male
Gene Expression Profiling

@article {pmid42450333,
year = {2026},
author = {Tao, H and Fujisawa, K},
title = {Energy Homeostasis Disruption in Neurological Disorders: Mitochondrial Dysfunction, High-Energy Phosphate Transfer, and Extracellular ATP-Dependent Purinergic Dysregulation.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27136066},
pmid = {42450333},
issn = {1422-0067},
mesh = {Humans ; *Energy Metabolism ; *Homeostasis ; *Adenosine Triphosphate/metabolism ; Animals ; *Mitochondria/metabolism/pathology ; *Nervous System Diseases/metabolism/pathology ; },
abstract = {Mitochondrial dysfunction and impairment of high-energy phosphate transfer are increasingly recognised as shared pathogenic features across neurological disorders. Because neurons require large amounts of ATP to sustain synaptic transmission, ion gradients, axonal transport, and intracellular signalling, they are especially vulnerable to disturbances in energy metabolism. Neurological dysfunction, therefore, cannot be explained solely by reduced mitochondrial ATP production. It also involves failure of the creatine kinase/phosphocreatine (CK/PCr) and adenylate kinase/AMP-activated protein kinase (AK-AMPK) systems, which normally support local ATP buffering, high-energy phosphate transfer, and intracellular energy homeostasis. In parallel, extracellular ATP-dependent purinergic dysregulation contributes to glia-mediated inflammation, synaptic dysfunction, and cell death, linking intracellular energy failure to abnormal intercellular signalling. In this review, we integrate these mechanisms into a shared pathological continuum of disrupted energy homeostasis. We then compare Alzheimer's disease, Parkinson's disease, and epilepsy as representative disorders with shared and disease-specific manifestations of this continuum, characterised respectively by chronic cerebral energy crisis, selective metabolic fragility, and acute energy overload with purinergic dysregulation. Finally, we discuss how this comparative perspective may help identify shared therapeutic opportunities while preserving disorder-specific interpretation.},
}

Humans
*Energy Metabolism
*Homeostasis
*Adenosine Triphosphate/metabolism
Animals
*Mitochondria/metabolism/pathology
*Nervous System Diseases/metabolism/pathology

@article {pmid42450350,
year = {2026},
author = {Liu, X and Watanabe, S and Coleman, S and Shih, V and Telfer, WR and Kansagra, VD and Drak, L and Pesaladinne, LR and Kim, D and Sudan, S and Singhal, A and Toyo-Oka, K},
title = {ADNP Functions During Early Brain Development and Their Relevance to ASD and ADNP Syndrome.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27136085},
pmid = {42450350},
issn = {1422-0067},
support = {R21MH132839/MH/NIMH NIH HHS/United States ; AR220067//United States Department of Defense/ ; },
mesh = {Humans ; *Brain/metabolism/growth & development/embryology ; *Autism Spectrum Disorder/metabolism/genetics ; Animals ; *Nerve Tissue Proteins/metabolism/genetics ; Neurogenesis ; Neurodevelopment ; Homeodomain Proteins ; },
abstract = {The Activity-Dependent Neuroprotective Protein (ADNP) is an important regulator of early brain development, especially during cortical neurogenesis and neurite formation. De novo point mutations or haploinsufficiency of the ADNP gene result in ADNP syndrome, which is also known as Helsmoortel-Van der Aa syndrome, a complex neurodevelopmental disorder recognized as a leading single-gene cause of syndromic autism spectrum disorder (ASD) and intellectual disability. ADNP works as both a transcription factor and a microtubule (MT) regulator. As a transcription factor, ADNP is a key component of chromatin remodeling complexes such as ChAHP (CHD4 (Chromodomain Helicase DNA-binding Protein 4)-ADNP-HP1 (Heterochromatin Protein 1)) and SWI/SNF (Switch/Sucrose Non-Fermentable), and it tightly regulates the expression of numerous essential developmental genes. ADNP also modulates the Wnt/β-catenin signaling pathway. During neural differentiation, ADNP is redistributed from the nucleus to the cytoplasm, and this redistribution is regulated by binding to 14-3-3 proteins, which are phosphorylated by protein Kinase C (PKC). After relocating to the cytoplasm, ADNP functions as an MT regulator by binding to microtubule end-binding proteins (EB1 and EB3) and Tau to control neurite formation. Previous studies have focused on NAP (also known as Davunetide, a peptide derived from ADNP) in MT regulation and its therapeutic potential for autism spectrum disorder (ASD) and neurodegenerative diseases, such as Alzheimer's disease. This review highlights the functions of full-length ADNP and NAP in early brain development, particularly in neurogenesis and neurite formation during cortical development. We will also discuss the potential of NAP as a therapeutic medication for neurodevelopmental disorders, especially ASD and ADNP syndrome.},
}

Humans
*Brain/metabolism/growth & development/embryology
*Autism Spectrum Disorder/metabolism/genetics
Animals
*Nerve Tissue Proteins/metabolism/genetics
Neurogenesis
Neurodevelopment
Homeodomain Proteins

@article {pmid42450355,
year = {2026},
author = {Arendash, GW},
title = {Neuronal Microtubules and Radiofrequency Waves: The Quantum Core of Human Consciousness, Memory, and Pathway to Memory Enhancement/Recovery.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27136090},
pmid = {42450355},
issn = {1422-0067},
support = {AG025711, 1R43NS090653-01A, and 9R44AG073096-02A1//NIA-designated Florida Alzheimer's Disease Research Center/ ; },
mesh = {Humans ; *Microtubules/metabolism ; *Memory/physiology/radiation effects ; *Consciousness/physiology ; *Radio Waves ; Animals ; *Neurons/metabolism ; Quantum Theory ; },
abstract = {A unifying theory of both human consciousness and memory is presented that is based on neuronal microtubules (MTs) being central to both, and different populations of pyramidal cells in neocortex and hippocampus being responsible for consciousness or memory. First, two quantum theories of consciousness are presented-the Orchestrated Objective Reduction (Orch OR) theory of Penrose/Hameroff and the Environmental-Induced Decoherence Theory (EID) theory of Neven. A Hybrid (MT/EID) theory is proposed in the context of "consciousness"-dedicated pyramidal cells in Layer V of the cerebral cortex. This MT/EID theory involves the MT vibrations of the Orch OR Theory, along with the continual superposition qubit (SPQ) formation and SPQ entanglement of the EID Theory to collectively induce SPQ formation/entanglement in Layer V of the cerebral cortex. Orch OR's objective reduction (collapse of the waveform) is not included in this Hybrid theory because the system of SPQs themselves continuously collapses due to EID. For memory, it is proposed that Orch OR forms its basis with three specific modifications: (1) presenting "endogenous" radiofrequency (RF) vibrations generated by neuronal microtubules as forming a microtubule/RF wave "vibrational fabric" involving microtubular crystalline water cores, (2) refining Orch OR for memory by proposing SPQ formation for short-term memory and objective reduction of those qubits primarily in "memory-dedicated" pyramidal cells within cortical Layers II/III for long-term memory storage through "Quantum Darwinism" (SPQ/OR), and (3) integrating SPQ/OR with the ability of "externally" applied RF waves at 1 GHz to beneficially influence human memory through microtubule-enhancing mechanisms. It is proposed that a vibrational fabric consisting of MTs, RF waves, and generated photons provides the Photonic/RF-wave quantum coherence necessary for brain memory processing. Strong evidence for beneficial effects of exogenous RF wave treatment on memory is provided by a new bioengineered technology-Transcranial Radiofrequency Wave Treatment (TRFT; also known as TEMT). This evidence is presented in both pre-clinical and clinical studies involving normal and Alzheimer's Disease (AD) transgenic mice, and AD patients bearing memory loss. In support of MT involvement in memory, TRFT would appear to be an ideal non-pharmacologic technology to beneficially modulate the microtubule/RF wave vibrational fabric-an intraneuronal fabric that may be at the deep core of human memory, and thus the key to Alzheimer's Disease memory rescue.},
}

Humans
*Microtubules/metabolism
*Memory/physiology/radiation effects
*Consciousness/physiology
*Radio Waves
Animals
*Neurons/metabolism
Quantum Theory

@article {pmid42450365,
year = {2026},
author = {Alkandari, AF and Madhyastha, S and Rao, MS},
title = {Correction: Alkandari et al. N-Acetylcysteine Amide Against Aβ-Induced Alzheimer's-like Pathology in Rats. Int. J. Mol. Sci. 2023, 24, 12733.},
journal = {International journal of molecular sciences},
volume = {27},
number = {13},
pages = {},
doi = {10.3390/ijms27135898},
pmid = {42450365},
issn = {1422-0067},
abstract = {In the original publication [...].},
}

@article {pmid42450578,
year = {2026},
author = {Li, J and Cheng, S and Zhang, W and Qiao, S and Zhang, L and Yao, M and Zhang, Y and Wang, B and Wu, C},
title = {Mulberroside A Alleviates Scopolamine-Induced Cognitive Deficits by Suppressing Neuroinflammation and Oxidative Stress via the Dubosiella-Associated Microbiota-Gut-Brain Axis.},
journal = {Biology},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/biology15131030},
pmid = {42450578},
issn = {2079-7737},
support = {262102310255//Henan Provincial Science and Technology Key Project/ ; 26A180030//Key Scientific Research Foundation of Henan Colleges and Universities/ ; 252300423668//Natural Science Foundation of Henan/ ; ZKNUC2024030//Zhoukou Normal University High-level Talent Start-up Foundation/ ; },
abstract = {Mulberroside A (MsA) possesses neuroprotective effects, but whether it alleviates Alzheimer's disease (AD)-like cognitive impairment through the microbiota-gut-brain axis remains unclear. Using a scopolamine-induced mouse model of acute cognitive impairment (male ICR mice, n = 10/group), we demonstrated that daily administration of MsA (10, 20, and 30 mg/kg/day) for 5 weeks significantly ameliorated cognitive performance in novel object recognition and Morris water maze tests. At the optimal dose (30 mg/kg/day), MsA suppressed hippocampal microglial activation, reduced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), and attenuated oxidative stress by decreasing malondialdehyde (MDA) while restoring superoxide dismutase (SOD) and glutathione (GSH) levels. MsA also strengthened intestinal barrier integrity (ZO-1, occludin) and significantly altered the gut microbiota, notably increasing the beneficial genus Dubosiella. Brain metabolomics indicated that MsA reversed scopolamine-induced metabolic disturbances, mainly restoring phospholipid balance. Correlation analysis demonstrated a strong gut-brain connection, with Dubosiella abundance positively associated with neuroprotective phospholipids and negatively with stress markers. Furthermore, fecal microbiota transplantation from MsA-treated donors successfully replicated these behavioral improvements in recipient mice, underscoring the functional involvement of the reshaped microbiome rather than a simple autonomous recovery. These results suggest that MsA alleviates AD-like cognitive impairment by reducing neuroinflammation and oxidative stress through microbiota remodeling, enhancing the intestinal barrier, and modulating the Dubosiella-associated gut-metabolite-brain axis, making MsA a promising multi-target nutraceutical for ameliorating AD-like cognitive deficits.},
}

@article {pmid42450618,
year = {2026},
author = {Yang, Y and Li, Q and Luo, S and Sun, J and Ouyang, Y},
title = {Establishment and Characterization of an Aβ-Related Alzheimer's Disease-like Tree Shrew Model Following CA1-Coordinate-Directed Stereotaxic AAV Delivery of Human Triple-Mutant APP.},
journal = {Biology},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/biology15131071},
pmid = {42450618},
issn = {2079-7737},
support = {2023GXNSFDA026069//Guangxi Natural Science Foundation, China/ ; 32260137//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is characterized by cognitive decline and amyloid-β (Aβ)-related pathology. Non-rodent models that capture selected aspects of human AD remain limited. We established and characterized a human APP-driven, Aβ-related AD-like tree shrew model following AAV-mediated delivery of triple-mutant human amyloid precursor protein (hAPP-SLA) carrying the Swedish, Austrian, and London mutations by bilateral stereotaxic injection directed at CA1 coordinates. Adult tree shrews received bilateral AAV-hAPP-SLA injections directed at CA1 coordinates and were evaluated by bioluminescence imaging, behavioral testing, PCR, RT-qPCR, Western blotting, ELISA, and histopathology. Vector-associated reporter signals remained detectable for 6 months. The experimental group showed exogenous hAPP expression and reduced endogenous tsAPP expression, increased relative hippocampal Aβ42 protein level, enhanced 4G8-reactive APP/Aβ-related signals, elevated total Aβ immunoreactivity, increased serum Aβ42/Aβ40 ratio, cytoarchitectural alterations, reduced Nissl staining, and Thioflavin S-reactive aggregate-associated signals. AT8 (Ser202/Thr205), GFAP, and Iba-1 immunoreactivity increased, whereas Synaptophysin and PSD-95 immunoreactivity was reduced. These changes were accompanied by reduced short-delay recognition-related performance and reduced social approach and social novelty preference. Aged tree shrews showed partly overlapping alterations. This model provides a non-rodent platform for studying human APP-driven Aβ-related pathology.},
}

@article {pmid42450638,
year = {2026},
author = {Tang, C and Shi, L and Xu, S},
title = {Integrating Structural and Metabolic Neuroimaging Biomarkers for Alzheimer's Disease Diagnosis and Cognitive Score Estimation via Cross-Modal Gated Learning.},
journal = {Biology},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/biology15131091},
pmid = {42450638},
issn = {2079-7737},
abstract = {Structural atrophy and metabolic dysfunction provide complementary biomarkers for Alzheimer's disease (AD), and their joint modeling may support diagnostic assessment and cognitive score estimation. However, many multimodal methods rely on global fusion and insufficiently enhance cross-modal consistency before interaction, limiting the discriminative quality and clinical relevance of learned representations. We propose CGMF-Net, a cross-modal gated learning framework for joint AD classification and clinical score estimation using paired structural MRI (sMRI) and fluorodeoxyglucose PET (FDG-PET) data. CGMF-Net extracts multi-scale representations from both modalities, introduces a Cross-Modal Similarity Gate to strengthen consistent structural-metabolic responses before fusion, and employs bi-directional cross-attention to capture complementary interactions. The shared representation is optimized with classification supervision, MMSE-based auxiliary regression, and HSIC regularization to improve discriminability and reduce redundant coupling between directional representations. Experiments on ADNI demonstrate that CGMF-Net achieves the best overall classification performance among the compared methods, with 94.22% ACC and 97.74% AUC for AD vs. CN, and 86.67% ACC and 94.84% AUC for AD vs. MCI, while also showing favorable ADNI-2 to ADNI-1 generalization and competitive estimation of ADAS13, CDRSB, and MMSE. These results suggest that cross-modal gated learning provides clinically relevant multimodal representations for AD diagnosis and cognitive score estimation.},
}

@article {pmid42451075,
year = {2026},
author = {Wang, JQ and Hu, BB and Wang, YY and Lu, YW and Gong, XJ and Tang, S and Song, LJ and Sun, YS and Zhang, JT and Wang, Z and Li, W},
title = {Maltol Protects Neuronal Cells by Alleviating Chronic Neuroinflammation, Pyroptosis, and Ferroptosis via HSP70 Upregulation in Microglia.},
journal = {Nutrients},
volume = {18},
number = {13},
pages = {},
doi = {10.3390/nu18132071},
pmid = {42451075},
issn = {2072-6643},
support = {No. 82104465//National Natural Science Foundation of China/ ; 2023YFD1601600//National Key Research and Development Program/ ; },
mesh = {*Microglia/drug effects/metabolism ; Animals ; *HSP70 Heat-Shock Proteins/metabolism/genetics ; *Pyroptosis/drug effects ; *Neurons/drug effects/metabolism ; Mice ; Up-Regulation/drug effects ; Humans ; Toll-Like Receptor 4/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; *Neuroprotective Agents/pharmacology ; Myeloid Differentiation Factor 88/metabolism ; Cell Line ; *Pyrones/pharmacology ; Male ; },
abstract = {Objectives: Neuroinflammation is recognized as a significant characteristic of Alzheimer's disease (AD). Currently, there is a notable absence of effective pharmacological agents to prevent or treat neuroinflammatory processes associated with AD. Heat shock protein 70 (HSP70) is pivotal in the progression of neuroinflammation. In this study, we explored the potential of maltol, a Maillard reaction product derived from red ginseng, as a therapeutic agent for neuroinflammation. Methods: In vitro, HMC3 microglial cell models were developed to examine the regulatory effects of gradient concentrations of maltol (12.5, 25, 50 μM) on the TLR4/MyD88/NF-κB p65 signaling pathway, neuroinflammation, and pyroptosis. Analyses of the GEO database and Gene Set Enrichment Analysis (GSEA) were performed to identify the core targets of maltol, followed by HSP70 gene silencing experiments to validate the targeted regulatory mechanism. Results: Maltol significantly mitigated LPS-induced neuronal damage and cognitive deficits in mice. It effectively suppressed microglia-mediated neuroinflammation and pyroptosis, reversed oxidative stress-induced neuronal ferroptosis, and inhibited neuronal apoptosis. In vitro experiments demonstrated that maltol obstructed TLR4/MyD88 binding, thereby inhibiting NF-κB p65-mediated neuroinflammation and pyroptosis, while also alleviating excessive ROS accumulation to enhance oxidative stress and ferroptosis. Bioinformatics analysis identified HSP70 as a crucial target for the anti-inflammatory and antioxidant effects of maltol. Subsequent gene silencing experiments confirmed that maltol exerted its inhibitory effects on LPS-induced neuroinflammation and pyroptosis in an HSP70-dependent manner. Conclusions: Maltol exhibits significant protective effects against Alzheimer's disease-related neuroinflammation, oxidative stress, pyroptosis, and ferroptosis through the targeting of HSP70. This study elucidates the molecular mechanisms by which maltol improves neuroinflammatory injury and provides a novel theoretical foundation and therapeutic strategy for the intervention of Alzheimer's disease neuroinflammation using traditional Chinese medicine.},
}

*Microglia/drug effects/metabolism
Animals
*HSP70 Heat-Shock Proteins/metabolism/genetics
*Pyroptosis/drug effects
*Neurons/drug effects/metabolism
Mice
Up-Regulation/drug effects
Humans
Toll-Like Receptor 4/metabolism
*Neuroinflammatory Diseases/drug therapy/metabolism
Oxidative Stress/drug effects
Signal Transduction/drug effects
*Neuroprotective Agents/pharmacology
Myeloid Differentiation Factor 88/metabolism
Cell Line
*Pyrones/pharmacology
Male

@article {pmid42451086,
year = {2026},
author = {Soni, N and Debnath, N and Rekapally, E and Jabbar, A and Tyagi, SC and Bissa, B and Tyagi, N},
title = {Vitamin D Signaling in Neurodegenerative Disorders: Mechanisms, Therapeutic Potential, and Clinical Implications.},
journal = {Nutrients},
volume = {18},
number = {13},
pages = {},
doi = {10.3390/nu18132082},
pmid = {42451086},
issn = {2072-6643},
support = {971566; 24 TPA1304527 and 25 TPA1481771 to Neetu Tyagi.//American Heart Association/ ; },
mesh = {Humans ; *Vitamin D/metabolism/therapeutic use ; *Neurodegenerative Diseases/metabolism/drug therapy/etiology ; *Signal Transduction ; Vitamin D Deficiency/complications ; Animals ; Oxidative Stress/drug effects ; Receptors, Calcitriol/metabolism ; Blood-Brain Barrier/metabolism ; Neuroprotective Agents ; },
abstract = {Vitamin D has long been recognized for its role in calcium homeostasis and bone metabolism; however, it is now emerging as an important regulator of central nervous system (CNS) function. Recent evidence suggests that vitamin D signaling contributes to the pathogenesis and progression of several neurodegenerative disorders. Vitamin D exerts neuroprotective effects through multiple mechanisms, including regulation of calcium homeostasis, modulation of immune responses, reduction in oxidative stress, stimulation of neurotrophic factors, and maintenance of blood-brain barrier (BBB) integrity. Vitamin D receptors and metabolizing enzymes are widely distributed across several brain regions, highlighting their direct involvement in neuronal function. This review summarizes the biosynthesis, metabolism, and signaling pathways of vitamin D. It explores its role in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, and traumatic brain injury (TBI). Evidence from experimental and clinical studies indicates that vitamin D deficiency is associated with an increased risk and severity of these conditions, while supplementation may provide therapeutic benefits.},
}

Humans
*Vitamin D/metabolism/therapeutic use
*Neurodegenerative Diseases/metabolism/drug therapy/etiology
*Signal Transduction
Vitamin D Deficiency/complications
Animals
Oxidative Stress/drug effects
Receptors, Calcitriol/metabolism
Blood-Brain Barrier/metabolism
Neuroprotective Agents

@article {pmid42451124,
year = {2026},
author = {Abdulraheem, RA and Martins, RN and Krishnamoorthy, R and Alshuniaber, MA and Bharadwaj, P and Li, Z and Coorey, R and Jayasena, V and Johnson, SK and Fernando, WMADB},
title = {Neuroprotective Effects of Sorghum Polyphenol in Alzheimer's Disease: In Vitro and In Silico Analyses.},
journal = {Nutrients},
volume = {18},
number = {13},
pages = {},
doi = {10.3390/nu18132121},
pmid = {42451124},
issn = {2072-6643},
mesh = {*Polyphenols/pharmacology/isolation & purification ; *Alzheimer Disease/drug therapy/metabolism ; *Sorghum/chemistry/genetics ; *Neuroprotective Agents/pharmacology ; Amyloid beta-Peptides/metabolism ; Oxidative Stress/drug effects ; Humans ; Cell Survival/drug effects ; *Plant Extracts/pharmacology ; Animals ; Computer Simulation ; Peptide Fragments/metabolism ; Mitochondria/drug effects/metabolism ; Mice ; Cell Line ; Signal Transduction/drug effects ; },
abstract = {BACKGROUND/OBJECTIVE: Accumulation of amyloid-beta (Aβ) senile plaques in the human brain is a major hallmark of Alzheimer's disease (AD), which manifests as progressive decline in memory and cognitive functions and currently lacks effective disease-modifying therapies. Emerging evidence demonstrates that polyphenol-rich plant foods are potential complementary therapies for AD.

METHODS: In this study, we investigated crude polyphenol extracts (CPEs) and purified polyphenol extracts (PPEs) from three sorghum genotypes for their ability to inhibit Aβ42-induced toxicity in MC-65 cells. Thioflavin T fluorescence, cell viability, mitochondrial function, oxidative stress assays, and Western blotting, along with RNA sequencing and computational analyses, were used to characterise both functional and transcriptomic responses of the cells to polyphenol treatments.

RESULTS: CPEs and PPEs inhibited Aβ42 aggregation by 67-76% and significantly reduced Aβ oligomer species. The extracts increased cell viability against Aβ-induced toxicity by more than 70%, decreased intracellular oxidative stress, and enhanced mitochondrial activity by over 80%. Transcriptomic profiling revealed differential modulation of genes associated with ferroptosis and MAPK/NF- κB signalling pathways, indicating regulation of inflammatory and oxidative-stress responses are mechanisms underlying the observed neuroprotection.

CONCLUSIONS: This study demonstrates that polyphenol extracts from black and red sorghum genotypes exert strong multitarget neuroprotection against Aβ42 toxicity in MC-65 cells. These findings support further evaluation of sorghum-derived polyphenols as complementary therapeutic candidates for AD, with in vivo studies required to establish efficacy and translational potential.},
}

*Polyphenols/pharmacology/isolation & purification
*Alzheimer Disease/drug therapy/metabolism
*Sorghum/chemistry/genetics
*Neuroprotective Agents/pharmacology
Amyloid beta-Peptides/metabolism
Oxidative Stress/drug effects
Humans
Cell Survival/drug effects
*Plant Extracts/pharmacology
Animals
Computer Simulation
Peptide Fragments/metabolism
Mitochondria/drug effects/metabolism
Mice
Cell Line
Signal Transduction/drug effects

@article {pmid42451136,
year = {2026},
author = {Yu, Y and Ya, W and Zhang, J and Wang, J and Sun, B},
title = {Recent Advances in Medium-Chain Triglycerides in Chronic Disease Prevention.},
journal = {Nutrients},
volume = {18},
number = {13},
pages = {},
doi = {10.3390/nu18132133},
pmid = {42451136},
issn = {2072-6643},
support = {20240484678//Beijing Nova Program/ ; 32401988//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Triglycerides/chemistry/metabolism/administration & dosage/pharmacology ; Chronic Disease/prevention & control ; Animals ; Energy Metabolism ; Lipid Metabolism ; Gastrointestinal Microbiome/drug effects ; },
abstract = {Medium-chain triglycerides (MCTs) are functional lipids with unique physicochemical properties and metabolic advantages. Recently, their regulatory roles in various chronic diseases have attracted considerable attention. This review systematically summarizes recent research progress and the proposed mechanisms of MCTs and their metabolites in metabolic diseases, neurological disorders, gut health, and muscle function. In the metabolic field, MCTs offer potential nutritional strategies for managing obesity, type 2 diabetes mellitus (T2DM), and various metabolic liver diseases. These effects are primarily mediated by improving insulin sensitivity, regulating lipid metabolism, and modulating energy expenditure. In neurological diseases, MCTs demonstrate potential for preventing and treating Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy through multiple pathways, including ketogenic energy supply, anti-inflammatory and antioxidant effects, and mitochondrial protection. Regarding gut health, MCTs and their derivatives may benefit digestive health by modulating gut microbiota and enhancing barrier function. For muscle health, MCTs help optimize energy metabolism and protein homeostasis, showing promise for countering sarcopenia and improving exercise performance. In conclusion, the prospects for MCTs are broad. Future research should focus on promoting their scientific application in precision nutrition and disease therapy, and more rigorous clinical trials are needed to confirm their efficacy and safety.},
}

Humans
*Triglycerides/chemistry/metabolism/administration & dosage/pharmacology
Chronic Disease/prevention & control
Animals
Energy Metabolism
Lipid Metabolism
Gastrointestinal Microbiome/drug effects

@article {pmid42451200,
year = {2026},
author = {Mora-Ortiz, M and Cardelo, MP and Porras-Pérez, E and Serrán-Jiménez, A and Ledesma-Escobar, CA and Priego-Capote, F and Conde-Gavilán, C and Agüera-Morales, E and Pineda Reyes, R and Malagon, MM and Yubero-Serrano, EM and Camargo, A and Katsiki, N and López-Miranda, J and Perez-Martinez, P},
title = {Gut Microbiota Composition and Plasma Metabolomic Profile Are Associated with Amyloid Pathology and Cognitive Performance in Patients with Mild Cognitive Impairment.},
journal = {Nutrients},
volume = {18},
number = {13},
pages = {},
doi = {10.3390/nu18132200},
pmid = {42451200},
issn = {2072-6643},
support = {PI16/01777//Instituto de Salud Carlos III/ ; PI-0055-2021//Regional Government of Andalusia/ ; },
mesh = {Humans ; *Cognitive Dysfunction/blood/microbiology/metabolism/psychology ; Male ; *Gastrointestinal Microbiome/physiology ; Female ; Aged ; *Amyloid beta-Peptides/blood ; Metabolomics ; Biomarkers/blood ; Cross-Sectional Studies ; Double-Blind Method ; *Cognition ; Cross-Over Studies ; *Metabolome ; Peptide Fragments/blood ; RNA, Ribosomal, 16S ; },
abstract = {BACKGROUND/OBJECTIVES: The gut-brain axis and systemic metabolic dysregulation are increasingly implicated in Alzheimer's disease (AD) pathogenesis. This study aimed to characterize gut microbiota and plasma metabolomic profiles associated with amyloid pathology and cognitive impairment in patients with mild cognitive impairment (MCI).

METHODS: A cross-sectional multi-omics baseline analysis was performed in 47 MCI patients enrolled in a randomized, double-blind, crossover dietary intervention trial (NCT05029765). Gut microbiota composition was assessed by 16S rRNA sequencing (n = 47), and plasma metabolomics by untargeted LC-MS/MS (n = 45 after exclusion of two PCA-defined metabolomic outliers). Patients were stratified according to plasma amyloid-beta 42/40 ratio (BA42/40) and ADAScog11 score, representing complementary biomarkers of amyloid burden and cognitive impairment, respectively.

RESULTS: Higher amyloid burden and worse cognitive performance were associated with significant gut microbiota alterations, including increased alpha diversity and distinct beta diversity profiles. Differential abundance analyses consistently showed enrichment of Bacteroides-associated taxa and Akkermansia, alongside depletion of short-chain fatty acid-producing genera such as Faecalibacterium, Blautia, and Phascolarctobacterium. Plasma metabolomics identified a coherent signature associated with elevated BA42/40, characterized by accumulation of secondary bile acid sulfates and depletion of sphingolipids, neuroactive steroids, and anti-inflammatory lipid mediators, including pregnenolone sulfate, resolvin E1, and anandamide. A valid OPLS-DA discriminant model was obtained for BA42/40, whereas no predictive model was achieved for ADAScog11. Critically, this dissociation, characterized by significant microbiota differences but no metabolomic separation for ADAScog11, is itself an informative finding, suggesting that gut microbiota dysbiosis and plasma metabolomic alterations are not equally coupled to both dimensions of MCI pathophysiology.

CONCLUSIONS: MCI patients with greater amyloid pathology and cognitive impairment exhibited gut microbiota dysbiosis. However, metabolic associations were observed only for BA42/40, but not for ADAScog11. These findings provide a mechanistic framework for evaluating the impact of Mediterranean diet and probiotic interventions in the longitudinal phase of the trial.},
}

Humans
*Cognitive Dysfunction/blood/microbiology/metabolism/psychology
Male
*Gastrointestinal Microbiome/physiology
Female
Aged
*Amyloid beta-Peptides/blood
Metabolomics
Biomarkers/blood
Cross-Sectional Studies
Double-Blind Method
*Cognition
Cross-Over Studies
*Metabolome
Peptide Fragments/blood
RNA, Ribosomal, 16S

@article {pmid42451206,
year = {2026},
author = {Rao, RV and Subramaniam, KG and Gregory, J and Bredesen, AL and Coward, C and Okada, S and Kelly, L and Bredesen, DE},
title = {KetoFLEX 12/3 Diet and Cognitive Health: A Precision-Nutrition Perspective on Mechanisms, Emerging Evidence, and Future Directions.},
journal = {Nutrients},
volume = {18},
number = {13},
pages = {},
doi = {10.3390/nu18132206},
pmid = {42451206},
issn = {2072-6643},
mesh = {Humans ; *Alzheimer Disease/diet therapy ; *Precision Medicine/methods ; *Diet, Ketogenic/methods ; *Cognition ; Cognitive Enhancement ; *Cognitive Dysfunction/diet therapy ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by impaired glucose metabolism, mitochondrial dysfunction, inflammation, oxidative stress, and progressive cognitive decline. Because currently available pharmacological therapies provide only modest symptomatic benefit, nutrition-based interventions are increasingly being explored as complementary strategies for supporting brain metabolism and cognitive resilience. The KetoFLEX 12/3 dietary pattern, developed within the ReCODE (Reversal of Cognitive Decline) program, is a plant-rich, mildly ketogenic nutrition and lifestyle framework that integrates low-glycemic nutrition, time-restricted eating, and personalized metabolic optimization. The diet emphasizes deeply pigmented non-starchy vegetables, extra-virgin olive oil, nuts and seeds, omega-3-rich seafood, and minimally processed foods while limiting refined carbohydrates, sugars, processed foods, and selected grains and dairy products. Emerging mechanistic and clinical evidence suggests that KetoFLEX 12/3 may influence several pathways relevant to AD pathophysiology, including insulin signaling, mitochondrial bioenergetics, neuroinflammation, oxidative stress, autophagy, detoxification pathways, and gut-brain axis function. Observational findings from ReCODE-related studies have reported improvements in metabolic parameters, mood-related outcomes, cognitive measures, and brain volumetrics in participants adhering to multimodal precision-medicine interventions incorporating the KetoFLEX principles. Compared with traditional dietary models such as the Mediterranean or MIND diets, KetoFLEX 12/3 places greater emphasis on mild nutritional ketosis, meal timing, and metabolic personalization based on factors such as ApoE genotype and insulin sensitivity. The objective of this Perspective is to examine the mechanistic rationale, emerging evidence, limitations, and future research priorities for KetoFLEX 12/3 as a precision-nutrition framework for cognitive health in AD. Although much of the current evidence remains mechanistic, observational, or derived from multimodal intervention studies, the framework offers a biologically plausible precision-nutrition model that may inform future research and clinical investigation in cognitive decline.},
}

Humans
*Alzheimer Disease/diet therapy
*Precision Medicine/methods
*Diet, Ketogenic/methods
*Cognition
Cognitive Enhancement
*Cognitive Dysfunction/diet therapy
Brain/metabolism

@article {pmid42451343,
year = {2026},
author = {Ramineni, V and Kim, JH and Kwon, GR},
title = {Interpretable 2D Deep Learning for Alzheimer's Detection from sMRI: A Lightweight Residual CNN Approach with Comprehensive Preprocessing and Stratified Data Partitioning.},
journal = {Sensors (Basel, Switzerland)},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/s26134100},
pmid = {42451343},
issn = {1424-8220},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; *Deep Learning ; Convolutional Neural Networks ; *Magnetic Resonance Imaging/methods ; Humans ; Image Processing, Computer-Assisted/methods ; Neuroimaging/methods ; },
abstract = {Neuroimaging is a promising modality for early AD detection, facilitating timely clinical intervention. This study proposes an enhanced deep learning framework that extracts critical AD biomarkers from structural MRI (sMRI) data acquired from the ADNI. Our novel CNN architecture integrates conventional convolutional layers with residual and skip connections for efficient feature extraction, achieving substantially lower computational cost than standard deep architectures such as VGG-16 (138 M), while remaining more parameter-intensive than highly compact architectures such as MobileNet and EfficientNet, which are designed explicitly for resource-constrained deployment. A comprehensive preprocessing pipeline converts 3D MRI scans into 2D slices through quality control (discarding slices with mean intensity < 5% of the maximum), bilinear resizing to 96 × 96 pixels, normalization using training-set statistics, and data augmentation. Stratified, subject-level data partitioning combined with robust statistical validation via bootstrapping demonstrates superior multiclass classification performance across AD, early and late MCI, and cognitively normal groups compared to state-of-the-art methods. Additionally, Grad-CAM-based interpretability maps were generated to highlight disease-relevant brain regions, confirming consistent activation around the hippocampus and temporal lobe.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
*Deep Learning
Convolutional Neural Networks
*Magnetic Resonance Imaging/methods
Humans
Image Processing, Computer-Assisted/methods
Neuroimaging/methods

@article {pmid42451432,
year = {2026},
author = {Bensefia, A and Al Hashlamoun, N},
title = {Handwriting as a Biomarker for Early Detection of Parkinson's and Alzheimer's Diseases: A Comprehensive Guide for Researchers.},
journal = {Sensors (Basel, Switzerland)},
volume = {26},
number = {13},
pages = {},
doi = {10.3390/s26134190},
pmid = {42451432},
issn = {1424-8220},
mesh = {*Handwriting ; *Alzheimer Disease/diagnosis ; Humans ; *Parkinson Disease/diagnosis ; *Biomarkers ; Early Diagnosis ; Deep Learning ; Convolutional Neural Networks ; },
abstract = {Neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) present a significant and growing challenge to the healthcare systems worldwide. Both conditions are progressive and often undetected early, making timely diagnosis crucial. Recently, breakthroughs in computer vision and artificial intelligence have enabled the development of non-invasive and cost-effective screening and decision-making tools, allowing for earlier detection of the disease. This review serves as a comprehensive guide, providing structured insights into computational research methods for automated detection of PD and AD, with focus on handwriting analysis as a subtle behavioral biomarker of neurological impairment. A range of methodologies is examined, including static and dynamic handwriting assessment, feature engineering procedures, deep learning and classical ML-based approaches. The analysis emphasizes the most effective methods, the handwriting features found to be most revealing, the datasets most used in the literature, and the performance levels reported for each disease. Several studies report that transfer learning based on convolutional neural networks and transformer-based architectures for Parkinson's disease diagnosis is regularly able to achieve high accuracy, frequently above 95% on benchmark datasets. In contrast, Alzheimer's disease research is progressively benefitting from multimodal approaches combining kinematic and spatial handwriting features to capture cognitive and motor changes. Structured summaries of publicly available handwriting datasets are provided, and critical advancements, ongoing challenges, and future research priorities are discussed. The integration of insights across the studies, through this work, aims to assist researchers and clinicians in the development and translation of handwriting-based, AI-guided diagnostic tools for neurodegenerative diseases.},
}

*Handwriting
*Alzheimer Disease/diagnosis
Humans
*Parkinson Disease/diagnosis
*Biomarkers
Early Diagnosis
Deep Learning
Convolutional Neural Networks

@article {pmid42451691,
year = {2026},
author = {Singh, AA and Arukha, AP and Song, M},
title = {Indole-Derived Compounds as Redox-Modulators: Antioxidant Mechanisms in Neuronal Protection.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {13},
pages = {},
doi = {10.3390/molecules31132323},
pmid = {42451691},
issn = {1420-3049},
mesh = {Humans ; *Antioxidants/pharmacology/chemistry ; *Indoles/chemistry/pharmacology ; Animals ; *Neuroprotective Agents/pharmacology/chemistry ; Oxidation-Reduction/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neurons/drug effects/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis, are distinguished by progressive neuronal dysfunction caused primarily by oxidative stress, mitochondrial impairment, neuroinflammation, and redox imbalance. Growing evidence suggests that indole-derived compounds have significant neuroprotective potential due to their antioxidant, anti-inflammatory, and redox-modulating properties. This review summarizes the structural and biological significance of indole scaffolds, focusing on the mechanisms by which natural, endogenous, microbiota-derived, and synthetic indole compounds protect neuronal networks. Indole-3-carbinol, 3,3'-diindolylmethane, indole-3-propionic acid, and melatonin are major indole derivatives that control important neuroprotective pathways like Nrf2/ARE signaling, mitochondrial bioenergetics, neurotrophic factor expression, apoptotic regulation, and suppression of proinflammatory mediators. These compounds also maintain synaptic plasticity, reduce reactive oxygen species production, and improve neuronal survival in neurodegenerative disease models. Additionally, updated information from translational and clinical research indicates that indole-based compounds may have promising therapeutic applications; however, obstacles like low bioavailability, metabolic instability, and blood-brain barrier penetration continue to be major obstacles to clinical application. Development in nanoparticle delivery systems, microbiome-targeted interventions, and rational structural optimization may improve therapeutic efficacy and translational potential. Overall, indole-derived compounds are a versatile class of redox modulators with potential applications in the prevention and treatment of neurodegenerative diseases via integrated antioxidant and neuroprotective mechanisms.},
}

Humans
*Antioxidants/pharmacology/chemistry
*Indoles/chemistry/pharmacology
Animals
*Neuroprotective Agents/pharmacology/chemistry
Oxidation-Reduction/drug effects
*Neurodegenerative Diseases/drug therapy/metabolism
*Neurons/drug effects/metabolism
Oxidative Stress/drug effects
Signal Transduction/drug effects
Reactive Oxygen Species/metabolism

@article {pmid42452303,
year = {2026},
author = {Patil, N and Chandel, V and Rana, A and Jain, M and Kaushik, P},
title = {Correction: Patil et al. Investigation of Cannabis sativa Phytochemicals as Anti-Alzheimer's Agents: An In Silico Study. Plants 2023, 12, 510.},
journal = {Plants (Basel, Switzerland)},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/plants15132041},
pmid = {42452303},
issn = {2223-7747},
abstract = {In this publication [...].},
}

@article {pmid42452600,
year = {2026},
author = {Latella, D and Scorza, C and Bonanno, M and Calderone, A and Quartarone, A and Quattrini, F and Calabrò, RS},
title = {Neurogenic Pelvic Floor Dysfunctions Across Neurological Disorders: Mechanisms, Phenotypes, and Precision Rehabilitation Pathways-A Narrative Review.},
journal = {Journal of clinical medicine},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/jcm15135140},
pmid = {42452600},
issn = {2077-0383},
support = {RRC-2025-23686388//Ministry of Health/ ; },
abstract = {Background: Pelvic floor dysfunction (PFD) is frequent in neurological disorders, but it is often approached as a secondary urological or gynecological problem rather than a functional rehabilitation target. Neurological disease can disturb cortical, pontine, spinal, sacral, autonomic, somatic, and sensory pathways that regulate bladder storage, voiding, bowel evacuation, sexual function, and pelvic pain modulation. Methods: This narrative review synthesized biomedical evidence identified through PubMed searches from database inception to 2 May 2026. Search concepts included neurogenic lower urinary tract dysfunction, urinary and bowel dysfunction, sexual dysfunction, pelvic pain, pelvic floor rehabilitation, biofeedback, electrical stimulation, neuromodulation, telerehabilitation, robotics, and major neurological disorders. The review was oriented according to the Scale for the Assessment of Narrative Review Articles (SANRA) and was not designed as a systematic review or meta-analysis. Results: Evidence from multiple sclerosis, stroke, Parkinson's disease, Alzheimer's disease and related dementias, spinal cord injury, and fibromyalgia or nociplastic pain syndromes supports a phenotype-based framework in which pelvic floor muscle training, bladder and bowel training, biofeedback, neuromuscular electrical stimulation, posterior tibial nerve stimulation, sacral neuromodulation, telerehabilitation, robotics, and multidisciplinary care are considered complementary rather than interchangeable strategies. Conclusions: PFD in neurological disorders may be more appropriately conceptualized as a multidimensional neurorehabilitation target. Effective care depends on disease-informed phenotyping, individualized rehabilitation goals, attention to cognition and adherence, and standardized outcome measurement. Future studies should test phenotype-specific pathways that integrate bladder, bowel, sexual, pain, participation, safety, and caregiver outcomes.},
}

@article {pmid42452755,
year = {2026},
author = {Bijoch, J and Jędrasiak, K},
title = {Red Complex Pathogens, Periodontal Dysbiosis and Periodontal Therapy in Alzheimer's Disease and Dementia.},
journal = {Journal of clinical medicine},
volume = {15},
number = {13},
pages = {},
doi = {10.3390/jcm15135296},
pmid = {42452755},
issn = {2077-0383},
abstract = {This narrative review synthesizes evidence linking periodontal dysbiosis with Alzheimer's disease, all-cause dementia, and dementia-relevant mechanisms, focusing on the red complex pathogens P. gingivalis, T. denticola, and T. forsythia and on the translational meaning of periodontal therapy. A PubMed-centered literature search up to May 2026 informed this synthesis (a narrative review, not a registered systematic review or meta-analysis) of 46 periodontal-scope sources, supplemented by five contextual references identified outside the periodontal search (51 references in total). P. gingivalis shows the strongest mechanistic support, including gingipains, lipopolysaccharide, outer membrane vesicles, endothelial stress, and neuroinflammatory signaling; T. denticola shows moderate biological plausibility; and T. forsythia remains mainly hypothesis-generating. Human studies associate periodontitis, tooth loss, oral-hygiene indicators, and periodontal-care exposure with dementia-relevant outcomes, but residual confounding, reverse causation, dental-care access, and heterogeneous endpoints preclude causal inference. Notably, direct targeting of a single periodontal pathogen has not shown clinical benefit, as the gingipain inhibitor atuzaginstat failed in the GAIN trial, contrasting with the modest success of amyloid-targeting therapies. Current evidence supports graded plausibility rather than causal certainty, and a registered multi-database systematic review with neurological endpoints is needed before meta-analytic clinical claims can be made.},
}

@article {pmid42452962,
year = {2026},
author = {Al-Ghraiybah, NF and Alkhalifa, AE and Spivey, D and Averill, T and Engelkemier, B and Haro Lopez, P and Stuckey, MG and Jenkins, L and Kaddoumi, A},
title = {Serotonergic System Dysregulation in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00236},
pmid = {42452962},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by several key hallmarks, including the accumulation of amyloid-β (Aβ), neurofibrillary tangles (NFTs), neuroinflammation, and blood-brain barrier (BBB) dysfunction. Similar to other neurodegenerative diseases, AD involves disturbances in neurotransmitter homeostasis. However, the serotonergic system is complex, involving numerous mechanisms and pathways, which complicates the establishment of direct correlations with AD. This review examines the serotonergic system, focusing on alterations in serotonin (5-HT), its transporter, and its receptors in the context of AD, to identify current knowledge gaps and highlight ongoing research directions. It also emphasizes the role of 5-HT in vascular regulation and BBB integrity, and links the gut-brain axis to the serotonergic system.},
}

@article {pmid42453112,
year = {2026},
author = {Giorelli, M and Paola, CAD and Vallarelli, R and Negri, F and Morgese, R and Balzano, RF and Fazio, PD and Tatò, D and Procacci, C and Masi, G and Carpagnano, FL and Dimatteo, T},
title = {Preparedness and quality of dementia care in an Italian health authority when introducing anti-Aβ therapies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70403},
pmid = {42453112},
issn = {2352-8729},
abstract = {INTRODUCTION: We aimed to assess dementia care organizations within a southern Italian local health authority (Azienda Sanitaria Locale di Barletta Andria Trani) and to propose an equitable implementation framework for anti-amyloid therapies.

METHODS: We performed a retrospective analysis of dementia-related outpatient activity in 2024 patients across 18 district clinics (primary care clinics) and three specialized centers for cognitive disorders and dementia (specialized memory centers), integrating booking, clinical, imaging, and prescribing data.

RESULTS: Among 1158 initial evaluations, specialized memory centers showed substantially higher quality indicators than district clinics: Mini-Mental State Examination documentation (80.0% vs. 6.6%, p < 0.001), full clinical documentation (95.5% vs. 10.0%), higher use of magnetic resonance imaging and amyloid positron emission tomography, and 5-fold higher rate of prescribing acetylcholinesterase inhibitors. Validated radiological scoring and biomarker facilities (cerebrospinal fluid, apolipoprotein E genotyping) were largely unavailable.

DISCUSSION: Major organizational gaps limit readiness for disease-modifying Alzheimer's disease therapies. A four-tier hub-and-spoke model may improve equity, efficiency, and safe implementation.},
}

@article {pmid42453113,
year = {2026},
author = {Jung, YH and Lee, ES and Park, YJ and Lee, S and Chung, SJ and Lim, JJ and Kim, SW and Kang, HJ and Eo, JS and Oh, K and Koh, SB and Kim, HS and Kang, SH},
title = {Association of plasma irisin levels with amyloid burden in the Alzheimer's disease spectrum.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70418},
pmid = {42453113},
issn = {2352-8729},
abstract = {INTRODUCTION: This study investigated the association between plasma myokines, including irisin, and cerebral amyloid burden across the Alzheimer's disease (AD) continuum.

METHODS: A total of 100 participants were classified into four groups: amyloid-negative cognitively unimpaired (A- CU), amyloid-positive CU (A+ CU), A+ mild cognitive impairment (MCI), and A+ dementia of the Alzheimer's disease type (DAT). All participants underwent neuropsychological testing, brain magnetic resonance imaging, amyloid positron emission tomography, and plasma myokine assessment. Multivariable linear regression and mediation analyses were performed adjusting for covariates.

RESULTS: Irisin levels were significantly lower in all AD continuum groups compared to A- CU participants (p < 0.001), while brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 21 (FGF21) showed no group differences. Higher irisin levels were associated with lower amyloid burden (r = -0.24, p = 0.019). Mediation analysis demonstrated that amyloid burden mediated the relationship between irisin and cognitive outcomes, whereas no such effects were observed for BDNF or FGF21.

DISCUSSION: Irisin may play a key role in the muscle-brain axis by linking amyloid pathology to cognitive decline in AD.},
}

@article {pmid42453150,
year = {2026},
author = {Shim, Y and Lim, EY},
title = {Baseline facial emotion recognition is associated with clinical decline across the Alzheimer's disease spectrum: a multi-instrument longitudinal assessment study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1863175},
pmid = {42453150},
issn = {1663-4365},
abstract = {BACKGROUND: Facial emotion recognition (FER) is increasingly recognized as a functionally relevant domain in the Alzheimer's disease (AD) spectrum, yet whether baseline FER is associated with subsequent clinical decline remains insufficiently established.

METHODS: We studied 328 participants [subjective cognitive decline (SCD) n = 94, mild cognitive impairment (MCI) n = 142, AD dementia n = 92] from a longitudinal memory clinic cohort; 148 had follow-up assessments (mean 1.59 ± 0.67 years). FER was assessed using the Korean version of the Florida Affect Battery (K-FAB; five subtests, FER_mean). Linear mixed-effects models examined group-differential trajectories of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SOB), and FER_mean, adjusted for age, sex, education, and baseline values.

RESULTS: FER_mean decreased stepwise across groups at baseline (SCD 17.3 ± 1.5, MCI 16.4 ± 2.1, AD 15.3 ± 2.0; p < 0.001). CDR-SOB showed more consistent group-differential longitudinal trajectories: MCI increased at +0.550 points/year (p < 0.001), with SCD significantly slower (β = -0.491, p = 0.008) and AD faster (β = +0.371, p = 0.038). FER_mean showed a modest decline in MCI (β = -0.169/yr., p = 0.078) and SCD showed significantly attenuated decline relative to MCI (β = +0.376, p = 0.035). Lower baseline FER was associated with faster CDR-SOB worsening (ρ = -0.221, p = 0.006) but not MMSE decline (ρ = 0.093, p = 0.255). FER change rates showed a weak, non-significant correlation with MMSE change (ρ = 0.004, p = 0.960) but a modest significant correlation with CDR-SOB change (ρ = -0.195, p = 0.018), suggesting partially distinct longitudinal patterns.

CONCLUSION: Baseline FER was modestly associated with longitudinal worsening in clinical severity (CDR-SOB), but not cognitive screening performance (MMSE) across the pre-dementia to dementia spectrum. FER trajectories showed limited correlation with traditional measures. These findings indicate that FER may have a potential complementary role of social cognitive assessment in the AD continuum, pending further validation.},
}

@article {pmid42453256,
year = {2026},
author = {Asyah, SKA and Saad Algethami, E and Alzaidi, BA and Althomali, RN and Alzahrani, NJ and Alhothaly, SK and Alsulaimani, WT and Almalki, AA and Ghazy, RM},
title = {Prevalence and risk factors of cognitive impairment among geriatric patients at Prince Sultan Military Hospital, Taif, Saudi Arabia.},
journal = {Journal of family medicine and primary care},
volume = {15},
number = {4},
pages = {1666-1673},
pmid = {42453256},
issn = {2249-4863},
abstract = {BACKGROUND: Cognitive impairment and dementia represent a growing public health challenge among the aging population in Kingdom of Saudi Arabia. This study aimed to determine the prevalence of cognitive impairment and identify associated risk factors.

METHODS: A cross-sectional study was conducted at the Prince Sultan Military Hospital Geriatric Clinic in Taif from November 2024 to May 2025. A sample of patients aged ≥65 years were recruited via simple random sampling. Data on sociodemographics, clinical history, and lifestyle were collected. Cognitive function was screened using the Arabic version of the Eight-item Alzheimer's Dementia (AD8) questionnaire, administered to knowledgeable informants who had known the participant for at least 5 years with a score ≥ 2 indicating likely impairment.

RESULTS: The study sample consisted of 182 geriatric patients. Bivariate analysis revealed that cognitive impairment was significantly associated with below-average income (P = 0.01), requiring daily assistance (P = 0.001), depression (P = 0.034), hypothyroidism (P = 0.026), lack of regular exercise (P = 0.01), and subjective cognitive complaints (P < 0.001). After multivariable adjustment using stepwise logistic regression, independent predictors of cognitive impairment were: any cognitive complaint (aOR = 17.99, 95% CI: 7.8-46.3, P < 0.001), hypothyroidism (aOR = 4.27, 95% CI: 1.4-14.3, P = 0.014), below-average income (aOR = 3.40, 95% CI: 1.6-7.8, P = 0.003), and lack of regular exercise (aOR = 2.61, 95% CI: 1.1-6.2, P = 0.027).

CONCLUSION: This study found a high prevalence of cognitive impairment among geriatric clinic patients in Taif. Key predictors include modifiable risks like physical inactivity, treatable conditions such as hypothyroidism, and socioeconomic and personal factors. The findings support routine cognitive screening and highlight priority areas for multidisciplinary interventions to reduce cognitive decline.},
}

@article {pmid42453339,
year = {2026},
author = {Thapa Magar, TB and Kim, M and Kim, Y and Choi, EY and Choi, YK and Kim, DE and Kim, KB and Park, JE},
title = {Pharmacokinetics, Target Engagement of an Immunoproteasome Subunit Low-Molecular-Mass Polypeptide‑2 (LMP2) Inhibitor AR-01, and Its Anti-Alzheimer's Effects in Rodents.},
journal = {ACS pharmacology & translational science},
volume = {9},
number = {7},
pages = {1869-1880},
pmid = {42453339},
issn = {2575-9108},
abstract = {Previously, we reported that AR-01, an irreversible macrocyclic peptide epoxyketone, selectively inhibits the immunoproteasome catalytic subunit LMP2 (low-molecular mass polypeptide-2). We also showed that LMP2 inhibition produces anti-Alzheimer's effects in animal models of Alzheimer's disease (AD) by suppressing microglia-mediated inflammation. As such, AR-01 is being developed as a potential treatment for AD. Typically, CNS drugs with peptide backbones face significant challenges due to unfavorable properties for crossing the blood-brain barrier. In this report, we evaluated the pharmacokinetic properties of AR-01, including brain permeability (i.e., brain-to-plasma partition coefficient), in healthy mice and rats as part of early stage drug development. We also verified AR-01 target engagement in the brain using two alternative approaches: (i) LMP2 activity assay and (ii) LMP2 band shift on Western blotting, which is caused by the formation of an irreversible LMP2:AR-01 adduct. The results confirmed that a single intravenous administration of AR-01 inactivates LMP2 in the mouse brain in a dose-dependent manner. Multiple doses of AR-01 led to cumulative LMP2 adduct formation in the mouse brain and improved cognitive function in 5xFAD mice, a widely used model of amyloidogenesis. Taken together, the results suggest that AR-01 has promising pharmaceutical properties as an AD therapeutic.},
}

@article {pmid42453345,
year = {2026},
author = {Anil, V and Sherin, DR},
title = {Recent Advances in Organofluoroprobes for Brain Imaging: Progress, Challenges, and Future Directions.},
journal = {ACS pharmacology & translational science},
volume = {9},
number = {7},
pages = {1652-1703},
pmid = {42453345},
issn = {2575-9108},
abstract = {The precise and early diagnosis of neurodegenerative diseases remains a major challenge because of their highly complex and multifactorial pathophysiology. However, in recent years, the potential of organofluoroprobes(?)organic molecules designed to function as fluorescent probes in bioimaging(?)has become increasingly prominent. These probes enable visualization of essential biomarkers, including amyloid-beta (Aβ), tau, reactive oxygen and nitrogen species (ROS/RNS), neurotransmitters, and abnormal metal ions, facilitating early detection and monitoring of diseases such as Alzheimer's and Parkinson's. This review focuses on small-molecule organofluoroprobes, which consist of curcumin-, boron-dipyrromethane (BODIPY)-, cyanine-, coumarin-, benzothiazole-, thiophene-, naphthalene-, oxazine-, and organometallic-based systems. We also address biomarker-activated probes, nanoengineered aggregation-induced emission (AIE) luminogens, and photoacoustic probes that provide greater tissue penetration and multimodal imaging. Nevertheless, these imaging probes still have shortcomings, including poor specificity, limited penetration through the blood-brain barrier (BBB), and inefficient near-infrared II (NIR-II) emission. Notably, the design and optimization of fluoroprobes are being revolutionized by the integration of artificial intelligence (AI) and computational methods, such as deep learning, generative models, and virtual screening. These approaches provide new avenues for predictive modeling of physicochemical properties, target affinity and in vivo performance, thereby significantly reducing the time and cost of development. The review concludes by discussing current challenges and future perspectives, including the convergence of AI-assisted molecular design and synthetic chemistry in bioimaging, ultimately leading to the clinical translation of next-generation brain imaging probes.},
}

@article {pmid42453424,
year = {2026},
author = {Ding, Y and Li, SY and Zhang, WF and Chu, MM and Wang, XJ and Zhang, YG and Zhang, HW and Zhang, YT and Xu, L and Liu, X and Morita, T and Baba, O and Ren, ZJ and Zhang, YJ and Zhang, ZY and Li, L},
title = {PYGL-driven glycogenolysis impairs microglial autophagic flux via SNAP29 O-GlcNAcylation in Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {7},
pages = {4367-4388},
pmid = {42453424},
issn = {2211-3835},
abstract = {Aberrant metabolic alterations underlie microglial dysfunction, which plays an important role during neurodegenerative progression. However, the role of aberrant glycogen metabolism remains elusive. Here, we identified glycogen accumulation and upregulated glycogenolytic enzymes in brain microglia from patients with Alzheimer's disease (AD) and transgenic animal models. Particularly, the principal microglial glycogenolytic enzyme PYGL exhibited the most notable spatiotemporal upregulation during disease progression. Specific knockdown of microglial PYGL ameliorated neuropathological changes and cognitive deficits in AD mice. Bioinformatics analysis and experimental validation confirmed that enhancing microglial autophagic flux-dependent Aβ clearance was the underlying mechanism. Furthermore, among all possible glycogenolytic pathways, PYGL downregulation primarily reduced hexosamine biosynthesis pathway activity, diminished UDP-GlcNAc and O-GlcNAcylation of the autophagy key protein SNAP29, and thereby facilitated formation of the SNARE complex, which is essential for autophagosome-lysosome fusion. These findings reveal a glycogenolysis-driven post-translational pathway regulating microglial autophagy, establishing PYGL as a therapeutic target for AD.},
}

@article {pmid42453520,
year = {2026},
author = {Tsai, ST and Liew, HK and Wang, MJ and Hung, WT and Huang, HY},
title = {Tracking pericyte dysfunction in Alzheimer's disease: The emerging role of cerebrospinal fluid platelet-derived growth factor receptor-β.},
journal = {Tzu chi medical journal},
volume = {38},
number = {3},
pages = {275-288},
pmid = {42453520},
issn = {2223-8956},
abstract = {Growing human and experimental evidence redefine Alzheimer's disease (AD) as a neurovascular disorder because the early neurovascular unit (NVU) injury triggers proteinopathy. Among NVU, pericytes are a pivotal regulator of capillary tone, blood-brain barrier (BBB) integrity, and amyloid-β (Aβ) clearance. Injured or lost pericytes promote non-selective transcytosis, induce endothelial de-zonation, weaken tight junctions, and drive heterogeneous capillary flow and rarefaction. Here, we collect data from clinical imaging, cerebrospinal fluid (CSF) biomarkers, and transgenic mice with platelet-derived growth factor receptor-β (PDGFRβ) signal defects to discuss the role of CSF soluble PDGFRβ (sPDGFRβ) as a marker of BBB damage across the AD continuum. During normal aging, sPDGFRβ rises slightly, consistent with low-grade pericyte stress. In mild cognitive impairment, sPDGFRβ is elevated and associates with BBB breakdown and accelerated cognitive decline, often independent of core AD biomarkers, suggesting early vascular changes before AD onset. In early AD, pericyte dysfunction (characterized by elevated sPDGFRβ) attenuates pericyte-dependent Aβ processing and endothelial lipoprotein receptor-related protein 1-mediated Aβ efflux, leading to impaired perivascular drainage and favoring Aβ40-rich vascular deposition and capillary cerebral amyloid angiopathy. During AD progression, despite persistent leakage, sPDGFRβ frequently plateaus, reflecting severe pericyte depletion and reduced discrimination of disease stage. We propose a practical approach that integrates sPDGFRβ with BBB imaging analysis and Aβ biomarkers to distinguish between parenchymal-dominant and vascular-dominant pathology in AD. These indicators can identify patients at high risk of developing amyloid-related imaging abnormalities during anti-amyloid therapy and can serve as pharmacodynamic endpoints for BBB-stabilizing or pericyte-targeted interventions to advance personalized dementia care.},
}

@article {pmid42453526,
year = {2026},
author = {Varinthra, P and Ibiayo, AG and Liu, CH and Pakaprot, N and Paromi, IN and Do, TT and Raza, M and Liu, IY},
title = {Therapeutic advances in Alzheimer's disease: Current strategies and future possibilities.},
journal = {Tzu chi medical journal},
volume = {38},
number = {3},
pages = {263-274},
pmid = {42453526},
issn = {2223-8956},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing memory, cognitive, and behavioral impairments in older adults and poses a major worldwide health challenge. The pathophysiology of AD is highly complex and multifactorial, arising from interrelated processes such as amyloid-β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, mitochondrial impairment, and oxidative stress. In addition, both genetic predisposition and environmental or lifestyle factors play critical roles in disease susceptibility and progression. Despite decades of investigation, therapeutic options with robust disease-modifying potential remain limited. Based on published studies from 2021 to 2025, current treatments primarily focus on symptomatic management with cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, and combined therapies, complemented by nonpharmacological interventions to support cognition and quality of life. Recently, advances in disease-modifying strategies, particularly monoclonal antibodies targeting Aβ, tau-directed therapies, and approaches modulating neuroinflammation, have generated cautious optimism for shifting the treatment paradigm. Importantly, emerging evidence suggests that specific herbal extracts with antioxidant, anti-inflammatory, and neuroprotective properties may serve as promising adjuncts to conventional therapy. Effective long-term management of AD may ultimately require multimodal strategies that integrate pharmacological, herbal, and lifestyle interventions with precision medicine approaches guided by biomarkers and neuroimaging. This minireview summarizes current therapeutic strategies, emerging advances, and persistent challenges, while highlighting future directions to enable earlier intervention and more effective modulation of disease progression.},
}

@article {pmid42453588,
year = {2026},
author = {Li, C and Lin, C and Li, Z and Lv, F and Yang, W and Ji, L and Cai, X},
title = {Anti-obesity medications and cognitive disorder risk: a discrepancy between RCTs and real-world evidence.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1859388},
pmid = {42453588},
issn = {1663-9812},
abstract = {OBJECTIVES: To investigate the association between anti-obesity medication (AOM) use and the risk of cognitive disorder in individuals with overweight and obesity.

METHODS: We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science and Clinicaltrials.gov from inception to August 2025 for randomized controlled trials (RCTs) and observational studies of AOMs. Relative risks were calculated using a random-effect model.

RESULTS: Our analysis included 4 RCTs (n = 35,924; 17,963 AOM users, 17,961 placebo recipients) and 2 retrospective cohort studies (n = 2,303,492; 1,151,746 GLP-1RA users, 1,151,746 non-users). In RCTs, the use of AOMs was not associated with a lower risk of cognitive disorder (RR = 0.94, 95% CI 0.39 to 2.25, P = 0.88) or dementia (RR = 1.02, 95% CI 0.41 to 2.54, P = 0.97) versus placebo. Every 5-kg weight reduction mediated by AOMs was not associated with a decreased risk of cognitive disorder (RR = 0.95, 95% CI 0.44 to 2.05, P = 0.82) compared with placebo. Meta-regression further confirmed that neither absolute weight loss nor weight reduction difference between AOM and placebo groups was associated with a reduced risk of cognitive disorder. However, retrospective cohort studies showed that GLP-1RA users had lower risks of cognitive disorder (OR = 0.44, 95% CI 0.21 to 0.91, P = 0.03) and Alzheimer's disease (OR = 0.43, 95% CI 0.19 to 0.97, P = 0.04) than non-users.

CONCLUSION: While short-term RCTs did not observe a substantial cognitive benefit of AOMs, real-world evidence indicated that GLP-1RAs may offer potential protection against cognitive disorders. These divergent findings highlight the need for long-term prospective trials with dedicated cognitive endpoints.},
}

@article {pmid42453713,
year = {2026},
author = {Arachchige, ASPM and Schmiliver, B and Alves, GAM},
title = {Alzheimer's disease: A comprehensive review of epidemiology, pathophysiology, diagnosis, and treatment.},
journal = {AIMS neuroscience},
volume = {13},
number = {2},
pages = {208-243},
pmid = {42453713},
issn = {2373-7972},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, representing a major global public health challenge as populations age. It accounts for roughly 60%-80% of all dementia and is characterized by progressive cognitive decline, memory impairment, and eventual loss of independence in daily functioning. The disease unfolds over decades, with neuropathological alterations preceding the onset of clinical symptoms by many years. Alzheimer's disease is closely linked to the accumulation and deposition of cerebral amyloid-β (Aβ) and represents the most common cerebral amyloid deposition disorder. Recent advances in molecular biology, neuroimaging, and biomarker science have revealed a complex, multifactorial pathogenesis involving protein misfolding, neuroinflammation, synaptic dysfunction, vascular factors, and network-level propagation of pathology. This review synthesizes current knowledge on AD terminology, epidemiology and risk factors, clinical phenotypes and natural history, pathophysiological mechanisms, diagnostic approaches (including imaging and fluid biomarkers), and established as well as emerging therapeutic strategies, while also outlining key challenges and future directions.},
}

@article {pmid42453899,
year = {2026},
author = {Smirnov, DS and Dickinson, SM and Estrella, MF and Goodwill, VS and Headley, AJ and Pizzo, DP and Galasko, D and Salmon, DP and Hiniker, A},
title = {Neurofibrillary tangle distribution in posterior cortical atrophy and typical early-onset Alzheimer's Disease.},
journal = {Free neuropathology},
volume = {7},
number = {},
pages = {18},
pmid = {42453899},
issn = {2699-4445},
abstract = {Background and objectives: Posterior Cortical Atrophy (PCA) is a focal variant of Alzheimer's Disease (AD) characterized by disproportionate and early visuospatial deficits with relative sparing of other cognitive abilities. PCA commonly arises before age 65, consistent with early onset AD (EOAD). Because studies of PCA pathology in patients with detailed cognitive assessment are rare, relationships between severity and distribution of neurofibrillary tangle (NFT) density and visuospatial deficits in PCA are not fully known. Our objectives were to: (1) determine if ratio of NFT density in occipital cortex (OC) versus hippocampus (HC) is higher in PCA than typical EOAD and (2) determine if this ratio correlates with severity of visuospatial deficits in EOAD generally. Methods: We determined density of tau NFT pathology in primary visual cortex (OC), midfrontal cortex (MF), and HC and calculated ratios of these densities for EOAD patients with PCA (n = 12) or non-PCA (n = 33) clinical phenotypes. Groups were compared using linear regression that adjusted for age at death and sex. Correlation between NFT density and visuospatial and other cognitive domain scores were examined using linear regression that adjusted for age at cognitive testing, education, sex and test-death interval. Analyses were repeated with the non-PCA EOAD patients grouped into those with mild (EOAD-Typical, n = 21) or severe (EOAD-Visual, n = 12) visuospatial impairment. Results: PCA patients had lower HC (β = -11.7 ± 5.7, p = 0.045) and a trend toward higher OC (β = 6.9 ± 3.7, p = 0.07) NFT density, and higher OC/HC (β = 0.30 ± 0.14, p = 0.04) and OC/MF (β = 0.56 ± 0.16, p = 0.001) ratios, than typical non-PCA EOAD patients. The EOAD-Visual had higher OC/HC NFT ratios (β = 0.38 ± 0.13, p = 0.008) than the EOAD-Typical non-PCA patients even though they did not meet clinical criteria for PCA. Correlations between OC/HC NFT ratios and visuospatial domain scores were strong (β = -1.29 ± 0.45, p = 0.008) and remained significant when limited to the non-PCA EOAD group (β = -1.22 ± 0.43, p = 0.008). Discussion: PCA is associated with a distribution of NFT pathology (i.e., high OC/HC NFT ratio) that coincides with early predominant visuospatial impairment. Non-PCA EOAD with a memory-predominant presentation and concomitant visuospatial impairment has an NFT distribution profile similar to PCA. NFT pathology in occipital cortex may moderate degree of visuospatial impairment in EOAD regardless of clinical syndrome.},
}

@article {pmid42453957,
year = {2026},
author = {Geraiely, B and Kianmehr, E and Iraji, A and Bukhari, SNA and Mohammadi, H and Mojtabavi, S and Mahdavi, M and Saeedi, M},
title = {Design and synthesis of new donepezil-based chalcones as multi-target-directed ligands against Alzheimer's disease: biological evaluation, molecular dynamics, and zebrafish model studies.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42453957},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease characterized by several hallmarks, including cholinergic dysfunction, aggregation of amyloid beta (Aβ), oxidative stress, and metal ion dyshomeostasis. A series of donepezil-derived chalcones 7a-q were synthesized and tested for their ability to inhibit cholinesterase (ChE) and amyloid beta (Aβ) aggregation, antioxidant properties, and metal chelation. Of these, compound 7j with a 2-chloroaryl moiety showed moderate anti-AChE activity (IC50 = 17.96 µM) and showed potent inhibition of Aβ aggregation, both in the presence of self-induced (72.5%) and AChE-induced (77.6%) conditions, and had good Cu[2+] chelation ability, which was confirmed by ultraviolet-visible (UV-vis) spectroscopy. Compound 7p, an analog containing furan, exhibited both anti-ChE activity (IC50 = 22.70 µM for AChE and 19.14 µM for BuChE, respectively) and moderate anti-Aβ aggregation activity, as well as moderate antioxidant activity. The two compounds were found to be safe, also in PC12 cells and SH-SY5Y cells. Their results are all encouraging for their use as multi-target directed ligands (MTDLs) against AD. Finally, the molecular dynamics simulations in the active site of AChE of compound 7j showed stable binding for 100 nanoseconds. In vivo experiments in zebrafish showed that compound 7p markedly enhanced locomotor and exploratory behavior, with a therapeutic profile compared to the standard drug donepezil, and compound 7j exhibited moderate therapeutic effects.},
}

@article {pmid42454127,
year = {2026},
author = {Hu, H and Wang, Y and Xu, Y and Chen, L},
title = {Diabetic retinopathy and the risk of all-cause dementia, Alzheimer's disease, and vascular dementia: a systematic review and meta-analysis.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1716648},
pmid = {42454127},
issn = {2296-858X},
abstract = {BACKGROUND: Existing evidence on the association between diabetic retinopathy (DR) and the risk of all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VD) remains inconsistent. To address this gap, we performed a systematic review and meta-analysis to quantitatively assess the relationship between DR patients and subsequent dementia risk, aiming to inform evidence-based prevention strategies.

METHODS: We systematically searched PubMed, Embase, and Web of Science for cohort studies investigating the association between DR and the risk of ACD, AD, and VD. The searches covered all available literature from the inception of database to September 2025. After literature screening, data extraction, and risk-of-bias assessment, meta-analysis was conducted using Stata 14.0. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated.

RESULTS: A total of 10 studies involving 1,720,128 participants were included. The meta-analysis showed that DR was significantly associated with higher risks of ACD (HR = 1.24, 95%CI [1.14, 1.36], p < 0.00001), VD (HR = 1.20, 95%CI [1.05, 1.37], p = 0.009), and AD (HR = 1.23, 95%CI [1.11, 1.37], p < 0.00001).

CONCLUSION: Current evidence indicates that DR is associated with an elevated risk of ACD, AD, and VD. Clinically, early screening and regular monitoring of cognitive function should be strengthened in patients with DR, and these assessments should be integrated into comprehensive diabetes care. Given the inherent limitations of this study, further high-quality prospective cohort studies are needed to confirm these findings.},
}

@article {pmid42454188,
year = {2026},
author = {Du, X and Xu, S and Zhou, X and Zhou, H and Jin, B and Peng, Z and Nüssler, AK and Liu, L and Chen, J and Yang, W},
title = {Biological properties and potential pathogenic mechanisms of oral bacterial-derived extracellular vesicles in oral and systemic diseases.},
journal = {Extracellular vesicles and circulating nucleic acids},
volume = {7},
number = {2},
pages = {813-832},
pmid = {42454188},
issn = {2767-6641},
abstract = {This review summarizes the biological characteristics of oral bacterial extracellular vesicles (O-BEVs) and their proposed roles in disease pathogenesis. As nanosized lipid bilayer structures secreted by oral bacteria, O-BEVs encapsulate virulence factors, nucleic acids, and metabolites, enabling them to traverse biological barriers and modulate host cellular functions. Studies suggest that O-BEVs are involved in the progression of oral diseases, including periodontitis, dental caries, and oral cancer through mechanisms such as immune activation, tissue destruction, and cellular behavior modulation. Furthermore, O-BEVs can enter the systemic circulation. Through synergistic interactions among their protein, lipid, and nucleic acid components, O-BEVs activate inflammatory pathways and compromise barrier integrity, thereby contributing to the pathogenesis of systemic diseases, including Alzheimer's disease, atherosclerosis, diabetes mellitus, rheumatoid arthritis, adverse pregnancy outcomes, and osteoporosis. However, most current evidence derives from preclinical (in vitro and animal) studies, while direct clinical evidence linking O-BEVs to human diseases remains limited, and causal relationships have not been firmly established. Understanding the mechanisms of O-BEVs may enable targeted diagnostic approches, therapies, and prevention strategies along the "oral-systemic axis", with important clinical and public health implications.},
}

@article {pmid42454195,
year = {2026},
author = {Fan, H and Wang, S and Li, Z and Yu, T and Ma, C and Sun, C},
title = {Stem cell extracellular vesicles for neuropsychiatric disorders and translation.},
journal = {Extracellular vesicles and circulating nucleic acids},
volume = {7},
number = {2},
pages = {764-785},
pmid = {42454195},
issn = {2767-6641},
abstract = {Neuropsychiatric disorders represent a major global health challenge due to their high prevalence, chronic disability, and substantial socioeconomic burden. Although stem cell-based therapies offer regenerative potential, their clinical application is limited by poor post-transplantation survival, restricted targeted integration, and potential tumorigenicity. Stem cell-derived extracellular vesicles (SC-EVs), particularly exosomes, have emerged as a promising cell-free therapeutic approach. These vesicles can cross the blood-brain barrier (BBB) and exhibit high biocompatibility and low immunogenicity. This review summarizes the cellular origins and biogenesis of SC-EVs and evaluates current preclinical and clinical evidence supporting their therapeutic potential. Particular attention is given to acute ischemic stroke and progressive neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. In addition, the molecular mechanisms underlying their neuroprotective and regenerative effects are discussed, with a focus on modulating neuroinflammation, promoting neurogenesis, and enhancing synaptic plasticity. Finally, key advances and major challenges in the clinical translation of SC-EVs are outlined. Integrating current evidence, this review provides a framework and practical perspective for the continued development of SC-EV-based therapies for complex neurological disorders.},
}

@article {pmid42454499,
year = {2026},
author = {Johnson, AL and Wyman, MF and Gjertsen, M and Shapiro, S and Bouges, S and Singer, J and Chin, N},
title = {A Model for Implementing Psychotherapy for Individuals With Cognitive Impairments.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/07317115.2026.2699243},
pmid = {42454499},
issn = {1545-2301},
abstract = {OBJECTIVES: Individuals with mild cognitive impairment (MCI) and Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) are at greater risk for mental health concerns than those without cognitive impairments. We report the implementation of psychological services for patients with MCI and mild AD/ADRD within a large public health-care system in the United States.

METHODS: Preimplementation process included identifying a clinic champion. Referrals were initially provided by the clinic champion and then opened to the entire Memory Assessment Clinic with predetermined eligibility guidelines. Patients were seen on a short-term basis, using CBT- or ACT-based therapy. Initial sessions were conducted in person; follow-up sessions were in person and via telehealth.

RESULTS: Patients saw an average of a 2.2-point reduction in depression symptoms and a 2-point reduction in anxiety symptoms. Implementation barriers and facilitators are listed in the full-text of the article.

CONCLUSIONS: This clinic implementation demonstrates the feasibility of evidence-based psychotherapy clinics within existing geriatric clinics. Future work should examine the impact of CBT and ACT to treat anxiety and depression in patients with these neurocognitive disorders. CLINICAL IMPLICATIONS: Patients with MCI and mild AD/ADRD show a clear interest in psychotherapy services, and initial efficacy data suggest there is a clinical benefit for mental health symptoms.},
}

@article {pmid42454584,
year = {2026},
author = {Ahmadi, B and Armstrong, M and Asken, BM and Reisi-Gahrooei, M and Babajani-Feremi, A and , and , },
title = {Deep learning-based MRI analysis reveals Lewy body co-pathology accelerates brain aging in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71593},
doi = {10.1002/alz.71593},
pmid = {42454584},
issn = {1552-5279},
support = {//Mangurian-Fixel-McKnight Collaboration/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid ; *Magnetic Resonance Imaging/methods ; Female ; *Brain/pathology/diagnostic imaging ; *Aging/pathology ; *Deep Learning ; Aged ; Male ; Aged, 80 and over ; alpha-Synuclein/cerebrospinal fluid ; *Lewy Bodies/pathology ; Atrophy/pathology ; Amyloid beta-Peptides/cerebrospinal fluid ; *Lewy Body Disease/pathology ; Neuroimaging ; Cognitive Dysfunction/pathology ; },
abstract = {INTRODUCTION: Lewy body (LB) co-pathology is common in Alzheimer's disease (AD), yet its in vivo impact on neurodegeneration remains unclear.

METHODS: We trained a 3D-DenseNet on multi-cohort T1-weighted magnetic resonance imaging (MRI) from cognitively unimpaired individuals to estimate brain age (BA) and applied it to cognitively impaired Alzheimer's Disease Neuroimaging Initiative (ADNI) participants stratified by cerebrospinal fluid (CSF) p-tau181/Aβ42 (AD) and α-synuclein seed amplification assay (LB) status into: AD+LB+, AD+LB-, AD-LB+, and AD-LB-. We compared baseline and longitudinal brain-age gap (BAG), identified saliency-derived anatomical contributors, assessed regional atrophy and cognition, and evaluated whether BAG explains LB-related clinical decline within AD.

RESULTS: The model robustly captured normative aging. AD+LB+ exhibited the greatest and fastest-increasing BAG, with saliency maps emphasizing regions that also showed steeper longitudinal atrophy and concordant cognitive decline, and BAG mediated a substantial portion of LB-related cognitive impairment within AD+.

DISCUSSION: LB co-pathology confers an additional neurodegenerative burden in AD, underscoring the importance of combined biomarker assessment and targeted interventions.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid
*Magnetic Resonance Imaging/methods
Female
*Brain/pathology/diagnostic imaging
*Aging/pathology
*Deep Learning
Aged
Male
Aged, 80 and over
alpha-Synuclein/cerebrospinal fluid
*Lewy Bodies/pathology
Atrophy/pathology
Amyloid beta-Peptides/cerebrospinal fluid
*Lewy Body Disease/pathology
Neuroimaging
Cognitive Dysfunction/pathology

@article {pmid42454694,
year = {2026},
author = {Zakaria, FN and Baharuldin, MTH and Mat Taib, CN and Hamid, HA and Hamid, HA and Chiroma, SM and Moklas, MAM},
title = {Delta-9-tetrahydrocannabinol delineates D-galactose and aluminium chloride-induced cognitive dysfunction and neurodegeneration in the hippocampus of the Wistar rat model.},
journal = {Journal of biosciences},
volume = {51},
number = {},
pages = {},
pmid = {42454694},
issn = {0973-7138},
mesh = {Animals ; Aluminum Chloride/toxicity ; Galactose/toxicity ; Rats ; Male ; Rats, Wistar ; *Dronabinol/pharmacology ; Neurogenesis/drug effects ; Disease Models, Animal ; *Alzheimer Disease/drug therapy/chemically induced/pathology/genetics ; Doublecortin Protein ; Hippocampus/drug effects/pathology/metabolism ; *Cognitive Dysfunction/chemically induced/drug therapy/pathology/genetics/metabolism ; tau Proteins/genetics/metabolism ; Dentate Gyrus/drug effects/pathology/metabolism ; Calbindins/genetics/metabolism ; Chlorides/toxicity ; Aluminum Compounds/toxicity ; Glial Fibrillary Acidic Protein/genetics/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Maze Learning/drug effects ; Cognition/drug effects ; Nerve Tissue Proteins ; Antigens, Nuclear ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterised by neurodegeneration and a decline in cognition and memory. D-galactose (D-gal) and aluminium chloride (AlCl3) have been used to induce cognitive deterioration in rat models that mimic the alterations observed in AD. This study assessed the neurotherapeutic effect of Δ9-tetrahydrocannabinol (Δ9THC) on cognitive abilities, brain morphology, neurogenesis activity and neuropathological markers in Wistar rats induced by D-gal plus AlCl3. Male albino Wistar rats received D-gal (60 mg/kg, intraperitoneally) and AlCl3 (200 mg/kg, orally) daily for 10 weeks. The rats were then treated with increasing concentrations of Δ9THC (0.75, 1.5 and 3.0 mg/kg) for 28 days. Cognitive performance was evaluated using the novel object recognition and modified elevated plus maze tests. Dentate gyrus viable granule cells, neurogenesis markers, amyloid precursor protein and phosphorylated tau (p‑tau Thr231) were assessed histologically and molecularly. Δ9THC treatment improved cognitive performance, prevented granule cell loss in the dentate gyrus, increased neurogenesis-related markers (GFAP+, DCX+, calbindin+ and NeuN immunoreactivity), and reduced amyloid precursor protein and p‑tau Thr231 expression. These findings suggest that Δ9THC possesses promising therapeutic potential against Alzheimer's disease.},
}

Animals
Aluminum Chloride/toxicity
Galactose/toxicity
Rats
Male
Rats, Wistar
*Dronabinol/pharmacology
Neurogenesis/drug effects
Disease Models, Animal
*Alzheimer Disease/drug therapy/chemically induced/pathology/genetics
Doublecortin Protein
Hippocampus/drug effects/pathology/metabolism
*Cognitive Dysfunction/chemically induced/drug therapy/pathology/genetics/metabolism
tau Proteins/genetics/metabolism
Dentate Gyrus/drug effects/pathology/metabolism
Calbindins/genetics/metabolism
Chlorides/toxicity
Aluminum Compounds/toxicity
Glial Fibrillary Acidic Protein/genetics/metabolism
Amyloid beta-Protein Precursor/genetics/metabolism
Maze Learning/drug effects
Cognition/drug effects
Nerve Tissue Proteins
Antigens, Nuclear

@article {pmid42454751,
year = {2026},
author = {Biessels, GJ and Debette, S and Elahi, FM and Geranmayeh, F and Hansra, G and Hughes, TM and Ihara, M and Isaacs, J and Jokinen, H and Nott, A and Pendlebury, S and Peters, R and Schneider, J and Smith, C and Smith, EE and Vemuri, P and Wardlaw, J and Webb, A and Wilcock, DM and Hainsworth, AH},
title = {The Vascular Contribution to Dementia. World Stroke Organisation Scientific Statement.},
journal = {International journal of stroke : official journal of the International Stroke Society},
volume = {},
number = {},
pages = {17474930261470506},
doi = {10.1177/17474930261470506},
pmid = {42454751},
issn = {1747-4949},
abstract = {Alzheimer's disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one third of the population attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50-70%).The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy) and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischaemic stroke and intracerebral haemorrhage also contribute. In this World Stroke Organisation (WSO) scientific statement we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive.We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia, and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalogue transcriptomic and proteomic studies that have revealed novel candidate molecules (COL4A1/4A2, HTRA1, TRIM47, FOXF2) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease, and potential biochemical markers (VEGF-A, PLGF, IL-6, MMP9, CTSB). We highlight the potential for vascular interventions to treat not only vascular dementia, but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signalling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3-fatty acid, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia.},
}

@article {pmid42455059,
year = {2026},
author = {Ahmad, S and Jo, MH and Ikram, M and Khan, A and Kim, MO},
title = {RETRACTED: Ahmad et al. Deciphering the Potential Neuroprotective Effects of Luteolin Against Aβ1-42-Induced Alzheimer's Disease. Int. J. Mol. Sci. 2021, 22, 9583.},
journal = {International journal of molecular sciences},
volume = {27},
number = {14},
pages = {},
doi = {10.3390/ijms27146230},
pmid = {42455059},
issn = {1422-0067},
abstract = {The journal retracts the article titled "Deciphering the Potential Neuroprotective Effects of Luteolin against Aβ1-42-Induced Alzheimer's Disease" [...].},
}

@article {pmid42455424,
year = {2026},
author = {Quan, S and Fu, X and Cai, H and Zhang, W and Geng, Y and Tian, Q and Ren, Z and Xu, Y and An, C and Li, J and Wang, W and Jia, L},
title = {Higher physical activity levels mitigate synaptic protein loss and cognitive deterioration in aging and in Alzheimer's disease: a 10-year longitudinal study.},
journal = {Molecular biomedicine},
volume = {7},
number = {1},
pages = {},
pmid = {42455424},
issn = {2662-8651},
support = {82471210//National Natural Science Foundation of China/ ; U24A20681//National Natural Science Foundation of China/ ; Z201100005520016//Beijing Brain Initiative of the Beijing Municipal Science & Technology Commission/ ; 7202061//Beijing Municipal Natural Science Foundation/ ; 2022-2-2017//Capital's Funds for Health Improvement and Research/ ; 2022ZD0211600//STI 2030-Major Projects/ ; 2022ZD0211605//STI 2030-Major Projects/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology/blood ; *Aging/metabolism ; Longitudinal Studies ; Female ; Aged ; Male ; *Synapses/metabolism ; *Cognition ; Aged, 80 and over ; Disease Progression ; },
abstract = {Synaptic degeneration is a hallmark of Alzheimer's disease (AD) and is closely linked to cognitive decline. Although physical activity (PA) can preserve synaptic integrity and cognitive function, its long-term effects during aging and AD progression remain poorly characterized. Here, we conducted a 10-year longitudinal study to investigate the effects of different PA levels on synaptic proteins and cognitive function during aging and in AD progression. The study included 231 cognitively normal older adults (preclinical AD, 116; controls, 115), who were stratified based on their PA intensity. Plasma was collected every 2 years to quantify four synaptic proteins (GAP43, neurogranin, SNAP25, and synaptotagmin 1) in neuron-derived extracellular vesicles (EVs), with concurrent cognitive assessments. The results indicated that all synaptic proteins declined over time, with a greater reduction in AD than in normal aging (P < 0.05). Synaptic protein levels did not differ between PA groups at baseline (P > 0.05), but at the 10-year follow-up, participants with higher PA had significantly greater synaptic protein levels than those with lower PA in both AD and controls (P < 0.05). Consistently, higher PA alleviated synaptic protein loss during aging (P < 0.05). Furthermore, higher PA was associated with slower cognitive decline in patients with preclinical AD (P < 0.05). Our study suggests that higher levels of PA may mitigate age- and AD-related synaptic deterioration, thereby contributing to cognitive resilience in late life.},
}

Humans
*Alzheimer Disease/metabolism/physiopathology/blood
*Aging/metabolism
Longitudinal Studies
Female
Aged
Male
*Synapses/metabolism
*Cognition
Aged, 80 and over
Disease Progression

@article {pmid42455433,
year = {2026},
author = {Shokr, MM and Abu-Elsaoud, AM and Al Raish, SM},
title = {Plant-derived Natural Products in Neurological and Psychiatric Disorders: Mechanisms of Action and Synergistic Roles with Probiotics.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42455433},
issn = {1559-1182},
mesh = {Humans ; *Biological Products/therapeutic use/pharmacology ; Animals ; *Mental Disorders/drug therapy ; *Probiotics/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Neuroprotective Agents/therapeutic use/pharmacology ; Drug Synergism ; },
abstract = {Plant-derived natural products have emerged as promising therapeutic agents for neurological and psychiatric disorders due to their diverse bioactive compounds and multi-target mechanisms of action. This review provides a mechanistic overview of medicinal plants and probiotics in modulating key pathological processes underlying disorders such as Alzheimer's disease, epilepsy, autism spectrum disorder, and major depressive disorder. A systematic literature search was conducted across PubMed, Scopus, and Web of Science databases to identify relevant studies examining the neuroprotective, metabolic, and anti-inflammatory effects of plant-derived compounds, probiotics, and SGLT2 inhibitors. The findings highlight shared mechanisms, including attenuation of oxidative stress, suppression of neuroinflammation, modulation of mitochondrial function, and regulation of the gut-brain axis. Bioactive compounds such as polyphenols, flavonoids, alkaloids, and terpenoids demonstrate significant potential in improving neuronal survival and synaptic plasticity. Probiotics further contribute through microbiota-mediated regulation of neurotransmitters and immune responses. SGLT2 inhibitors are discussed as a comparative pharmacological model exhibiting overlapping mechanisms. Collectively, these integrative approaches provide a mechanistic framework for understanding how plant-derived compounds, probiotics, and metabolically active pharmacological models may influence shared pathways involved in neurological and psychiatric disorders. However, most proposed neuroprotective and synergistic effects require further validation through standardized formulations, well-designed clinical trials, and careful safety assessment before they can be translated into routine clinical practice.},
}

Humans
*Biological Products/therapeutic use/pharmacology
Animals
*Mental Disorders/drug therapy
*Probiotics/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy
Neuroprotective Agents/therapeutic use/pharmacology
Drug Synergism

@article {pmid42455475,
year = {2026},
author = {Maity, D and Gowtham, A and Mishra, Y and Kaundal, RK},
title = {Exosome Biology at the Interface of Neurodegeneration and Therapeutic Innovation.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42455475},
issn = {1559-1182},
mesh = {Humans ; *Exosomes/metabolism ; Animals ; *Neurodegenerative Diseases/therapy/metabolism/pathology ; Biomarkers/metabolism ; },
abstract = {Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are defined by progressive neuronal loss, protein misfolding, and chronic neuroinflammation, yet effective disease-modifying therapies remain absent. Exosomes have emerged as key mediators of central nervous system communication and are increasingly central to the biology of neurodegeneration. These nanoscale vesicles transport proteins, lipids, and nucleic acids across cellular and anatomical barriers, influencing synaptic function, immune signaling, and metabolic homeostasis. Under pathological conditions, exosomes facilitate the spread of misfolded proteins such as amyloid-β, p-tau, α-synuclein, and TDP-43, thereby accelerating network-level degeneration. At the same time, their cargo exhibits disease-specific molecular signatures detectable in peripheral biofluids, supporting their development as minimally invasive biomarkers for early diagnosis and longitudinal monitoring. Advances in exosome engineering further underscore their potential as therapeutic delivery vehicles capable of crossing the blood-brain barrier and targeting pathogenic pathways with RNA-based therapeutics, proteins, or gene-editing systems. Together, these findings position exosomes as pivotal contributors to both the mechanistic progression and translational targeting of neurodegenerative diseases.},
}

Humans
*Exosomes/metabolism
Animals
*Neurodegenerative Diseases/therapy/metabolism/pathology
Biomarkers/metabolism

@article {pmid42455572,
year = {2026},
author = {Ng, TKS and Beck, T and Sudhini, Y and Wilson, RS and Evans, DA and Rajan, KB},
title = {Salivary Cortisol and Cognitive Decline and Alzheimer Disease in Older Adults.},
journal = {JAMA network open},
volume = {9},
number = {7},
pages = {e2622955},
doi = {10.1001/jamanetworkopen.2026.22955},
pmid = {42455572},
issn = {2574-3805},
mesh = {Humans ; *Hydrocortisone/analysis/metabolism ; Female ; *Alzheimer Disease/epidemiology/metabolism ; Aged ; *Saliva/chemistry ; Male ; Chicago/epidemiology ; *Cognitive Dysfunction/metabolism/epidemiology ; Prospective Studies ; Aged, 80 and over ; Circadian Rhythm ; Hypothalamo-Hypophyseal System ; },
abstract = {IMPORTANCE: Alterations in hypothalamic-pituitary-adrenal axis activity have been implicated in cognitive aging, yet large, racially diverse studies using physiologically active salivary cortisol studies are limited.

OBJECTIVE: To determine whether diurnal salivary cortisol indices are associated with cognitive outcomes, including incident Alzheimer disease (AD), and whether distributions and associations differ by race.

This prospective cohort study was conducted from 2000 to 2011, with 11 years of follow-up, as part of the Chicago Health and Aging Project, a community-based study of older adults in urban Chicago. Participants provided salivary cortisol samples across a day (waking, afternoon, and bedtime) and completed cognitive assessments. Analyses were conducted from June to October 2025.

EXPOSURES: Five salivary cortisol indices capturing intraday variability (coefficient of variation [CV]), cumulative exposure (mean cortisol and area under the curve with respect to ground [AUCg]), and diurnal change (diurnal slope and AUC with respect to increase [AUCi]).

MAIN OUTCOMES AND MEASURES: Outcomes of interest were global cognition, cognitive decline, and incident AD, adjusted for demographic, health, and behavioral factors.

RESULTS: Among 3895 participants (mean [SD] age, 76.7 [6.8] years; 2509 [64.4%] women; 2503 Black participants [64.3%] and 1392 White participants [35.7%]), all cortisol indices were cross-sectionally associated with cognitive performance. Longitudinally, compared with the first quintile (Q1), medium to high cortisol intraday variability (CV) was associated with slower decline (Q3: β = 0.02 [95% CI, 0.001 to 0.04]; P = .04; Q4: β = 0.03 [95% CI, 0.01 to 0.04]; P = .003), whereas the highest cumulative exposure was associated with faster decline (mean cortisol Q5: β = -0.02 [95% CI, -0.04 to -0.004]; P = .02; AUCg Q5: β = -0.02 [95% CI, -0.03 to 0.00]; P = .046). Diurnal change indices (slope, AUCi) were not associated with decline or incident AD. Black participants exhibited lower cortisol exposure but flatter slopes and lower intraday variability, reflecting a blunted diurnal rhythm; associations with decline were similar across races.

CONCLUSIONS AND RELEVANCE: In this cohort study of Black and White older adults, altered diurnal cortisol patterning was associated with faster cognitive decline but not short-term AD risk. These findings support salivary cortisol as a potential early biomarker of neurocognitive aging. Racial differences in cortisol patterning suggest differential biological embedding of stress, consistent with structural inequities.},
}

Humans
*Hydrocortisone/analysis/metabolism
Female
*Alzheimer Disease/epidemiology/metabolism
Aged
*Saliva/chemistry
Male
Chicago/epidemiology
*Cognitive Dysfunction/metabolism/epidemiology
Prospective Studies
Aged, 80 and over
Circadian Rhythm
Hypothalamo-Hypophyseal System

@article {pmid42455771,
year = {2026},
author = {Alageel, NA and Hughes, CM and Alwhaibi, M and Barry, HE},
title = {Hospital pharmacists' knowledge about and attitudes towards dementia: a cross-sectional survey study.},
journal = {The International journal of pharmacy practice},
volume = {},
number = {},
pages = {},
doi = {10.1093/ijpp/riag092},
pmid = {42455771},
issn = {2042-7174},
support = {//PhD Scholarship from King Saud University/ ; },
abstract = {OBJECTIVES: This study explored hospital pharmacists' knowledge about and attitudes towards dementia, identified factors influencing these outcomes, and determined their educational experiences and future training needs.

METHODS: A cross-sectional survey study conducted among pharmacists in eight tertiary hospitals in Riyadh, Saudi Arabia, between December 2024 and March 2025. Eligible participants (n = 372) were directly involved in dispensing medications for people with dementia (PwD). Data were collected using a self-administered questionnaire comprising the Alzheimer's Disease Knowledge Scale, Dementia Attitudes Scale, and questions on demographics, prior dementia education, and training needs. Descriptive statistics summarized responses, and regression analyses identified predictors of respondents' knowledge and attitudes using Statistical Package for the Social Sciences v30.

KEY FINDINGS: In total, 224 pharmacists responded (response rate: 60.2%). Most respondents were female (n = 122, 54.5%), with a median age of 32 years, and 37.1% (n = 83) had graduated within the previous 5 years. The mean knowledge score was 18.90/30, with greatest gaps in the risk factors and caregiving domains. The mean attitude score was 93.50/140, indicating generally positive attitudes. Female gender (β = 0.22, P < .001) and professional experience with PwD (β = 0.14, P = .039) were linked to greater knowledge, while having a relative with dementia (β = 0.20, P = .004) and higher knowledge scores (β = 0.20, P = .003) were associated with more positive attitudes. Most respondents (n = 208, 93.0%) had never undertaken dementia-related training but expressed interest in future education.

CONCLUSIONS: Hospital pharmacists in Saudi Arabia demonstrated moderate knowledge and generally positive attitudes towards dementia. However, notable knowledge gaps and limited prior training were identified, highlighting the need for targeted educational initiatives.},
}

@article {pmid42455814,
year = {2026},
author = {Browne, B and Rogers, I and Ali, K and Tabet, N and Ford, E},
title = {Identifying the determinants of hospital readmission in dementia patients - A retrospective cohort study using electronic healthcare records in England.},
journal = {PloS one},
volume = {21},
number = {7},
pages = {e0351331},
doi = {10.1371/journal.pone.0351331},
pmid = {42455814},
issn = {1932-6203},
mesh = {Humans ; *Patient Readmission/statistics & numerical data ; *Dementia/mortality/epidemiology/therapy ; England/epidemiology ; Retrospective Studies ; Female ; *Electronic Health Records/statistics & numerical data ; Male ; Aged, 80 and over ; Aged ; Risk Factors ; },
abstract = {BACKGROUND: People living with dementia are at an increased risk of multiple hospital admissions due to acute illness, underlying vulnerability, progression of behavioural symptoms of dementia, or breakdown of care provision. Reducing readmission rates is a key clinical priority. This study used linked electronic health records from general practice and hospitals in England, to investigate the determinants associated with hospital readmissions and estimate the mortality risk of older adults with dementia within one year of hospital readmission.

METHODS: A retrospective cohort study using Clinical Practice Research Datalink and linked data. Patients were included if they were > 65y, diagnosed with dementia, and had a recorded acute general hospital admission. Outcome variables were readmission to hospital within 180 days of discharge, and in the readmitted group, mortality within one year of readmission. Demographics, long term conditions, polypharmacy, antipsychotic medication, medication review, post-discharge primary care appointments, and living in residential care were examined as determinants using stepwise logistic regression for readmission, and Cox regression for survival models.

RESULTS: 30,527 patients were included, median age 84y (62.7% female), with 12,351 (40.5%) readmitted within 180 days of discharge. Being male, having multiple long-term conditions, having a medication review or attending a primary care appointment post-discharge were positively associated with readmissions, while Alzheimer's type dementia, having 'Other' ethnicity, and living in residential care were negatively associated. We found a significant effect on mortality risk of age, sex, type of dementia, having two or more long-term conditions, body mass index, antipsychotic medication, polypharmacy, and living in residential care.

CONCLUSION: The findings of this cohort study suggest that biological, psychological, and social factors interact to influence hospital readmissions in older adults with dementia. Multiple long-term conditions emerged as the strongest determining factor for readmission, while age was important in survival. Future research should assess psychosocial factors such as social support, caregiver burden, and mental well-being. These findings have important implications for strengthening community-based healthcare for adults with dementia, to reduce hospital readmission.},
}

Humans
*Patient Readmission/statistics & numerical data
*Dementia/mortality/epidemiology/therapy
England/epidemiology
Retrospective Studies
Female
*Electronic Health Records/statistics & numerical data
Male
Aged, 80 and over
Aged
Risk Factors

@article {pmid42455917,
year = {2026},
author = {Kirac-Aydin, A and Pandey, BP and Mohanty, S and Mondal, R and Biswas, A and Pattnaik, AK and Mondal, S and Basavanakatti, VN and Bayrak, N and Jayaprakash, V and Kim, H and TuYuN, AF},
title = {Discovery of a Potent and Selective MAO-B Inhibitor From a Donepezil-Linked Chalcone Library With Promising Antiparkinsonian Activity.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70349},
doi = {10.1002/ddr.70349},
pmid = {42455917},
issn = {1098-2299},
support = {FDK-2024-40841//The Scientific Research Projects Coordination Unit of Istanbul University/ ; RS-2024-00347522//The National Research Foundation of Korea (NRF) funded by the Korean Government/ ; },
mesh = {*Monoamine Oxidase Inhibitors/pharmacology/chemistry ; Animals ; Monoamine Oxidase/metabolism ; Humans ; *Donepezil/chemistry/pharmacology ; Cholinesterase Inhibitors/pharmacology/chemistry ; *Chalcones/chemistry/pharmacology ; Rats ; Structure-Activity Relationship ; Molecular Docking Simulation ; Drug Discovery ; },
abstract = {A focused library of 19 donepezil-linked chalcones (DLCs) was efficiently synthesised through microwave-assisted Claisen-Schmidt condensation and subsequently profiled for their inhibitory activities against cholinesterases (AChE and BuChE) as well as monoamine oxidases (MAO-A and MAO-B). The DLCs exhibited potent and selective inhibition of MAO-B, with IC50 values ranging from 0.019 to 18.98 μM, whereas activity toward MAO-A was moderate to low (IC50 = 0.81 to > 20 μM). Among the tested DLCs, DLC9 and DLC14 showed the highest MAO-B inhibitory potential with IC50 values of 0.054 ± 0.004 μM and 0.019 ± 0.0015 μM, respectively, and high selectivity indexes (> 370 and > 1052, respectively), whereas DLC12 displayed notable MAO-A inhibition (IC50 = 0.81 ± 0.035 μM). Kinetic and reversibility studies revealed that the selected two lead DLCs (DLC9 and DLC14) acted as mixed-type reversible MAO-B inhibitors, with Kᵢ values of 20.0 ± 2.83 nM and 10.0 ± 2.82 nM, respectively. Furthermore, IC50 values of AChE inhibitory activities ranged from 5.40 to > 40 µM, whereas those of BuChE inhibitory activity range from 4.30 to > 40 µM. DLC6 showed the best AChE inhibitory potential with IC50 values of 5.40 ± 0.29 µM, while DLC13 revealed effective BuChE inhibitory potential with an IC50 value of 4.30 ± 0.89 µM. Molecular docking studies performed on hMAO-A and hMAO-B revealed that DLC14 establishes favourable π-π stacking within the aromatic cage of hMAO-B and maintains complementary hydrophobic contacts along the substrate cavity, whereas DLC6 lacks this key interaction due to steric interference of the ethoxy substituent. Among the three most potent MAO-B inhibitors (DLC2, DLC9, and DLC14), DLC2 exhibited the most favourable microsomal stability with the longest half-life and lowest intrinsic clearance, whereas DLC14 showed comparable metabolic profiles in rat and human liver microsomes. Experimental BBB permeability assays were hindered by compound-membrane interactions; however, in silico predictions indicated satisfactory oral bioavailability and brain penetration for all three candidates. In the MPTP-induced rat model of parkinsonism, the selective MAO-B inhibitor DLC14 and the non-selective inhibitor DLC6 significantly improved motor deficits and behavioural impairments across open field, pole, bar, rotarod, and forced swim tests, with progressive improvements observed up to Day 28. Notably, DLC14 consistently outperformed DLC6 and demonstrated an efficacy profile comparable to that of Selegiline, highlighting its therapeutic potential as an antiparkinsonian agent. These results indicate that DLC14 is potent and selective MAO-B inhibitor and could serve as promising candidate for the treatment of neurodegenerative disorders, such as Parkinson's disease.},
}

*Monoamine Oxidase Inhibitors/pharmacology/chemistry
Animals
Monoamine Oxidase/metabolism
Humans
*Donepezil/chemistry/pharmacology
Cholinesterase Inhibitors/pharmacology/chemistry
*Chalcones/chemistry/pharmacology
Rats
Structure-Activity Relationship
Molecular Docking Simulation
Drug Discovery

@article {pmid42456192,
year = {2026},
author = {Soussi, C and Gonneaud, J and Cabé, N and Laniepce, A and Marchant, NL and Collette, F and de Flores, R and Foyard, E and Landeau, B and Mezenge, F and Chételat, G and Segobin, S and Pitel, AL and , },
title = {Higher amyloid deposition and lower white matter volume in cognitively healthy seniors exceeding French alcohol recommendations.},
journal = {EBioMedicine},
volume = {130},
number = {},
pages = {106376},
doi = {10.1016/j.ebiom.2026.106376},
pmid = {42456192},
issn = {2352-3964},
abstract = {BACKGROUND: Older adults are particularly vulnerable to alcohol's effects. Our aim was to establish whether differences in neurocognitive health exist between cognitively healthy seniors, depending on whether they follow recent French health recommendations for stricter drinking limits beyond age 65.

METHODS: We conducted a retrospective cross-sectional study including 133 community-dwelling cognitively healthy participants aged over 65 from the Age-Well Study. Based on their compliance with recommendations, participants were classified as lower-risk or higher-risk. Neurocognitive health was assessed comprehensively through standard cognitive testing, and voxel-wise analyses of structural integrity and cortical amyloid PET burden.

FINDINGS: Higher-risk participants displayed more neocortical amyloid deposition (F = 7.577; p = 0.007; d = 0.553) and lower cerebral volume, in the absence of a difference in cognition (p > 0.1).

INTERPRETATION: These results highlight that alcohol consumption exceeding age-specific recommendations is associated with lower brain integrity, notably including elevated amyloid burden, a biomarker strongly linked with higher risk of Alzheimer's disease-related cognitive decline and dementia. Our findings emphasise the importance of strict adherence to lower-risk thresholds in older populations.

FUNDING: European Union's Horizon 2020 Research and Innovation Programme (No 667696); Institut National de la Santé et de la Recherche Médicale (INSERM); Fondation Entrepreneurs MMA; FONDATION ALZHEIMER; Région Normandie; Fondation Recherche Alzheimer; Association France Alzheimer; Fondation de France; Institut pour la Recherche en Santé Publique (IRESP).},
}

@article {pmid42456217,
year = {2026},
author = {Kim, E and Raji, MA and Polychronopoulou, E and Tzeng, HM and Milani, SA and Kuo, YF},
title = {Annual wellness visits, cognitive function, and early dementia diagnosis.},
journal = {Archives of gerontology and geriatrics},
volume = {150},
number = {},
pages = {106355},
doi = {10.1016/j.archger.2026.106355},
pmid = {42456217},
issn = {1872-6976},
abstract = {BACKGROUND: Diagnosing dementia early optimizes care and enables timely interventions for modifiable contributors. Impact of Medicare Annual Wellness Visits (AWVs) on rate of mild cognitive impairment (MCI) detection remains unclear.

OBJECTIVE: To assess association between AWVs and timeliness of diagnosis of MCI and Alzheimer's disease-related dementias (ADRD), adjusting for factors (not accounted for in prior studies) including education, poverty, residence, serial cognitive measures before and after AWV, instrumental activity of daily living, behavioral factors and non-clinical determinants of health-captured in Health and Retirement Study (HRS) survey database.

METHODS: Data from the Health and Retirement Study (HRS) linked to Medicare claims (2011-2019) were used. Propensity score-matched cohorts (AWV vs. non-AWV) were created for four calendar years. HRS survey-based scores before and after AWVs measured cognitive function. Kaplan-Meier and Cox models were used to estimate the risk of MCI/ADRD diagnoses within two years.

RESULTS: Demographic variables were well-matched (absolute standard difference < 10%). Both groups had similar cognitive decline, but the AWV group had higher cognitive scores before and after AWV than non-AWV group. MCI diagnoses were higher in the AWV group, while both groups had similar time to diagnosis for ADRD, independent of behavioral factors and non-clinical determinants of health.

CONCLUSION: AWVs are associated with earlier detection of MCI, which may guide patient-provider decisions on evaluations for modifiable factors (e.g. physical inactivity, smoking, hypothyroidism, sleep apnea) linked to cognitive decline and subsequent dementia.},
}

@article {pmid42456344,
year = {2026},
author = {An, P and Li, M and Zhang, S and Lian, D and Li, C and Wang, C and Yu, M and Wang, D and Kong, L and Ren, J and Li, Y and Wang, H and Yang, X and Wu, Z},
title = {Liquid crystal biosensing platform based on whispering gallery mode laser for Aβ42 detection.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {268},
number = {Pt 1},
pages = {115985},
doi = {10.1016/j.colsurfb.2026.115985},
pmid = {42456344},
issn = {1873-4367},
abstract = {Alzheimer's disease (AD) is an irreversible and progressively worsening neurodegenerative disorder. Amyloid beta (Aβ42) plays a crucial role in the early diagnosis of this disease. However, the concentration of Aβ42 in the blood is extremely low, which poses a challenge for Aβ42 detection. Herein, a liquid crystal (LC) biosensing platform based on whispering gallery mode (WGM) laser was developed for rapid and real-time monitoring of the AD-related biomarker Aβ42. The LC microcavities were functionally modified using cetyltrimethyl ammonium bromide (CTAB) and RNA aptamers. Based on this, the quantitative monitoring mechanism of Aβ42 was analyzed, stemming from the interaction between the negatively charged RNA aptamer and CTAB, leading to the reorientation of LC molecules. This alters the refractive index distribution within the microcavity, thereby enabling the shift of the WGM spectrum. The dynamic changes of molecular orientation in the LC microcavity were monitored by polarization optical microscopy and spectral analysis. The experimental results showed that the total shifts in the resonance spectrum were directly proportional to the concentration of Aβ42 within the range of 0-1000 pg/mL. The sensitivity of the sensor is 0.003 nm/pg/mL. The experiment further confirmed the practicability of this sensor in the mouse serum. The sensor is inexpensive, easy to manufacture and fast and it is potentially useful for AD-related biomarker screening after further validation.},
}

@article {pmid42456348,
year = {2026},
author = {Hashim, KN and Matsuba, Y and Hashimoto, S},
title = {Thioredoxin-dependent redox homeostasis modulates tau-seeded aggregation in HEK293 TauRD biosensor cells.},
journal = {Biochemical and biophysical research communications},
volume = {830},
number = {},
pages = {154297},
doi = {10.1016/j.bbrc.2026.154297},
pmid = {42456348},
issn = {1090-2104},
abstract = {Tau aggregation is a central pathological feature of Alzheimer's disease (AD) and other tauopathies. Although oxidative stress has been implicated in AD pathogenesis, the effects of intracellular redox perturbation on tau-seeded aggregation remain incompletely understood. In this study, we investigated the role of thiol redox homeostasis in tau-seeded aggregation using HEK293 TauRD fluorescence resonance energy transfer biosensor cells. Intracellular redox conditions were manipulated using the glutathione synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO) and through overexpression or knockdown of thioredoxin (TXN), a key regulator of cellular thiol redox balance. BSO treatment significantly reduced intracellular glutathione levels without causing overt cytotoxicity, confirming successful redox alteration. However, BSO treatment failed to significantly alter tau-seeded aggregation. By contrast, TXN knockdown resulted in a modest but reproducible reduction in seeded aggregation efficiency without affecting total tau reporter expression. These findings indicate that acute glutathione depletion alone is insufficient to modulate tau-seeded aggregation in this cellular model. Furthermore, disruption of the TXN system inluences tau seeding in a manner that cannot be explained simply by increased oxidative stress. Together, our results suggest that thiol redox homeostasis contributes to the regulation of tau-seeded aggregation through mechanisms beyond a simple shift toward an oxidizing intracellular environment.},
}

@article {pmid42442802,
year = {2026},
author = {Robles, CV and Robles, CV and Revilla, APA and de Jesús Valencia Suárez, V and Santander, MAS},
title = {The Role of Genetic Alterations in the Emergence of Alzheimer's Disease in Down Syndrome: A Review.},
journal = {The European journal of neuroscience},
volume = {64},
number = {1},
pages = {e70623},
doi = {10.1111/ejn.70623},
pmid = {42442802},
issn = {1460-9568},
mesh = {Humans ; *Down Syndrome/genetics/complications ; *Alzheimer Disease/genetics/epidemiology ; Amyloid beta-Protein Precursor/genetics ; Dyrk Kinases ; },
abstract = {Down syndrome (DS), the most common chromosomal disorder, is associated with an accelerated aging process, increasing the risk of early-onset Alzheimer's disease. This review examines genetic factors involved in the development of Alzheimer's disease (AD) in people with DS. A systematic search in major databases was conducted, and articles from 2020 to 2025 that met the predefined inclusion criteria were included. The results showed that the prevalence of AD was above 60% in people with DS older than 65 years, the mean age at diagnosis was 53 years, and the mortality occurred around 59 years. The main genetic factor identified was the overexpression of the APP gene, along with other genes such as DYRK1A, RCAN1, SOD1, APOEε4, and genes involved in the immune response, as well as posttranscriptional dysregulation. Diagnosis remains a challenge due to the pre-existent intellectual disability and the atypical clinical presentation of the disease; however, the development of adapted neuropsychological tests, biomarkers, and neuroimaging techniques is expected to facilitate early diagnosis. The connection between both diseases is the result of multiple genetic factors that lead to early onset and accelerated progression of AD. It is essential to achieve timely diagnosis and provide early treatment to improve quality of life of both patients and their caregivers.},
}

Humans
*Down Syndrome/genetics/complications
*Alzheimer Disease/genetics/epidemiology
Amyloid beta-Protein Precursor/genetics
Dyrk Kinases

@article {pmid42442908,
year = {2026},
author = {Dongre, S and Soni, N and Bissa, B},
title = {Role of ESCRT pathway and autophagy in neurodegenerative diseases.},
journal = {International review of neurobiology},
volume = {187},
number = {},
pages = {1-16},
doi = {10.1016/bs.irn.2026.05.022},
pmid = {42442908},
issn = {2162-5514},
mesh = {Humans ; *Endosomal Sorting Complexes Required for Transport/metabolism ; *Autophagy/physiology ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; },
abstract = {Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss resulting from impaired proteostasis and vesicular trafficking. Neurons are particularly vulnerable to these processes due to their post-mitotic nature and complex architecture. Autophagy and the endolysosomal system constitute the primary degradative pathways responsible for maintaining neuronal homeostasis. However, increasing evidence indicates that their effective function critically depends on coordination with the endosomal sorting complexes required for transport (ESCRT). Beyond their canonical role in multivesicular body biogenesis and membrane scission, ESCRT components are now recognized as essential regulators of autophagosome closure, amphisome formation, autophagosome-lysosome fusion, and endolysosomal membrane repair. Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia. This review synthesizes evidence from genetic, biochemical, and neuropathological studies to highlight shared molecular nodes, such as ESCRT-III components, the VPS4 ATPase, the adaptor protein ALIX, and late endosomal regulators, including Rab7, that couple membrane remodeling to autophagic flux. Failure of these regulatory checkpoints destabilizes endolysosomal integrity, arrests autophagic maturation, and promotes the accumulation of toxic protein species, thereby driving progressive neuronal degeneration. By framing neurodegeneration through the lens of ESCRT-autophagy coupling failure, this review provides a unified mechanistic perspective that links diverse pathogenic proteins to shared cellular vulnerabilities and identifies ESCRT-mediated membrane dynamics as a critical determinant of neuronal survival.},
}

Humans
*Endosomal Sorting Complexes Required for Transport/metabolism
*Autophagy/physiology
*Neurodegenerative Diseases/metabolism/pathology
Animals

@article {pmid42442909,
year = {2026},
author = {Iqbal, S and Shen, B},
title = {Crosstalk in Alzheimer's-delirium nexus: Molecular mechanisms and therapeutic repurposing.},
journal = {International review of neurobiology},
volume = {187},
number = {},
pages = {133-157},
doi = {10.1016/bs.irn.2026.01.004},
pmid = {42442909},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; Animals ; *Drug Repositioning ; *Blood-Brain Barrier/metabolism ; },
abstract = {Alzheimer's disease (AD) and delirium, though distinct in clinical tempo, converge mechanistically at the intersection of neurovascular dysfunction, glial activation, and metabolic collapse. This chapter explores the integrative framework of neurovascular-glia crosstalk, emphasizing how endothelial injury, astrocytic reactivity, and microglial hyperactivation collectively undermine brain energy metabolism. We highlight evidence that blood-brain barrier[c] (BBB) breakdown, mitochondrial insufficiency, and oxidative stress establish a "metabolic vulnerability state" predisposing the AD brain to delirium. Single-cell and transcriptomic analyses delineate shared molecular circuits involving MAPK, TP53, APOE, and δ-secretase (LGMN)-the latter regulated by disease-relevant miRNAs such as miR-124 and miR-146a. These networks couple neuroinflammation with impaired energy dynamics, bridging chronic neurodegeneration and acute encephalopathic stress. We further discuss how tyrosine-kinase signaling, serotonergic dysregulation, and glial-vascular miscommunication coalesce into a unified pathophysiological axis. Therapeutic repurposing strategies-ranging from tyrosine kinase inhibitors (nilotinib, imatinib) to metabolic modulators (metformin, pioglitazone)-offer promising cross-disease interventions. Finally, we underscore the transformative role of artificial intelligence (AI) and large language models (LLMs) in accelerating drug repurposing through integrative omics and pathway-based reasoning. Together, these advances redefine the AD-delirium nexus as a systems-level disorder of energy and communication, opening translational avenues for precision therapeutics that restore neurovascular balance and cognitive resilience.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
Animals
*Drug Repositioning
*Blood-Brain Barrier/metabolism