@article {pmid41417476,
year = {2025},
author = {Spezani, R and Mandarim-de-Lacerda, CA},
title = {Beyond diabetes and obesity: GLP-1 receptor agonists in disrupting the vicious cycle of metabolic dysfunction and neuroinflammation.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.70400},
pmid = {41417476},
issn = {1463-1326},
support = {E-26/203.981/2024//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; 305993/2021-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
abstract = {Neurodegenerative diseases, including debilitating conditions like Alzheimer's and Parkinson's, are characterized by progressive neuronal loss, a process fundamentally driven by persistent chronic neuroinflammation and central metabolic dysfunction. In these disorders, persistent danger signals, such as the aggregation of misfolded proteins, activate resident microglial cells, leading to a functional shift toward a detrimental, pro-inflammatory phenotype. This damaging cycle is critically exacerbated by impaired Insulin/Insulin-like Growth Factor 1 signalling, which compromises neuronal mitochondrial homeostasis, decreases energy production, and severely diminishes synaptic plasticity, thereby establishing a self-perpetuating cycle of metabolic disturbance and neuroinflammation. This review examines the burgeoning therapeutic potential of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs), a class of drugs traditionally used to manage type 2 diabetes mellitus and obesity, as neuroprotective agents. We discuss mechanistic insights demonstrating how GLP-1RAs operate through a crucial dual action: effectively mitigating central insulin resistance and directly suppressing the multi-faceted neuroinflammatory cascade. By activating specific neuronal and glial signalling pathways, GLP-1RAs are shown to restore mitochondrial function, increase neuronal resilience, and crucially, modulate adverse glial cell responses-inhibiting the release of major pro-inflammatory cytokines and significantly reducing cellular oxidative stress within the central nervous system. Clinical trials and comprehensive preclinical data, analysed through diverse experimental models of neurodegeneration, strongly support the translational potential relevance of these compounds. The accumulating evidence suggests that GLP-1RAs offer a promising, readily available therapeutic strategy to disrupt the core inflammatory and metabolic pathways common across many neurodegenerative conditions, warranting further investigation in large-scale human trials.},
}

@article {pmid41417293,
year = {2025},
author = {Sun, Y and Shao, M and Du, L and Gan, Y and Guan, Y and Cheng, G and Li, S and Jin, H and Li, B and Zhang, G and Yan, S and Xiao, X},
title = {Exploring neuroprotective effects of Chuanzhitongluo capsule on an alzheimer's disease rat model.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {5},
pmid = {41417293},
issn = {1573-7365},
support = {2021CXGCO10508//Major Scientific and Technological Innovation Project of Shandong Province/ ; 2019YFC1711205//National Key Research and Development Program of China/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Rats ; Male ; Disease Models, Animal ; Rats, Sprague-Dawley ; Oxidative Stress/drug effects ; Capsules ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) poses significant challenges to public health and well-being, with current treatments often providing limited efficacy. Chuanzhitongluo capsule (CZTL) has neuroprotective effects, and is expected to be used for the treatment of AD. In this study, the chemical composition, pharmacological effects and underlying mechanisms of CZTL against AD were systematically investigated. We identified the major components of CZTL through ultra-high-performance liquid chromatography coupled with a quadrupole time-of-flight mass spectrometer. AD rat model was established via scopolamine injection, followed by the administration of CZTL at various dosages, and pharmacological effects were then systematically evaluated. Furthermore, the potential mechanisms were explored using metabolomics and immunohistochemistry. Seventeen chemical constituents were identified from CZTL. Pretreatment with CZTL led to significant improvements in cognitive function and reductions in neuronal loss among AD rats. CZTL administration decreased abnormal protein aggregates (Aβ and Tau), along with markers of oxidative stress and inflammation. Metabolomic and immunohistochemical analyses indicated that CZTL modulated nicotinamide metabolism and impacted levels of NAD+, UMP, nitric oxide, and SIRT1 activity. These results suggest that CZTL effectively mitigates cognitive deficits and neuronal loss in AD by regulating nicotinamide and SIRT1, while inhibiting oxidative stress and inflammation. This study lies in their contribution to the development of novel anti-AD therapies derived from traditional Chinese medicine, paving the way for new approaches in managing neurodegenerative diseases.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/chemically induced
*Neuroprotective Agents/pharmacology/therapeutic use
*Drugs, Chinese Herbal/therapeutic use/pharmacology
Rats
Male
Disease Models, Animal
Rats, Sprague-Dawley
Oxidative Stress/drug effects
Capsules
Amyloid beta-Peptides/metabolism

@article {pmid41417199,
year = {2025},
author = {Jahan, S and Kumar, D and Ali, S and Siddiqui, AJ and Alaidarous, M and Khan, J and Khan, A},
title = {EVs from Stem Cells Improve Mitochondrial Dysfunction in Neuronal Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {313},
pmid = {41417199},
issn = {1559-1182},
mesh = {Humans ; *Mitochondria/metabolism/pathology ; Animals ; *Extracellular Vesicles/metabolism/transplantation ; *Stem Cells/metabolism ; *Neurons/metabolism/pathology ; },
abstract = {Mitochondrial dysfunction is a critical pathological trait of numerous neurodegenerative and inflammatory central nervous system (CNS) disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Cellular stressors can directly modulate mitochondrial metabolism and increase the production of reactive oxygen species (ROS), thereby triggering mitochondrial retrograde signaling that alters nuclear gene expression and promotes the release of deleterious signal components into the cytoplasm. These processes contribute to neuronal injury and the progression of disease pathology. Emerging evidence underlines the therapeutic potential of extracellular vesicles (EVs) derived from stem cells such as mesenchymal stem cells (MSCs), neuronal stem cells (NSCs), and induced pluripotent stem cells (iPSCs) in reversing mitochondrial dysfunction. These nanoscale vesicles, which encapsulate transcription factors, nucleic acids, proteins, lipids, and even mitochondria, facilitate intercellular communication and influence the biological behaviour of recipient cells. Notably, stem cell-derived EVs have been shown to enhance mitochondrial function by improving the maximal oxygen consumption rate and spare respiratory capacity in injured neuronal cells. The molecular cargo within EVs, including miR-21, miR-29, and antioxidant enzymes, has been implicated in regulating mitochondrial biogenesis, reducing oxidative stress, and modulating pathways associated with apoptosis, mitophagy, and energy metabolism. Importantly, EVs can cross the blood-brain barrier (BBB), offering a minimally invasive strategy for targeted CNS delivery. In conclusion, stem cell-derived EVs represent a promising, cell-free therapeutic approach to restoring mitochondrial homeostasis and preventing neuronal disorders.},
}

Humans
*Mitochondria/metabolism/pathology
Animals
*Extracellular Vesicles/metabolism/transplantation
*Stem Cells/metabolism
*Neurons/metabolism/pathology

@article {pmid41417196,
year = {2025},
author = {Ding, Z and Hou, Q and Shao, N and Gao, W and Cai, B and Hu, S},
title = {Polydatin Attenuates Cognitive Deficits and Neuroinflammation by Inhibiting the P2X7/NLRP1 Inflammasome Pathway in APP/PS1 Mice and Aβ-Treated HT22 Cells.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {311},
pmid = {41417196},
issn = {1559-1182},
support = {2023AH050830//Scientific Research Foundation of Education Department of Anhui Province/ ; 2022rcyb017//the Talent Project of Anhui University of Chinese Medicine/ ; },
mesh = {Animals ; *Glucosides/pharmacology/therapeutic use ; *Amyloid beta-Peptides/toxicity ; *Inflammasomes/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology/complications ; Mice, Transgenic ; *Presenilin-1/metabolism ; *Stilbenes/pharmacology/therapeutic use ; *Receptors, Purinergic P2X7/metabolism ; *Signal Transduction/drug effects ; Hippocampus/pathology/drug effects/metabolism ; Mice ; *Adaptor Proteins, Signal Transducing/metabolism ; Cell Line ; *Apoptosis Regulatory Proteins/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; *Cognition Disorders/drug therapy/metabolism/pathology/complications ; Pyroptosis/drug effects ; Alzheimer Disease/drug therapy ; Peptide Fragments/toxicity ; Cognitive Dysfunction/drug therapy ; Male ; Oxidative Stress/drug effects ; },
abstract = {Aβ deposition is a central pathological hallmarks of Alzheimer's disease (AD), contributing to oxidative stress, neuroinflammation, and neuronal pyroptosis. Polydatin (PD) is a natural polyphenolic compound with known anti-inflammatory and antioxidant properties, has been rarely studied in the context of AD. This study aims to investigate the neuroprotective effects and underlying mechanisms of PD in APP/PS1 transgenic mice and Aβ25-35-treated HT22 cells. Spatial exploration experiments indicate that PD administration (200 mg/kg/day) attenuated cognitive deficits. Histopathological analyses, including hematoxylin-eosin staining and transmission electron microscopy, revealed that PD mitigated hippocampal structural damage in APP/PS1 mice. Western blot and RT-qPCR results showed that PD markedly reduced the expression of pyroptosis-related proteins, including P2X7, NLRP1, ASC, caspase-1, and GSDMD, as well as oxidative stress markers in the hippocampus. In vitro, Aβ25-35 exposure led to an increased expression of P2X7 and components of the NLRP1 inflammasome in HT22 cells, which was reversed by PD treatment. What's more, siRNA knockdown experiments revealed that silencing P2X7 significantly downregulated NLRP1, whereas siNLRP1 had no significant effect on P2X7 expression, suggesting that P2X7 functions upstream of NLRP1. These findings indicate that PD alleviates AD-like pathology by suppressing P2X7/NLRP1 inflammasome-mediated pyroptosis, highlighting its potential as a multi-target therapeutic candidate for AD intervention.},
}

Animals
*Glucosides/pharmacology/therapeutic use
*Amyloid beta-Peptides/toxicity
*Inflammasomes/metabolism
*Neuroinflammatory Diseases/drug therapy/metabolism/pathology/complications
Mice, Transgenic
*Presenilin-1/metabolism
*Stilbenes/pharmacology/therapeutic use
*Receptors, Purinergic P2X7/metabolism
*Signal Transduction/drug effects
Hippocampus/pathology/drug effects/metabolism
Mice
*Adaptor Proteins, Signal Transducing/metabolism
Cell Line
*Apoptosis Regulatory Proteins/metabolism
*Amyloid beta-Protein Precursor/metabolism
*Cognition Disorders/drug therapy/metabolism/pathology/complications
Pyroptosis/drug effects
Alzheimer Disease/drug therapy
Peptide Fragments/toxicity
Cognitive Dysfunction/drug therapy
Male
Oxidative Stress/drug effects

@article {pmid41417181,
year = {2025},
author = {Zhang, R and Mu, S and Zhang, S and Qin, X and Du, G and Zhou, Y},
title = {Arctium lappa L. Leaves Alleviate Alzheimer's Disease-Like Pathologies by Modulating the Tricarboxylic Acid Cycle and Inhibiting STAT3/NF-кB Signaling.},
journal = {Plant foods for human nutrition (Dordrecht, Netherlands)},
volume = {81},
number = {1},
pages = {2},
pmid = {41417181},
issn = {1573-9104},
support = {No. 202403021212284//Fundamental Research Program of Shanxi Province/ ; No. 202403021211150//Fundamental Research Program of Shanxi Province/ ; No. 2024ZYY2A029//Shanxi Provincial Administration of Traditional Chinese Medicine research project/ ; No. 2024-021//Research Project Supported by Shanxi Scholarship Council of China/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; NF-kappa B/metabolism ; Plant Leaves/chemistry ; STAT3 Transcription Factor/metabolism ; Rats ; Signal Transduction/drug effects ; *Arctium/chemistry ; Male ; Hippocampus/drug effects/pathology ; Rats, Sprague-Dawley ; *Citric Acid Cycle/drug effects ; Disease Models, Animal ; *Plant Extracts/pharmacology ; Neuroprotective Agents/pharmacology ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Current drugs for Alzheimer's disease (AD) have limited efficacy and often cause adverse side effects. Burdock leaves, known for their heat-clearing and anti-inflammatory properties, can be consumed as a vegetable or brewed into tea. According to traditional Chinese medicine, heat-clearing and anti-inflammatory strategies are considered beneficial for the treatment of AD. Nevertheless, it remains unclear whether burdock leaves have neuroprotective effects or can alleviate neuroinflammation to delay AD progression. Herein, we found that the decline in learning and memory, as well as cognitive impairments in AD model rats, were significantly improved following burdock leaf intervention. Notably, the medium- and high-dose groups showed superior therapeutic outcomes compared to the low-dose group. Histopathological analysis of rat hippocampal tissue revealed that burdock leaves mitigated hippocampal lesions, neuronal loss, pathological amyloid β-protein accumulation, and abnormal phosphorylation of the microtubule-associated Tau protein. Metabolomics studies identified the tricarboxylic acid (TCA) cycle as a key metabolic pathway modulated by burdock leaves in AD regulation. Western blot analysis revealed that the therapeutic effects of burdock leaves may be mediated through the suppression of the STAT3/NF-κB signaling pathway and downregulation of inflammatory protein expression. Of note, the present study uncovered that burdock leaves could delay AD progression by ameliorating metabolic dysregulation and inhibiting STAT3/NF-κB-mediated inflammatory pathways, positioning them as a promising candidate for further exploration in AD therapeutics.},
}

*Alzheimer Disease/drug therapy/metabolism
Animals
NF-kappa B/metabolism
Plant Leaves/chemistry
STAT3 Transcription Factor/metabolism
Rats
Signal Transduction/drug effects
*Arctium/chemistry
Male
Hippocampus/drug effects/pathology
Rats, Sprague-Dawley
*Citric Acid Cycle/drug effects
Disease Models, Animal
*Plant Extracts/pharmacology
Neuroprotective Agents/pharmacology
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid41417174,
year = {2025},
author = {Maurya, AK and Srivastava, M and Vishwakarma, S and Ashish, A and Singh, NK and Yadav, AK and Singh, R},
title = {Association of MTHFR C677T and A1298C Polymorphisms in Metabolic Alterations, Neuroimaging, and Cognitive Decline in Alzheimer's Disease: Case-Control and Bioinformatics Insights.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {312},
pmid = {41417174},
issn = {1559-1182},
mesh = {Humans ; *Methylenetetrahydrofolate Reductase (NADPH2)/genetics ; *Alzheimer Disease/genetics/diagnostic imaging/metabolism ; Male ; Female ; *Cognitive Dysfunction/genetics/diagnostic imaging/metabolism ; Case-Control Studies ; Aged ; *Polymorphism, Single Nucleotide/genetics ; *Neuroimaging ; *Computational Biology/methods ; *Genetic Predisposition to Disease ; Homocysteine ; *Genetic Association Studies ; Folic Acid ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder influenced by genetic, metabolic, and lifestyle factors. Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, notably C677T and A1298C, may increase AD susceptibility through disruptions in one-carbon metabolism and homocysteine accumulation. This study examined the association of MTHFR C677T and A1298C variants with metabolic alterations, cognitive decline, and AD risk. A case-control study was conducted with 120 AD patients and 120 cognitively healthy controls. Cognitive function was assessed using the Hindi Mini-Mental State Examination (HMMSE) and Hindi Mattis Dementia Rating Scale (HMDRS). MRI evaluated white matter hyperintensities and cortical atrophy. Biochemical markers, including homocysteine, folate, and vitamin B12, were measured. Genotyping was performed via TaqMan SNP assays. Functional enrichment and protein-protein interaction analyses were conducted to investigate molecular mechanisms. AD cases demonstrated elevated homocysteine and blood glucose, reduced folate, and impaired cognition. Both MTHFR C677T and A1298C polymorphisms were significantly associated with AD risk under dominant and over-dominant models (ORs 3.41-4.09). Risk-allele carriers exhibited pronounced metabolic alterations. Bioinformatics analyses revealed disruption in one-carbon metabolism, oxidative stress defense, and vascular pathways, with indirect interactions between MTHFR and key AD genes (APP, PSEN1/2, MAPT, APOE, CLU, PICALM, SORL1). MTHFR C677T and A1298C variants contribute to AD susceptibility through metabolic and vascular mechanisms that exacerbate cognitive decline. Integrating genetic, biochemical, and cognitive assessments highlights potential targets for early prevention and therapeutic interventions.},
}

Humans
*Methylenetetrahydrofolate Reductase (NADPH2)/genetics
*Alzheimer Disease/genetics/diagnostic imaging/metabolism
Male
Female
*Cognitive Dysfunction/genetics/diagnostic imaging/metabolism
Case-Control Studies
Aged
*Polymorphism, Single Nucleotide/genetics
*Neuroimaging
*Computational Biology/methods
*Genetic Predisposition to Disease
Homocysteine
*Genetic Association Studies
Folic Acid

@article {pmid41416952,
year = {2025},
author = {Gamarra, M and Cruz-Gambra, A and Blanco-Urrejola, M and González, E and Azkargorta, M and Elortza, F and Falcón-Pérez, JM and Baleriola, J},
title = {Vesicular Rps6 Released by Astrocytes in an Experimental Model of AD Regulates Local Translation and Enhances Synaptic Integrity in Neurones.},
journal = {Journal of extracellular vesicles},
volume = {14},
number = {12},
pages = {e70216},
doi = {10.1002/jev2.70216},
pmid = {41416952},
issn = {2001-3078},
support = {PID2022-139451OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; RYC-2016-19837//Ministerio de Ciencia, Innovación y Universidades/ ; SAF2016-76347-R//Ministerio de Ciencia, Innovación y Universidades/ ; //The Alzheimer´s Association/ ; //Basque Government/ ; //Ikerbasque, Basque Foundation for Science/ ; //University of the Basque Country (UPV/EHU)/ ; },
mesh = {Animals ; *Astrocytes/metabolism ; *Neurons/metabolism ; *Alzheimer Disease/metabolism ; *Protein Biosynthesis ; *Extracellular Vesicles/metabolism ; *Synapses/metabolism ; *Ribosomal Protein S6/metabolism ; Mice ; Disease Models, Animal ; Cells, Cultured ; Humans ; },
abstract = {In neurones, like in any other cell, their function often relies on the fine-tuning of their protein levels, which is achieved by the balance between protein synthesis and turnover. Defects in protein homeostasis frequently lead to neuronal dysfunction and neurological disorders. Given their extreme morphological complexity and high compartmentalization, neurones highly depend on the asymmetrical distribution of their proteome. The common belief is that proteins that sustain axonal, dendritic and synaptic functions are synthesized in the soma and then transported to distal neuronal compartments. However, there is a complementary mechanism by which the mRNAs, and not the proteins, are transported to distal subneuronal domains, and once they reach their destination, they are locally translated. Although once considered heretical, local translation (or local protein synthesis) is now widely accepted by the scientific community. Nonetheless, there is one question that remains largely unexplored in the field, and that is whether local translation in dendrites, axons and synapses is fully regulated by the neurone itself or if non-neuronal cells (e.g., glia) can modulate this mechanism in a non-cell-autonomous manner. Here, we combined primary neuronal cultures, astrocyte-derived extracellular vesicle (EVs) isolation, and proteomics to investigate whether astroglial EVs modulate local translation in axons. We show that EVs released by astrocytes exposed to amyloid-β peptide (Aβ) enhance protein synthesis specifically in distal axons and increase synaptic integrity. Proteomics analysis and western blotting identified the ribosomal protein Rps6 as an astroglial Aβ-EV cargo delivered to axons. Interestingly, genetic downregulation revealed the contribution of vesicular Rps6 to translation regulation in axons and synaptic integrity. To our knowledge, this is the first report that directly demonstrates glial control of local translation in neurones through EVs, revealing a novel glia-to-neurone communication mechanism in an experimental model of Alzheimer's disease (AD).},
}

Animals
*Astrocytes/metabolism
*Neurons/metabolism
*Alzheimer Disease/metabolism
*Protein Biosynthesis
*Extracellular Vesicles/metabolism
*Synapses/metabolism
*Ribosomal Protein S6/metabolism
Mice
Disease Models, Animal
Cells, Cultured
Humans

@article {pmid41416926,
year = {2025},
author = {Taylor, JL and Baudel, MM and Pereira da Silva, E and Hell, JW and Nieves-Cintron, M and Navedo, MF},
title = {Amyloid β alters vascular CaV1.2 channel spatiotemporal properties.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP289276},
pmid = {41416926},
issn = {1469-7793},
support = {R01HL149127/HL/NHLBI NIH HHS/United States ; R01HL121059/HL/NHLBI NIH HHS/United States ; R01HL171014/HL/NHLBI NIH HHS/United States ; R01HL180444/HL/NHLBI NIH HHS/United States ; RF1AG055357/AG/NIA NIH HHS/United States ; R01NS123050/NS/NINDS NIH HHS/United States ; 1022782//American Heart Association/ ; },
abstract = {A hallmark of Alzheimer's disease is reduced cerebral blood flow, which appears to occur early in disease progression and has been associated with amyloid β (Aβ) accumulation. Cerebral artery diameter is regulated by calcium influx via voltage-gated L-type CaV1.2 channels, which contribute to arterial myocyte contractility. The potential effects of Aβ on vascular CaV1.2 channels remain unclear. To address this knowledge gap, we test the hypothesis that Aβ alters vascular CaV1.2 channel spatiotemporal properties. Using freshly dissected cerebral arteries and arterial myocytes from wild-type (WT) mice, super-resolution imaging revealed that Aβ1-42, but not Aβ1-40, increased the clustering of CaV1.2 channels in male but not female or ovariectomized female arterial myocytes. This Aβ1-42-associated CaV1.2 clustering appears to depend on NADPH oxidases, protein kinase C and protein kinase A signalling. Studies using male arterial myocytes from S1928A knockin mice suggested that Aβ1-42 effects on CaV1.2 clustering require phosphorylation of the α1C/CaV1.2 pore-forming subunit at serine-1928. Single-channel electrophysiology showed increased CaV1.2 channel activity and cooperative gating in WT male arterial myocytes exposed to Aβ1-42, but not in female WT or male S1928A myocytes. In functional studies, WT, but not S1928A, cerebral arteries acutely incubated with Aβ1-42 demonstrated enhanced constriction in response to the CaV1.2 channel agonist BayK8644. These findings provide insight into mechanisms by which Aβ may influence CaV1.2 properties and vascular contractility, potentially contributing to vascular changes in Alzheimer's disease. KEY POINTS: Specific amyloid-β peptide (Aβ1-42) induces α1C/CaV1.2 super-clustering in cerebral vascular smooth muscle, enhancing CaV1.2 activity. Aβ1-42 engages distinct pathways involving NOX-derived ROS-activated PKC and PKA (through unknown mechanisms) to drive α1C/CaV1.2 spatiotemporal reorganization leading to enhance cerebral artery contractile responses to CaV1.2 agonists. The Aβ1-42-mediated PKC- and PKA-dependent effects on α1C/CaV1.2 spatiotemporal remodelling and cerebral artery contractility require phosphorylation of α1C at S1928, as the effects are lost in S1928A tissue/cells. The molecular and functional changes occur exclusively in male vascular smooth muscle cells, revealing sex-specific vulnerabilities in amyloid β-related cerebrovascular pathology that are independent of sex hormones and establishing a potential mechanism for vascular dysfunction in conditions with elevated Aβ1-42.},
}

@article {pmid41416910,
year = {2025},
author = {Pond, B and Neri, M and Suarez Vargas, K and Yeh, J},
title = {Evaluating Dementia Training Programs for Home Care Workers: A Scoping Review.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnaf311},
pmid = {41416910},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: As the prevalence of Alzheimer's disease and related dementias (ADRD) continues to rise worldwide, so does the demand for home care workers who provide essential personal care that enables individuals living with ADRD to age in place. However, there is limited knowledge about dementia-specific training programs for home care workers. This scoping review aims to examine existing dementia training programs available for home care workers and evaluate their outcomes.

RESEARCH DESIGN AND METHODS: We searched five databases, including PubMed, Web of Science, CINAHL, Sociological Abstracts, and Scopus. We used the PRISMA Extension for Scoping Reviews (PRISMAScR) and Arksey and O'Malley's (2005) five-step scoping review framework. Eligibility criteria included relevant study population (paid home care workers), dementia education or training programs, original evaluations, and published in English.

RESULTS: Of the 903 articles identified through the five databases, 17 articles met eligibility criteria and 12 were included in the final analytic sample. The results are presented in three sections: 1) training details, 2) methods and measures, and 3) training outcomes.

DISCUSSION AND IMPLICATIONS: This scoping review has implications for three groups of stakeholders, including researchers, governments and policymakers, and home care workers. This work underscores the importance of further implementation and evaluation of dementia training programs for home care workers.},
}

@article {pmid41416891,
year = {2025},
author = {Walters, ME and Scambray, KA and Morris, EP and Palms, JD and Pierce, RM and Sol, K and Schupf, N and Brickman, AM and Zahodne, LB},
title = {Perceived Control, Brain Health, and Cognitive Reserve: Longitudinal Resilience Mechanisms in Black, White, and Hispanic Older Adults.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbaf270},
pmid = {41416891},
issn = {1758-5368},
abstract = {OBJECTIVES: Perceived control is a psychosocial factor consisting of internal (mastery) and external (constraints) control. We assessed whether mastery and constraints related to two longitudinal resilience mechanisms, brain maintenance and cognitive reserve.

METHODS: Participants included White (n=199), Black (n=262), and Hispanic (n=319) older adults (Mage=74.48, SD=6.04; 63% women) from the Washington Heights-Inwood Columbia Aging Project. Brain health measures included cortical thickness in Alzheimer's disease signature regions, total hippocampal volume, total gray matter volume, white matter hyperintensities, and their composite. Global cognition was a composite of four cognitive domains. Mastery and constraints were assessed separately in relation to longitudinal brain health and cognitive reserve (residual and moderation approaches). Univariate and bivariate latent growth curve models assessed patterns overall, and multiple-group models assessed differences by race and ethnicity. Covariates included age, sex/gender, years of education, intracranial volume, and race and ethnicity.

RESULTS: Greater mastery related to greater baseline cortical thickness for Hispanic participants. Greater constraints related to greater baseline hippocampal volume for Black participants, but faster hippocampal volume decline for White participants. Controlling for brain health, greater constraints related to worse cognition initially and over time for the entire group. Greater brain health decline more strongly related to greater cognitive decline at higher levels of constraints among Hispanic and Black individuals.

DISCUSSION: We found more evidence for cognitive reserve, rather than brain maintenance, as a resilience mechanism linking perceived control to cognitive health. Minoritized older adults may be particularly vulnerable to the negative impact of environmental constraints on cognitive reserve.},
}

@article {pmid41416889,
year = {2025},
author = {Meyer, K and Dorai, C and Puchalt, JP and Puga, F and Zauszniewski, J and Rodriguez, RA and Rodriguez, MG and Cola, P and Benton, D},
title = {AI-Enhanced Culturally Tailored Intervention for Latino Family Caregivers of Persons Living with Dementia: A Feasibility Study.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnaf305},
pmid = {41416889},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: CONFIDNECE is a culturally tailored intervention to reduce caregiver financial strain, which disproportionately impacts Latino family caregivers to persons living with dementia. CONFIDENCE demonstrated preliminary efficacy at lowering financial strain in a feasibility study, yet attendance in group videoconference sessions was low (62%). CONFIDENCE was revised to integrate the NeuViCare™ application (app) that leveraged an interactive artificial intelligence (AI) assistant and text message reminders to engage participants between sessions. This study examined whether app registration was associated with attendance, as well as overall utilization of app features.

RESEARCH DESIGN AND METHODS: CONFIDENCE was delivered in a community-based organization, where registration for the NeuViCare™ app was offered at no cost to complement the 4-week facilitated group-based intervention. Investigators tracked caregiver attendance in sessions, app registration, and uptake of app features. Bivariate statistics were used to assess the relationship between app registration and attendance.

RESULTS: Fifty-five (55) caregivers completed the CONFIDENCE intervention, among whom 50.9% (28) registered for the NeuViCare™ app. App users attended an average of 2.9 (72%) sessions, compared to 2.0 (50%) of non-users (p=.002). Interactive features of the app (e.g., messaging an AI digital assistant) were infrequently used by participants.

DISCUSSION AND IMPLICATIONS: Findings support further investigation into technology-enhanced psychoeducation for family caregivers of persons living with dementia to promote intervention adherence, particularly Latino caregivers who face greater caregiving burden and limited access to supportive resources despite higher dementia prevalence. These findings contribute to the emerging literature on technology adoption, including interactive AI, in service contexts.},
}

@article {pmid41416621,
year = {2025},
author = {Almeida, MF and Pait, MC and Rentschler, KM and Norton, CJ and Farizatto, KLG and Bahr, BA},
title = {Ginseng extract improves synaptic resiliency: A key factor for healthy cognitive aging.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70818},
doi = {10.1002/alz.70818},
pmid = {41416621},
issn = {1552-5279},
support = {R25-GM07763410/GM/NIGMS NIH HHS/United States ; T34-GM149434-01A1/GM/NIGMS NIH HHS/United States ; //USANA Health Sciences/ ; P30AG072958/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Panax ; *Plant Extracts/pharmacology ; Rats ; Hippocampus/drug effects/metabolism ; Cathepsin B/metabolism ; Autophagy/drug effects ; *Synapses/drug effects ; *Cognitive Aging ; Male ; Lysosomes/drug effects/metabolism ; *Cognition/drug effects ; *Aging/drug effects ; },
abstract = {INTRODUCTION: Disruption of the autophagy-lysosomal pathway (ALP) compromises proteostasis and contributes to aging-related proteinopathy. Many studies indicate that a healthy diet can improve cognitive health and reduce the risk of Alzheimer-type pathogenesis.

METHODS: Plant-based products were tested in hippocampal explants for amplifying the ALP component cathepsin B (CatB), a protease reported to reduce proteinopathy and synaptopathy. Proof-of-concept experiments also tested Panax quinquefolius extract (PanQ) for improving cognitive function in aging rats.

RESULTS: Among the natural extracts tested, PanQ emerged as the most effective for increasing the active CatB isoform in correspondence with enhanced levels of synaptic proteins and the autophagy marker LC3-II. PanQ also increased synaptic resilience in a model of lysosomal stress and improved cognitive performance in 20-month-old rats.

DISCUSSION: PanQ-mediated ALP enhancement implicates the proteostasis network in synaptic and cognitive maintenance mechanisms. This study also points to synaptic resiliency as an important factor underlying the influence of dietary components on cognitive health.

HIGHLIGHTS: Panax quinquefolius (PanQ) enhanced cathepsin B (CatB) in hippocampal explants. The CatB modulation corresponded with enhanced synaptic and autophagy markers. PanQ improved synaptic resilience in the chloroquine (Cqn) model of lysosomal stress. Age-related cognitive deficit was reduced by PanQ supplementation in Fischer rats.},
}

Animals
*Panax
*Plant Extracts/pharmacology
Rats
Hippocampus/drug effects/metabolism
Cathepsin B/metabolism
Autophagy/drug effects
*Synapses/drug effects
*Cognitive Aging
Male
Lysosomes/drug effects/metabolism
*Cognition/drug effects
*Aging/drug effects

@article {pmid41416584,
year = {2025},
author = {Lorenz, LMC and Rohde, SK and Luimes, MC and Rozemuller, AJM and Bank, NB and Hulsman, M and Graat, MJI and van der Hoorn, ME and Daatselaar, DAH and Gouda, M and Hoozemans, JJM and Sikkes, SAM and Teunissen, CE and Holstege, H},
title = {AD-related plasma biomarkers in centenarians: links to cognition and neuropathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70969},
doi = {10.1002/alz.70969},
pmid = {41416584},
issn = {1552-5279},
support = {/NWO_/Dutch Research Council/Netherlands ; //HorstingStuit Foundation/ ; //Hans und Ilse Breuer-Stiftung/ ; //Topsector Life Sciences & Health/ ; //Health∼Holland/ ; //Surf sara/ ; A2021031S//BrightFocus Foundation/ ; //VUmc foundation/ ; /ZONMW_/ZonMw/Netherlands ; },
mesh = {Humans ; *Biomarkers/blood ; Aged, 80 and over ; Male ; Female ; *Amyloid beta-Peptides/blood ; tau Proteins/blood ; *Alzheimer Disease/blood/pathology ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; Longitudinal Studies ; *Brain/pathology ; Peptide Fragments/blood ; *Cognition/physiology ; Neuropsychological Tests ; *Cognitive Dysfunction/blood/pathology ; },
abstract = {INTRODUCTION: Whether Alzheimer's disease (AD)-associated plasma biomarkers reflect cognitive performance and neuropathology in the oldest old remains unclear.

METHODS: In plasma samples from 255 centenarians from the longitudinal 100-plus Study (median age 101.2 years), we quantified biomarkers amyloid beta (Aβ)42/40 ratio, Aβ40, Aβ42, phosphorylated tau 181 (pTau-181)/Aβ42 ratio, pTau-181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) concentrations. These were associated with same-day measures of cognitive performance and, for centenarians who donated their brain (n = 60), with post mortem Aβ and tau neuropathology.

RESULTS: Cognition ranged from high to early cognitive decline (median Mini-Mental State Examination [MMSE] score = 26). Lower plasma Aβ40 and Aβ42 are associated with poorer executive functioning, attention/processing speed, and higher Aβ neuropathology. Elevated plasma NfL and GFAP are associated with poorer executive functioning, slower processing speed, and Aβ and tau neuropathology. Higher plasma pTau-181 and the pTau-181/Aβ42 ratio are associated with Aβ and tau neuropathology, but not with cognitive performance. The Aβ42/40 ratio was uninformative.

DISCUSSION: Plasma Aβ, NfL, and GFAP detected neuropathology and early cognitive decline in centenarians; plasma pTau-181 and the pTau-181/Aβ42 ratio primarily report more advanced neuropathology.

HIGHLIGHTS: Lower plasma Aβ40 and Aβ42 concentrations are associated with poorer executive functioning and higher Aβ neuropathology, and thus may detect early cognitive decline in centenarians. Higher plasma pTau-181 concentrations and the pTau-181/Aβ42 ratio are strongly associated with Aβ and tau neuropathology; however, they are not associated with cognitive performance. Higher NfL concentrations are associated with higher Aβ and tau neuropathology. Higher plasma NfL and GFAP concentrations are associated with poorer attention and processing speed and may detect early cognitive decline in centenarians.},
}

Humans
*Biomarkers/blood
Aged, 80 and over
Male
Female
*Amyloid beta-Peptides/blood
tau Proteins/blood
*Alzheimer Disease/blood/pathology
Glial Fibrillary Acidic Protein/blood
Neurofilament Proteins/blood
Longitudinal Studies
*Brain/pathology
Peptide Fragments/blood
*Cognition/physiology
Neuropsychological Tests
*Cognitive Dysfunction/blood/pathology

@article {pmid41416579,
year = {2025},
author = {Galvin, JE and Tolea, MI and Scharre, DW and Hamby, ME and Iaci, JF and Grundman, M and Caggiano, AO},
title = {Phase 2 study of zervimesine (CT1812) in participants with mild-to-moderate dementia with Lewy bodies (DLB).},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71004},
doi = {10.1002/alz.71004},
pmid = {41416579},
issn = {1552-5279},
support = {NCT05225415//SHIMMER/ ; R01 AG071643/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Lewy Body Disease/drug therapy ; Female ; Male ; Aged ; Double-Blind Method ; Aged, 80 and over ; Middle Aged ; Treatment Outcome ; Mental Status and Dementia Tests ; },
abstract = {INTRODUCTION: Zervimesine is in clinical development for Alzheimer's disease and dementia with Lewy bodies (DLB). This Phase 2a study evaluated zervimesine in participants with mild-to-moderate DLB.

METHODS: This was a multi-center, double-blind, placebo-controlled, parallel-design study. Participants aged 50 to 85 years, with probable DLB, a Mini-Mental State Examination score of 18 to 27, and without neurological co-morbidities were randomized to zervimesine 100 mg, zervimesine 300 mg, or placebo for 26 weeks to assess safety and efficacy.

RESULTS: Of 293 participants screened, 130 were randomized, and 109 (83.8%) completed the study. Baseline characteristics were similar between groups. Discontinuation rates for adverse events were 4.5% for zervimesine 100 mg, 16.3% for zervimesine 300 mg, and 4.8% for placebo.

DISCUSSION: This study demonstrated that zervimesine was safe and well tolerated. The favorable efficacy profile from exploratory outcomes provides a rationale for testing zervimesine in larger studies. This study was registered at ClinicalTrials.gov: NCT05225415.

HIGHLIGHTS: This study evaluated the safety and efficacy of zervimesine in Lewy body dementia. The incidence of adverse events was comparable to zervimesine 100 mg and placebo. Favorable, consistent trends were observed with zervimesine for exploratory endpoints.},
}

Humans
*Lewy Body Disease/drug therapy
Female
Male
Aged
Double-Blind Method
Aged, 80 and over
Middle Aged
Treatment Outcome
Mental Status and Dementia Tests

@article {pmid41416575,
year = {2025},
author = {Walter, S and Ptomey, L and Head, E and Cohen, A and Briones, JM and Shaw, H and Carter, B and Kishner, J and Pestolesi, W and Sciullo, A and Olmstead, KK and Carter, A and Kishner, S and Tucker, AK and Pestolesi, L and Briones, M and Sciullo, D and Sciullo, K and Shaw, P and Chen, P and Rafii, MS},
title = {"Being brave, being seen, and having your voice heard": Perspectives of self-advocates and families toward accessible and impactful research of Alzheimer's disease in down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70999},
doi = {10.1002/alz.70999},
pmid = {41416575},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; //US National Institute on Aging/ ; U01AG051406//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; U01AG051412//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
mesh = {Humans ; *Down Syndrome/complications ; *Alzheimer Disease ; *Biomedical Research ; *Patient Advocacy ; *Family/psychology ; },
abstract = {INTRODUCTION: Over 220,000 people live with Down syndrome (DS) in the United States, with an average life expectancy of 63.5 years of age. The high risk for Alzheimer's disease (AD) in DS means studies must be accessible and inclusive. We share our experience of building a collaborative group of self-advocates and care partners to provide meaningful feedback on research.

METHODS: Our research partnership group is supported by the Alzheimer's Clinical Trials Consortium-Down Syndrome (ACTC-DS) and Alzheimer's Biomarker Consortium Down Syndrome (ABC-DS). We synthesize feedback into themes and recommendations for researchers.

RESULTS: Feedback themes are broad, extending from the strong motivation to engage in research to the need to balance study burden and risk. Recommendations for researchers include providing support and connection to resources, sharing individual and study-level results, flexibility, and respectful communication.

DISCUSSION: Our collaborative approach will lead to more relevant and accessible research studies.

HIGHLIGHTS: Inclusive and accessible research is needed for Down syndrome and Alzheimer's disease. We built a collaborative group of self-advocates and care partners to provide feedback. Feedback includes a strong motivation to learn about brain health and engage in research. Respectful communication includes representative images and tailored materials. Recommendations include the choice to learn individual results, flexibility, and support.},
}

Humans
*Down Syndrome/complications
*Alzheimer Disease
*Biomedical Research
*Patient Advocacy
*Family/psychology

@article {pmid41416535,
year = {2025},
author = {Tablante, J and Casaletto, K and VandeVrede, L and Mamuyac, E and Gao, L and Esteban, JS and Guevarra, A and Johnson, J and Rios, M and Martinez, L and Roco, N and Allen, IE and Grasso, SM and Gorno-Tempini, ML and Grinberg, LT and Dronkers, N and Paolillo, EW and de Leon, J},
title = {The role of bilingualism on functional decline and neurodegeneration in distinct ADRD clinical syndromes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70991},
doi = {10.1002/alz.70991},
pmid = {41416535},
issn = {1552-5279},
support = {//Charles and Helen Schwab Foundation/ ; RF1NS050915/NS/NINDS NIH HHS/United States ; 2024-A-001-CTR//Larry L. Hillblom Foundation/ ; //Shenandoah Community Foundation/ ; AARF-22-974065/ALZ/Alzheimer's Association/United States ; /DC/NIDCD NIH HHS/United States ; R01AG075775/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; Male ; *Multilingualism ; tau Proteins/blood ; Aged ; Biomarkers/blood ; Neurofilament Proteins/blood ; Longitudinal Studies ; *Alzheimer Disease/psychology ; Disease Progression ; Middle Aged ; Neuropsychological Tests ; Aged, 80 and over ; },
abstract = {INTRODUCTION: We evaluated a large cohort (N = 408) of monolingual and bilingual speakers with Alzheimer's disease and related dementias (ADRD) syndromes and longitudinal markers of functional decline and neurodegeneration to determine whether bilingual speakers show more cognitive resilience to neurodegenerative processes.

METHODS: Participants (338 monolingual, 70 bilingual) were diagnosed based on established criteria and then categorized into five clinical groups (healthy controls and memory, language, behavioral, motor-predominant syndromes from participants living with ADRD). Linear mixed-effects models estimated longitudinal functional decline (Clinical Dementia Rating) and fluid ADRD biomarker trajectories (plasma neurofilament light chain (NfL) and plasma phosphorylated tau-217 (p-tau217).

RESULTS: Bilingual speakers showed slower progression of functional impairment and lower baseline NfL and p-tau217, but not slower biomarker trajectories, compared to monolingual speakers.

DISCUSSION: We found a protective effect of bilingualism on baseline levels of neuropathology and neurodegeneration and longitudinal functional decline, supporting a role of bilingualism in cognitive resilience across ADRDs.

HIGHLIGHTS: Explored longitudinal effects of bilingualism on functional decline, neurofilament light chain (NfL), andphosphorylated tau-217 (p-tau217). Used syndrome-defined cohorts of monolingual and bilingual speakers. First study using NfL and p-tau217 to study bilingualism's effects in cognitive resilience. Bilinguals showed slower progression of functional impairment. Bilinguals had lower baseline NfL and p-tau217 but longitudinal trajectories did not differ.},
}

Humans
Female
Male
*Multilingualism
tau Proteins/blood
Aged
Biomarkers/blood
Neurofilament Proteins/blood
Longitudinal Studies
*Alzheimer Disease/psychology
Disease Progression
Middle Aged
Neuropsychological Tests
Aged, 80 and over

@article {pmid41416492,
year = {2025},
author = {Ahmed, MAE and Ahmed, AH and Elmoghazy, NH and Shaheraldin, AA and Ghalwash, D},
title = {Pathophysiological Insights Into the Oral-Brain Axis: Evidence-Based Mechanisms Connecting Periodontitis and Alzheimer's Disease.},
journal = {The European journal of neuroscience},
volume = {62},
number = {12},
pages = {e70366},
doi = {10.1111/ejn.70366},
pmid = {41416492},
issn = {1460-9568},
mesh = {Humans ; *Alzheimer Disease/physiopathology/metabolism/immunology ; *Periodontitis/physiopathology/complications ; *Brain/physiopathology/metabolism ; Blood-Brain Barrier ; Animals ; *Mouth/physiopathology/microbiology ; },
abstract = {The bidirectional association between Alzheimer's disease (AD) and periodontitis (PD) has been recently demonstrated, indicating how the oral-brain axis connects the two conditions. Chronic oral inflammation caused by PD is accompanied by biological immunological responses, unchecked inflammation, and the spread of periodontal bacteria, all contributing to nervous system inflammation and AD pathogenesis. There are two primary pathways: (a) Inflammatory cascades, in which pro-inflammatory cytokines, such as IL-1β and TNF-α, originating from periodontal lesions, cause inflammation in the brain region of the head, resulting in tau hyperphosphorylation, amyloid beta (Aβ) accumulation, and disruption of the blood-brain barrier; (b) Microbial involvement, in which oral pathogens, such as Porphyromonas gingivalis (P. gingivalis), can enter the bloodstream, enter the trigeminal nerve, and activate microglia. The fact that AD patients are known to experience greater periodontal disease than others, together with additional research maintaining the connection between oral dysbiosis and neurodegeneration, further supports these pathways. In older patients, the collapse of the blood-brain barrier exacerbates inhibitor breaches, allowing poisons and microorganisms to enter, increasing the formation of Aβ and neurotoxicity. Conversely, periodontal infections may exacerbate AD over time by causing a loss in peri-oral neglect (cognitive decline) and self-oral care (hygiene). To clarify the directed causative links that therapeutic approaches seek to resolve, rather than an attributable association, systematic reviews help interdisciplinary approaches focus on the integral integration of oral healthcare into AD preventive policies built around proactive AD management systems and longitudinal research studies. This evidence synthesis sets the oral-brain interaction as an axis of critically heightened focus for investigating AD pathogenesis, maximally shifting the paradigm for proactive intervention and tailored care models.},
}

Humans
*Alzheimer Disease/physiopathology/metabolism/immunology
*Periodontitis/physiopathology/complications
*Brain/physiopathology/metabolism
Blood-Brain Barrier
Animals
*Mouth/physiopathology/microbiology

@article {pmid41416491,
year = {2025},
author = {Janve, VA and Seto, M and Sperling, RA and Aisen, PS and Rissman, RA and Koran, MEI and Dumitrescu, L and Buckley, RF and Hohman, TJ and , },
title = {Blood gene expression network expression strongly relates to brain amyloid burden.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70982},
doi = {10.1002/alz.70982},
pmid = {41416491},
issn = {1552-5279},
support = {//Eli Lilly and Co./ ; /ALZ/Alzheimer's Association/United States ; //GHR Foundation/ ; //National Institutes of Health-National Institute on Aging/ ; //Accelerating Medicines Partnership/ ; },
mesh = {Humans ; Male ; Female ; *Brain/metabolism/diagnostic imaging/pathology ; *Alzheimer Disease/genetics/diagnostic imaging/blood ; Aged ; Positron-Emission Tomography ; *Gene Regulatory Networks ; Histones/genetics ; *Amyloid/metabolism ; *Amyloidosis/genetics ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Amyloid deposition occurs decades before symptoms emerge in Alzheimer's disease (AD). We leveraged blood transcriptomics and positron emission tomography (PET) measures of amyloidosis to identify gene networks in the blood that relate to amyloid burden in the brain.

METHODS: Whole-blood RNA sequencing and amyloid PET were leveraged from 1739 cognitively unimpaired participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. Linear regression related gene module expression to amyloid covarying for age, sex, education, and apolipoprotein E (APOE) ε2 and ε4 genotypes.

RESULTS: Of the 18 gene modules, one histone gene cluster module was associated with amyloid (β = -0.55, false discovery rate-adjusted p value = 0.029). We also observed nominal associations for the predicted proportion of activated natural killer (NK) cells (β = -0.454, p = 0.02) and CD4+ activated memory T cells (β = -0.169, p = 0.03) with amyloid deposition.

DISCUSSION: Our results implicate the histone gene cluster on chromosome 6 and immune cell proportions as blood correlates of brain amyloid deposition in preclinical AD.

HIGHLIGHTS: Higher expression of network module with histone gene cluster on chromosome 6 associated with lower amyloid levels. Four histone genes, H1-5, H3C3, H2BC3, H2AC14, and RRM2, emerged as key genes driving this association, where H1-5 emerged as a hub gene for this module. Pathways, including nucleosome assembly and DNA damage, were enriched in the histone module. A higher fraction of activated NK and activated CD4+ T cells was related to lower amyloid burden.},
}

Humans
Male
Female
*Brain/metabolism/diagnostic imaging/pathology
*Alzheimer Disease/genetics/diagnostic imaging/blood
Aged
Positron-Emission Tomography
*Gene Regulatory Networks
Histones/genetics
*Amyloid/metabolism
*Amyloidosis/genetics
Aged, 80 and over

@article {pmid41416449,
year = {2025},
author = {Yang, MT and Temkin-Greener, H and Cai, S},
title = {Medicaid HCBS Caregiver Payment Policy and Post-Discharge Visits Among Dual-Eligible Older Adults With ADRD.},
journal = {Health services research},
volume = {},
number = {},
pages = {e70077},
doi = {10.1111/1475-6773.70077},
pmid = {41416449},
issn = {1475-6773},
support = {RF1AG063811/AG/NIA NIH HHS/United States ; RF1AG073052/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVE: To examine the association between state Home- and Community-Based Services (HCBS) caregiver payment policies and timely follow-up visits (in-person and telehealth) within 14 days of hospital discharge among Medicare-Medicaid dual-eligible older adults with dementia.

STUDY SETTING AND DESIGN: We categorized state HCBS caregiver payment policies into three groups: no caregiver payment, payment eligible for other friends/family, and payment eligible for two caregiver types (legally responsible relatives or other friends/family). The primary outcome was the mode of follow-up visit within 14 days post-hospital discharge (in-person, telehealth, or no visit). We used multinomial logistic regression with hospital random effects, adjusting for individual- and area-level and HCBS factors. Marginal effects were estimated.

We analyzed 2021 Medicare claims data linked with publicly available datasets. The analytic cohort comprised 51,633 dual-eligible Medicare beneficiaries with dementia who were hospitalized and discharged to the community in 2021.

PRINCIPAL FINDINGS: State HCBS caregiver payment policies were significantly associated with the mode of timely follow-up visits. Compared to states without providing caregiver payments, states providing payments to two caregiver types had a 6.8 percentage point higher probability (p < 0.01) of timely in-person visits but a 3.2 percentage point lower probability (p < 0.01) of timely telehealth visits. Similar, though smaller, significant differences were observed between states that provided payments to only other family or friends and those with no caregiver payments. Other HCBS generosity measures, as well as racial, ethnic, and geographic locations, were also associated with the mode of post-discharge visits.

CONCLUSION: Providing financial support to family caregivers through state HCBS policies may increase the rate of timely post-discharge visits, primarily driven by an increase in in-person visits. The effects were particularly prominent among states that allow payments to both types of caregivers.},
}

@article {pmid41416400,
year = {2025},
author = {Muthuramalingam, K and Lee, HJ},
title = {Carbon nanomaterials for tau targeting in Alzheimer's disease: Theranostic strategies and clinical prospects.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251407702},
doi = {10.1177/13872877251407702},
pmid = {41416400},
issn = {1875-8908},
abstract = {Tauopathies, including Alzheimer's disease (AD), are characterized by the pathological aggregation of tau proteins, culminating in progressive neurodegeneration and cognitive decline. Conventional therapeutic strategies remain limited by inadequate blood-brain barrier (BBB) penetration, insufficient specificity for tau pathology, and lack of real-time disease monitoring. While carbon-based nanomaterials have been extensively investigated for amyloid-β related applications, their potential for tau-directed theranostics remains at an early yet rapidly advancing state. Carbon-based nanomaterials-including carbon dots, fullerenes, graphene derivatives, and carbon nanotubes-exhibit exceptional physicochemical versatility, demonstrating potential to inhibit tau aggregation, scavenge reactive oxygen species (ROS), enable precision drug delivery, and facilitate ultrasensitive detection of tau biomarkers. Their inherent capacity for BBB penetration and dual diagnostic-therapeutic functionality positions them as transformative candidates for next-generation management of tauopathies. Despite this promise, most evidence remains preclinical, and major translational challenges persist. These include long-term biocompatibility and toxicological uncertainties, lack of standardized synthesis and functionalization protocols, production scalability, and the molecular heterogeneity of tau pathology across distinct tauopathies. This review provides a comprehensive assessment of carbon nanomaterials to date in the context of tau pathology, critically examining their theranostic potential and the barriers impeding clinical translation. By delineating current limitations and strategic priorities for future research, it underscores the urgent need for coordinated interdisciplinary efforts to convert these versatile nanoplatforms from conceptual promise to clinically actionable technologies for precision tau-targeted therapy.},
}

@article {pmid41416330,
year = {2025},
author = {R, R and Buttar, AS},
title = {Neuroprotective Potential of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors in Type 2 Diabetes: A Narrative Review.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e97103},
pmid = {41416330},
issn = {2168-8184},
abstract = {Once primarily celebrated for their glucose-lowering effect and their defense of the heart and kidneys, sodium-glucose cotransporter-2 (SGLT2) inhibitors are now at the center of a compelling new research question: do their benefits extend to the brain? As dementia rates climb globally, this can be linked with the rising prevalence of type 2 diabetes. With this, the search for neuroprotective strategies has become an urgent concern. This narrative review aims to navigate the current evidence to determine whether these drugs can protect patients with diabetes from cognitive decline. We uncover a fascinating dichotomy: a vast array of real-world observational data, encompassing hundreds of thousands of patients, consistently points toward a significant neuroprotective effect, suggesting that SGLT2 inhibitor use is associated with a markedly lower risk of dementia compared to other antidiabetic therapies such as dipeptidyl peptidase-4 (DPP-4) inhibitors or sulfonylureas. Unfortunately, this promising signal is met with silence from the highest level of evidence available to us, namely, evidence from meta-analyses of randomized controlled trials (RCTs), which, although methodologically rigorous, find no such association. We attempted to argue that this result is not a contradiction but rather a reflection of a scientific puzzle shaped by the limitations of current research. Observational studies offer the necessary long-term view but are susceptible to bias, while existing trials were too short and ill-equipped to capture the long latency of neurodegeneration. Delving deeper, we explore the powerful biological reasoning for neuroprotection, which includes reducing neuroinflammation and improving cerebral blood flow, where SGLT2 inhibitors may even rescue the brain from an energy crisis by providing it with an alternative fuel of ketones instead of glucose. The current landscape, therefore, is one of cautious optimism. While it is too soon to declare any kind of victory, the convergent evidence from real-world data and strong plausibility presents a powerful case for potential, demanding definitive answers from a new generation of focused, long-term clinical trials.},
}

@article {pmid41415893,
year = {2025},
author = {Zhang, M and Hou, H and Li, H and Bai, X and Song, H and Wang, L and Jiang, LH},
title = {The mechanosensitive Piezo1 channel mechanism of Alzheimer's disease and implications for the development of therapeutic or early detection strategies.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1707659},
pmid = {41415893},
issn = {1663-4365},
}

@article {pmid41415891,
year = {2025},
author = {Gi, Y and Park, S and Lim, H and Lee, J and Jung, AH and Baek, SH and Kim, JH and Kim, BJ and Yoon, M},
title = {Anatomically refined entorhinal cortex segmentation improves MRI-based early diagnosis of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1682106},
pmid = {41415891},
issn = {1663-4365},
abstract = {INTRODUCTION: The entorhinal cortex (EC) is one of the earliest cortical regions affected in Alzheimer's disease (AD) and serves as a key target for magnetic resonance imaging (MRI) biomarkers. However, conventional segmentation pipelines based on the Desikan-Killiany atlas do not clearly distinguish the EC from the adjacent perirhinal cortex, leading to mixed labels and reduced diagnostic sensitivity.

METHODS: To address these anatomical ambiguities, we developed a refined EC segmentation framework that combines expert-guided anatomical correction with deep learning. FreeSurfer-derived EC labels were manually refined by removing anterior perirhinal extensions and other anatomically inconsistent regions that are functionally distinct from the EC. These expert-corrected labels were then used to train a no-new-Net (nnU-Net) model on Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) MRI data, enabling anatomically precise and scalable EC delineation across individuals and scanners.

RESULTS: The refined EC segmentation preserved anatomically valid boundaries and demonstrated stronger group-level differentiation among cognitively normal, mild cognitive impairment, and AD groups. When incorporated into volumetric and classification analyses, it provided more specific imaging biomarkers of early neurodegeneration and improved discrimination between diagnostic stages. External validation further confirmed reliable generalization across datasets.

DISCUSSION: These findings demonstrate that anatomically precise and expert-informed EC delineation improves the sensitivity of MRI-based biomarkers for early AD diagnosis. The proposed framework offers a practical and reproducible approach for studying subtle cortical changes that precede overt clinical symptoms.},
}

@article {pmid41415890,
year = {2025},
author = {Jia, S and Li, Q and Rui, X and Qin, W and Zhang, W and Dou, J and Zhang, X},
title = {The ubiquitin-proteasome system in Alzheimer's disease: mechanism of action and current status of treatment.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1730206},
pmid = {41415890},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative disorders; current therapies can neither cure AD nor prevent its progression. The pathological hallmark of AD is the excessive deposition of abnormal proteins in the brain, primarily including β-amyloid (Aβ) and phosphorylated Tau proteins. The ubiquitin-proteasome system (UPS), a central intracellular protein degradation mechanism that removes misfolded proteins and maintains cellular homeostasis by inhibiting aberrant protein aggregation, plays an important role in the regulation of various physiological functions, as well as in the development of disease. Any abnormality in this process leads to protein misfolding and aggregation, and the accumulation and aggregation of ubiquitinated proteins is a common feature of many neurodegenerative diseases, including AD. A growing number of studies have confirmed the significance of UPS in the AD process, which may act in conjunction with other mechanisms leading to the development of AD, and may even be the direct cause of AD. UPS offers a whole new possibility for the development of drugs for AD prevention and treatment, as well as new strategies and approaches for the treatment of neurodegenerative diseases. Therefore, this review is based on UPS, describes the possible mechanisms of action of UPS in AD, and summarizes the preclinical studies of modulating UPS for the treatment of AD.},
}

@article {pmid41415888,
year = {2025},
author = {Wang, Y and Cui, L and Pan, FF and Zhang, Z and Huang, L and Miao, Y and Guan, YH and Guo, QH},
title = {Validation of the robustness of blood-based biomarkers for predicting amyloid-β positivity in Chinese populations.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1660755},
pmid = {41415888},
issn = {1663-4365},
abstract = {BACKGROUND: Blood-based biomarkers (BBBs) of Alzheimer's disease (AD) provide a promising, minimally invasive alternative for detecting cerebral amyloid-β (Aβ) pathology. However, a lack of robust validation across diverse platforms and populations has hindered their broader clinical adoption.

OBJECTIVE: This study aimed to cross-platform validation of the robustness of BBBs for predicting Aβ positivity in a Chinese population.

METHODS: The whole cohort (N = 1,254) of AD clinical spectrum underwent cognitive assessments, cranial MRI scans, and Aβ PET scans. Subcohort 1 (N = 504) underwent Simoa-based quantification of peripheral blood Aβ40, Aβ42, p-tau181, and NfL. Subcohort 2 (N = 262) underwent additional single molecule assays (Simoa) based quantification of p-tau217 and GFAP. The whole cohorts (Subcohort 1, Subcohort 2, and the remaining population) were measured for the aforementioned six biomarkers (Aβ40, Aβ42, p-tau181, p-tau217, NfL, and GFAP) using light-initiated chemiluminescent assays (LiCA). We validated the robustness of BBBs for predicting Aβ positivity in Chinese populations, with a focus on p-tau217.

RESULTS: The BBBs of Aβ42/40, p-tau181, p-tau217, GFAP, and NfL have demonstrated remarkable robustness in identifying Aβ positivity within the Chinese population, as evidenced by both LiCA and Simoa assays. Among these markers, p-tau217 has emerged as the most accurate, performing robustness in both the whole cohort and cognitively normal individuals. Utilizing a dual-threshold approach for p-tau217, only 16% of samples fell into the intermediate range, thus requiring additional Aβ PET testing.

CONCLUSION: Blood-based biomarkers have demonstrated good robustness for predicting Aβ pathology in the Chinese population, with plasma p-tau217 standing out as the most promising marker for early detection of AD-related changes.},
}

@article {pmid41415610,
year = {2025},
author = {Maity, S and Alrubayan, M and Khan, MM and Pradhan, P},
title = {Alterations of brain tissue structural complexity and disorder in Alzheimer's disease (AD): Fractal, multifractal, fractal transformation, and disorder strength analyses.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {41415610},
issn = {2331-8422},
abstract = {Alzheimer's disease (AD) is characterized by progressive microstructural deterioration in brain tissue, yet conventional imaging and histopathology often lack the sensitivity needed to detect subtle early-stage changes. Here, we present a multiparametric framework combining fractal and multifractal analysis and their distributions to quantify structural alterations in human brain tissue affected by AD. Moreover, from the fractal and multifractal formalism, we introduced an innovative fractal functional distribution method, a novel technique that transforms fractal distribution into a Gaussian form. Statistically, these distribution parameters are easy to interpret and can distinguish between control and diseased tissues. Across samples, we identify pronounced threshold-dependent behavior of fractal and multifractal parameters, reflecting the intrinsic sparsity and heterogeneous intensity landscape of brain tissue. These threshold-sensitive signatures provide a framework for quantitative stage detection and may serve as biomarkers for early pathological transitions. In addition, we studied structural disorder and complexity using our established light localization technique, inverse participation ratio (IPR) analysis. IPR-based analysis demonstrates that increasing IPR pixel size highlights the elevation of structural alterations with disease progression. Together, these integrative analyses establish a robust, multi-scale quantitative framework for detecting microstructural alterations in AD, providing a promising foundation for early diagnosis and improved pathological assessment.},
}

@article {pmid41415504,
year = {2025},
author = {Amin, N and Kaushik, P and Belbasis, L and Xiao, S and Argentieri, MA and Ahmad, S and Husain, M and Kaddurah-Daouk, R and van Duijn, CM},
title = {Proteomic profiling of Alzheimer's disease and Vascular dementia reveals unique underlying signatures.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.08.25341836},
pmid = {41415504},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and vascular dementia (VaD) account for most dementia cases. AD biomarkers remain costly and invasive, and no specific biomarkers exist for VaD.

METHODS: We analyzed plasma and brain proteomics in the UK Biobank (N=53,000) and ROSMAP (N=512) to identify shared and distinct proteomic signatures of AD and VaD and assess the influence of the APOE ε4 variant.

RESULTS: We identified 55 AD-associated and 49 VaD-associated proteins, with 13 shared. AD proteins were enriched in glycosaminoglycan binding and cholesterol metabolism; VaD proteins in virus receptor activity, cytokine activity and metalloproteinases. Both showed IGF pathway dysregulation. APOE ε4 stratification revealed distinct AD proteomic signatures beyond GFAP and NeFL. Mendelian randomization suggested causal links for SNAP25 in AD, EDA2R and TIMP4 in VaD, and PVR in both.

DISCUSSION: Findings underscore the importance of APOE genotype and highlight SNAP25, EDA2R, TIMP4, and PVR as potential biomarkers and therapeutic targets.},
}

@article {pmid41415502,
year = {2025},
author = {Montaña-Valverde, G and Martínez-Molina, N and Aquilué-Llorens, D and Patow, G and Kringelbach, ML and Hinzen, W and Deco, G},
title = {Disrupted Brain Hierarchical Organization in Alzheimer's Disease Progression.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.11.25342039},
pmid = {41415502},
abstract = {Alzheimer's disease (AD) arises from synergistic interactions between amyloid-β, tau, and neurodegeneration, yet it remains unclear how these mechanisms reshape the hierarchical organization of large-scale brain dynamics. Here, we quantified directed causal interactions across 134 participants spanning the AD continuum, comprising 46 amyloid-negative healthy controls (HC-), 36 amyloid-positive healthy controls (HC+), 31 amyloid-positive individuals with mild cognitive impairment (MCI+), and 21 amyloid-positive patients with AD dementia (AD+). Resting-state fMRI was modelled using generative effective connectivity, and hierarchical organization was assessed via trophic levels and directedness. Healthy older adults exhibited a canonical hierarchy in which sensorimotor and frontoparietal regions acted as causal sources, the default mode network (DMN) occupied an intermediate mediating position, and visual-limbic areas functioned as sinks. In contrast, AD+ individuals exhibited elevated trophic levels in the visual network and reduced levels in somatomotor, salience, control, and DMN systems. This shift was accompanied by decreased directedness, indicating a more flattened and less stratified architecture with reduced computational flexibility. MCI+ participants exhibited disruptions in somatomotor and dorsal attention networks. Compared to early-stage HC+, visual and DMN showed similar alterations while the control system returned to baseline before decreasing in AD+. Machine-learning classification distinguished all stages, including subtle differences between HC- and HC+. Hierarchical alterations were shaped by ATN biomarkers and strongly associated with cognitive decline, highlighting trophic metrics as sensitive neuroimaging biomarkers of AD progression. Together, these findings suggest that reduced hierarchical structure represents a core systems-level signature of AD, offering a promising avenue for early detection and therapeutic targeting.},
}

@article {pmid41415447,
year = {2025},
author = {Chin, D and Luo, Y and Lau, Y and Dutta, N and He, Z and Yin, C and Williams, RM and Balachandran, S and Vicens, Q and Dröge, P and Luo, D},
title = {Cryo-EM structures of anti Z-DNA antibodies in complex with antigen reveal distinct recognition modes of a left-handed geometry.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.12.693871},
pmid = {41415447},
issn = {2692-8205},
abstract = {Double-stranded nucleic acids can undergo transitions from canonical B/A-forms to alternate left-handed Z-DNA/Z-RNA (Z-NAs). Z-NAs are implicated in processes such as neuroinflammation in Alzheimer's disease, Lupus Erythematosus, microbial biofilms, and type I interferon-mediated human pathologies. Since endogenous Z-NA sensors like the Zα domain can induce B-to-Z transitions, monoclonal antibodies (mAbs) Z-D11 and Z22 have been regarded as conformation-specific tools to confirm Z-NA in situ , although high-resolution structural information is missing. Here, we employed single-particle cryo-electron microscopy to solve structures of Z-D11 and Z22 bound to synthetic d(CG) 6 12mer Z-DNA duplex. Both mAbs form filamentous trimers around the Z-DNA axis, further stabilized by Fab-Fab interactions. The mAbs achieve specificity through extensive contacts to both Z-form backbone strands and the exposed guanine/cytosine bases in the major groove. This mode of recognition is dictated by shape complementarity rather than sequence specificity, sensing the alternating syn/anti backbone torsions and the phosphate zig-zag geometry unique to Z-DNA. Our data also suggest that these mAbs are not inducing B-to-Z transitions under normal physiological conditions. Finally, comparison to other double-stranded NA-binding mAbs defines a similar structural logic adapted to different helical geometry recognition patterns, thus providing a framework for engineering highly specific nucleic acid probes.},
}

@article {pmid41415446,
year = {2025},
author = {Linden, AK and Affaneh, A and Aylward, A and Wong, Y and Kessler, JA and Peng, CY},
title = {Differential Regulation of APOE4-Mediated Astrocytic Lipid Metabolism by BMP Signaling Exacerbates Alzheimer's Disease Pathologies in Neurons.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.14.694212},
pmid = {41415446},
issn = {2692-8205},
abstract = {The two greatest risk factors for Alzheimer's Disease (AD) are aging and Apolipoprotein E4 (APOE4) polymorphism, yet how these factors interact remain unclear. In this study, we investigate how bone morphogenetic protein (BMP) signaling, which increases with age, contributes to APOE4-induced lipid metabolic dysfunctions using induced-pluripotent stem cell (iPSC)-derived astrocytes and cocultured neurons. Surprisingly, BMP signaling differentially altered lipid droplet formation, cholesterol synthesis and breakdown, and fatty acid-oxidation in APOE4 compared to APOE3 astrocytes, and increased secretion of oxidized LDL (oxLDL). Furthermore, neurons cocultured with BMP4-treated APOE4 astrocytes showed altered transcriptomic profiles based on scRNA-seq as well as increased tau phosphorylation (p-tau). oxLDL treatment similarly increased p-tau and reduced neuronal survival. Conversely, lipid uptake inhibition in neurons rescued the BMP4/APOE4 astrocyte-induced neuronal phenotype. These data demonstrate key interactions between APOE4 and aging-associated molecular signaling in AD pathogenesis and establish a causal linkage between astrocytic lipid metabolism and neuronal tau hyperphosphorylation.},
}

@article {pmid41415431,
year = {2025},
author = {Nada, H and Zhang, L and Kaur, B and Vázquez, NG and Gabr, M},
title = {Restoring Amyloid Clearance via Astrocytes: Z17 Is a Selective Inhibitor of CHI3L1 in Alzheimers Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.07.692801},
pmid = {41415431},
issn = {2692-8205},
abstract = {Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, accumulation of hallmark protein aggregates and substantial neuroinflammation. Chitinase-3-like protein 1 (CHI3L1) which is predominantly produced by activated astrocytes in the central nervous system (CNS). Overexpression of CHI3L1 has been implicated with AD progression and worsening of symptoms. Herein, we report the identification of Z17 as a novel and selective CHI3L1 inhibitor which directly bind to CHI3L1 an equilibrium dissociation constant (KD) of 6.0 µM. In human iPSC-derived astrocytes, Z17 acted as a dual-action regulator by reinstating astrocytic function and suppressing inflammation. Additionally, Z17 rescued CHI3L1-induced impairment by dose-dependently restoring Aβ uptake and normalizing lysosomal proteolytic activity and pH. Furthermore, Z17 effectively blocked CHI3L1-driven activation of the NF-κB pathway in human astrocytes, providing a mechanistic explanation for the functional rescue. The in vitro pharmacokinetic (PK) profiling of Z17 demonstrated favorable drug-like properties for CNS development. These findings support the advancement of Z17 as a selective CHI3L1 inhibitor capable of simultaneously mitigating neuroinflammation and restoring astrocytic clearance mechanisms, making it a highly promising therapeutic candidate for Alzheimers disease.},
}

@article {pmid41415117,
year = {2025},
author = {Rollison, J and McCleskey, SG and Davoust, M and Shiferaw, M and Bialas, A},
title = {Evaluation of the BOLD Public Health Center of Excellence on Dementia Caregiving.},
journal = {Rand health quarterly},
volume = {13},
number = {1},
pages = {2},
pmid = {41415117},
issn = {2162-8254},
abstract = {This study presents an evaluation of the University of Minnesota's BOLD Public Health Center of Excellence on Dementia Caregiving, which supports public health agencies in implementing dementia caregiving initiatives. The evaluation covers the Center's activities from 2021 to 2025, focusing on resources provided, usage by public health agencies, partnerships, equitable access, and agency capacity improvements.},
}

@article {pmid41415105,
year = {2025},
author = {Zheng, W and Pan, Y and Wang, Y and Zhu, L},
title = {Comprehensive evaluation and clinical implications of kernel extreme learning machine long short term memory transformer framework.},
journal = {American journal of translational research},
volume = {17},
number = {11},
pages = {8742-8756},
pmid = {41415105},
issn = {1943-8141},
abstract = {OBJECTIVES: To develop and validate a hybrid deep learning model to enhance diagnostic and predictive accuracy of Alzheimer's disease (AD) using readily available clinical data.

METHODS: A triple-architecture joint model was constructed, integrating a Kernel Extreme Learning Machine (KELM), a Long Short-Term Memory (LSTM) network, and a Transformer. This framework was designed to capture nonlinear associations, temporal dynamics, and global feature dependencies. The model was trained and validated on 2,149 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and externally tested on an independent cohort of 1,012 subjects.

RESULTS: In internal validation, the model achieved state-of-the-art performance with 95.42% accuracy, 95.63% recall, and an area under the curve (AUC) of 0.981. It also demonstrated strong generalizability in the external cohort, achieving 93.81% accuracy and an AUC of 97.25%. In a longitudinal sub-analysis, the model accurately predicted the 3-year conversion from mild cognitive impairment to AD with 92.78% accuracy. Ablation analyses confirmed the essential contribution of each model component.

CONCLUSIONS: The proposed KELM-LSTM-Transformer model provides a powerful and robust framework for AD prediction. Its high accuracy and strong generalizability suggest potential as an effective and accessible tool for early risk stratification, supporting timely clinical interventions.},
}

@article {pmid41414713,
year = {2025},
author = {Jia, G and Li, J and Khan, A and Kaushik, AC and Wu, D and Chen, H and Li, R and Wang, J and Zhang, C and Farooq, A and Mao, X and Mehmood, A and Zhang, W and Wang, H and Wei, DQ},
title = {WGX-50 Promotes Healthy Ageing in Caenorhabditis elegans: A Combined Computational and Experimental Study.},
journal = {Chemical biology & drug design},
volume = {106},
number = {6},
pages = {e70214},
doi = {10.1111/cbdd.70214},
pmid = {41414713},
issn = {1747-0285},
support = {2023YFE0199200//Intergovernmental International Scientific and Technological Innovation and Cooperation Program of the National Key R&D Program/ ; 2024YFA1306402//National Key Research and Development Program of China/ ; 32030063//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Caenorhabditis elegans/metabolism/drug effects/genetics/physiology ; Caenorhabditis elegans Proteins/metabolism/genetics ; Transcription Factors/metabolism/genetics ; Longevity/drug effects ; Forkhead Transcription Factors/metabolism/genetics ; Molecular Dynamics Simulation ; DNA-Binding Proteins/metabolism/genetics ; Signal Transduction/drug effects ; *Healthy Aging/drug effects ; *Aging/drug effects ; Mice ; Animals, Genetically Modified ; },
abstract = {WGX-50, a previously reported drug candidate for Alzheimer's disease, is derived from Zanthoxylum bungeanum Maxim commonly called Sichuan pepper. Its pharmacological actions for the long run benefit of human health have been extensively investigated. However, in terms of its anti-aging effect, it totally remains unexplored. In this work, WGX-50 was first reported to promote healthy aging in Caenorhabditis elegans with insights from drug target prediction and molecular dynamics simulations. Further investigations have experimentally demonstrated that: Firstly, both daf-16 and skn-1 genes are causative to WGX-50 mediated longevity. WGX-50 failed to extend lifespan upon depletion of these genes in transgenic worms. Their orthologs Foxo1 and Nrf2 were also activated even in D-galactose (D-gal) induced aging and Zmpste24[-/-] progeria mice intestines. Secondly, WGX-50 inhibits IIS signaling via downregulating daf-2, and activating daf-16 and skn-1 genes, which thus enable downstream pro-longevity effectors increasing stress resistance and promoting healthier aging. WGX-50 increased expression levels of sod-3, ctl-1, gst-7/8/12/33, gsto-1, and heat shock protein genes such as hsp-12.2, hsp-90, F44E5.4/0.5, T05E11.9 and their inducer hsf-1. In addition, the accumulation of lipofuscin, fat, and reactive oxygen species levels with age was decreased significantly upon WGX-50 supplementation without physiological impairments. Thirdly, in progeria, D-gal and naturally aged mice, WGX-50 is incapable of inducing aging. Senescent genes and SASP factors were not produced at higher levels in livers and small intensities. No impact was observed on key organ indices, blood biochemistry parameters, and bone histomorphometry. WGX-50 perhaps prolongs lifespan through other mechanisms such as reducing fertility, inducing dietary restriction, and improving proteostasis with lowered levels of polyQ35 aggregates. Our findings thus provide primary insights for the potential medical use of WGX-50 in anti-aging and long-term healthcare.},
}

Animals
*Caenorhabditis elegans/metabolism/drug effects/genetics/physiology
Caenorhabditis elegans Proteins/metabolism/genetics
Transcription Factors/metabolism/genetics
Longevity/drug effects
Forkhead Transcription Factors/metabolism/genetics
Molecular Dynamics Simulation
DNA-Binding Proteins/metabolism/genetics
Signal Transduction/drug effects
*Healthy Aging/drug effects
*Aging/drug effects
Mice
Animals, Genetically Modified

@article {pmid41413866,
year = {2025},
author = {Zhang, HE and Xiao, ML and Ji, JJ and Cheng, YR and Lu, F},
title = {Integrating machine learning and experiments to elucidate the potential molecular mechanisms of methylparaben-induced Alzheimer's disease: evidence from a Tau hyperphosphorylation cell model.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-025-04582-x},
pmid = {41413866},
issn = {1471-2377},
support = {BRWEP2024Z014170102//The excellence clinical research program in research-oriented wards parallel project/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) was a progressive neurodegenerative disorder characterised by an insidious onset and gradual cognitive decline. It remained a significant global health challenge. Methylparaben (MEP), a preservative commonly used in cosmetics and food processing, had been associated with the development and progression of AD.

METHODS: First, we acquired the initial three-dimensional (3D) structure of MEP from PubChem (CID: 7456), followed by structural optimization via energy minimization using Chem3D software to complete its 3D structural characterisation. This was followed by systematic target prediction across the SwissTargetPrediction, SEA, GeneCards and OMIM databases. We then constructed protein-protein interaction (PPI) networks using STRING and visualised them in Cytoscape to identify core targets. Molecular docking simulations using CB-Dock2 elucidated the binding affinities between MEP and the key proteins. Experimental validation combined Gene Expression Omnibus (GEO) database analysis with quantitative reverse transcription polymerase chain reaction (qRT-PCR) to quantify transcriptional changes in SK-N-SH neural cells.

RESULTS: A total of 153 potential targets associated with MEP and AD were identified. Ten core targets were determined through screening using the STRING platform and Cytoscape software, including HIF1A, IGF1R, PDGFRB, PTK2, VCAM1, CXCL12, ERBB2, ESR1, JAK2 and BCL2L1. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that the core MEP targets in AD primarily concentrate on the following key signalling pathways: Neuroactive ligand-receptor interactions, EGFR tyrosine kinase inhibitor resistance, HIF-1 signalling pathway and gamma-aminobutyric acid (GABA) synapse. Molecular docking simulations using CB-Dock2 confirmed a high binding affinity between MEP and these core targets. To investigate the mechanism of action of MEP, we validated the findings using clinical datasets and the human neuroblastoma cell line SK-N-SH. Upregulation of ten transcriptional expressions was observed, suggesting that MEP might influence cognitive function in patients with AD.

CONCLUSION: This study elucidated the potential molecular mechanisms of MEP in the progression of Alzheimer's disease-related tau pathology, offering new insights for the prevention and intervention of degenerative diseases that might be triggered by excessive exposure to MEP environments.},
}

@article {pmid41413662,
year = {2025},
author = {Green, NFO and Sutton, GJ and Pérez-Burillo, J and Wang, J and Bagot, S and Danon, HG and Walsh, K and Gokool, A and Miles, SA and Yang, G and Herring, CA and Liang, Y and Pfundstein, G and Sytnyk, V and Alinejad-Rokny, H and Lister, R and Rosenbluh, J and Gagnon-Bartsch, JA and Voineagu, I},
title = {CRISPRi screening in cultured human astrocytes uncovers distal enhancers controlling genes dysregulated in Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41413662},
issn = {1546-1726},
support = {2020814//Department of Health | National Health and Medical Research Council (NHMRC)/ ; },
abstract = {Genetic variants associated with complex traits often lie in distal enhancers. While candidate enhancers have been mapped genome wide, their functional state and gene targets in specific cell types remain unclear. Here we present AstroREG, a resource of enhancer-gene interactions in human primary astrocytes, generated by combining CRISPR inhibition (CRISPRi), single-cell RNA-seq and machine learning. By functionally testing nearly 1,000 PsychENCODE enhancers, we identified more than 150 regulatory interactions, revealing enhancers that control key astrocyte functions and genes implicated in Alzheimer's disease. The CRISPRi screen also provided valuable ground-truth data from a primary cell type for training and benchmarking prediction models of enhancer activity. We thus developed EGrf, a random forest (RF) model trained on these data, and applied it genome wide to predict regulatory interactions with high specificity. Together, our data provide a comprehensive functional map of enhancer-mediated regulation in a key glial cell type, shedding light on brain function and disease.},
}

@article {pmid41413592,
year = {2025},
author = {Lu, J and Wang, J and Zhang, H and Wu, J and Yang, Y and Wang, M and Ma, X and Bao, W and Xiao, Z and Lin, H and Zhou, X and Ju, Z and Yan, S and Jiao, F and Liang, X and Liu, Y and Zheng, L and Li, M and Ge, J and Ding, D and Yen, TC and Guan, Y and Zuo, C and Zhao, Q},
title = {Utility of [18]F-Florzolotau PET as a prognostic and monitoring biomarker in a memory clinic cohort.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01938-w},
pmid = {41413592},
issn = {1758-9193},
support = {24PJD010//Shanghai Magnolia Talent Program Pujiang Project/ ; 25ZR1402042//Shanghai Science and Technology Natural Science Foundation/ ; 82272039//National Natural Science Foundation of China/ ; 82071200//National Natural Science Foundation of China/ ; 2022ZD0211600//Science, Technology and Innovation 2030 Major Project/ ; SQ2021AAA010157//National Ministry of Science and Technology/ ; },
}

@article {pmid41413577,
year = {2025},
author = {Chu, C and Wang, Y and Ma, L and Ouyang, Y and Zisis, G and Masters, CL and Goudey, B and Jin, L and Pan, Y and , },
title = {Development and validation of an interpretable clinical scoring model to monitor the progression of preclinical Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01931-3},
pmid = {41413577},
issn = {1758-9193},
support = {GNT2007912//National Health and Medical Research Council/ ; 23AARF-1020292/ALZ/Alzheimer's Association/United States ; },
}

@article {pmid41413527,
year = {2025},
author = {Gong, Z and de Rouen, A and Zhang, N and Alisch, JSR and Bilgel, M and An, Y and Bae, J and Fox, NY and Guo, AY and Resnick, SM and Mazucanti, CH and Klistorner, S and Klistorner, A and Egan, JM and Bouhrara, M},
title = {Age-related differences in choroid plexus structural integrity are associated with changes in cognition.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-025-00749-3},
pmid = {41413527},
issn = {2045-8118},
abstract = {BACKGROUND: The choroid plexus (CP) plays a critical role in maintaining central nervous system (CNS) homeostasis, producing cerebrospinal fluid, and regulating the entry of specific substances into the CNS from blood. CP dysfunction has been implicated in various neurological and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis.

METHODS: This study investigates the relationship between CP structural integrity and cognitive decline in normative aging, using structural and advanced magnetic resonance imaging techniques, including CP volume, diffusion tensor imaging indices (mean diffusivity, MD, and fractional anisotropy, FA) and relaxometry metrics (longitudinal, T1, and transverse, T2, relaxation times).

RESULTS: Our results show that lower CP microstructural integrity, as reflected by higher T1, T2, and MD values, or lower FA values, is associated with lower cognitive performance in processing speed and fluency. Notably, CP microstructural measures demonstrated greater sensitivity to cognitive decline than macrostructural measures, i.e. CP volume. Longitudinal analysis revealed that individuals with lower CP structural integrity exhibit steeper cognitive decline over time. Furthermore, structural equation modeling revealed that a latent construct representing CP integrity predicts faster overall cognitive decline, with an effect size comparable to that of age.

CONCLUSIONS: These findings highlight the importance of CP integrity in maintaining cognitive health and suggest that a holistic approach to assessing CP integrity could serve as a sensitive biomarker for early detection of cognitive decline. Further research is needed to elucidate the mechanisms underlying the relationship between CP structural integrity and clinical decline and to explore the potential therapeutic implications of targeting CP function to prevent or treat age-related cognitive deficits.},
}

@article {pmid41413200,
year = {2025},
author = {Yang, S and Datta, D and Krienen, FM and Woo, E and May, A and Anderson, GM and Galvin, VC and Gonzalez-Burgos, G and Lewis, DA and Ling, E and McCarroll, SA and Arnsten, AF and Wang, M},
title = {Kynurenic acid signaling expands in human and nonhuman primates and impairs dorsolateral prefrontal cortical cognition that is key to mental illness.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41413200},
issn = {1476-5578},
support = {RF1 AG083090/AG/NIA NIH HHS/United States ; 2015276//National Science Foundation (NSF)/ ; },
abstract = {Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer's disease, where impairments are correlated with kynurenine inflammatory signaling. Kynurenine synthesis from tryptophan is increased under conditions of inflammation, then further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and α7-nicotinic receptors (nic-α7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may contribute to higher cognitive deficits in these disorders. The current study employed several methods to examine the expression of KYNA and its synthetic enzyme, KAT II, in primate dlPFC, and to determine its effects on working memory-related dlPFC neuronal firing and cognitive functioning in aging macaques with naturally-occurring neuroinflammation. We found that KYNA, its synthetic enzyme, KAT II, and the gene encoding KAT II (AADAT), have greatly expanded expression in macaque and human dlPFC in both glia and neurons, with AADAT especially prominent in primate neurons compared to rodent PFC. In macaques, like humans, plasma kynurenine/tryptophan ratios increased with age, consistent with age-related increasing inflammation. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-α7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys. These data show that KYNA inflammatory signaling expands in primate dlPFC, and that inhibition of kynurenine-KYNA production may provide a powerful therapeutic avenue for treating higher cognitive deficits in neuroinflammatory disorders.},
}

@article {pmid41412515,
year = {2025},
author = {Andréasson, C and Ben-Zvi, A},
title = {Protein quality control: from molecular mechanisms to aging and disease - EMBO workshop, May 18-23, 2025, Hersonissos, Greece.},
journal = {Cell stress & chaperones},
volume = {},
number = {},
pages = {100139},
doi = {10.1016/j.cstres.2025.100139},
pmid = {41412515},
issn = {1466-1268},
abstract = {Cells safeguard the functionality of the proteome using complex pathways of protein quality control. The centerpiece of this proteostasis network is a large set of molecular chaperones and proteases that impact the entire lifespan of proteins by controlling protein folding and degradation. Dysfunction of the proteostasis network is associated with many diseases and age-associated functional decline of neurons, including Alzheimer's and Parkinson's diseases, as well as several motor neuron diseases. The 2025 EMBO workshop "Protein quality control: from molecular mechanisms to aging and disease" gathered the large and interdisciplinary community of researchers that study protein quality control, from its fundamental molecular mechanisms via higher order organization in organisms to its impact on and use in the medical field. Here we summarize the workshop and report research findings.},
}

@article {pmid41412008,
year = {2025},
author = {Türkeş, C},
title = {Machine learning-guided repurposing of FDA-approved quinolones as dual cholinesterase inhibitors: A multi-level docking, molecular dynamics, DFT, and SHAP-based analysis.},
journal = {Journal of molecular graphics & modelling},
volume = {143},
number = {},
pages = {109259},
doi = {10.1016/j.jmgm.2025.109259},
pmid = {41412008},
issn = {1873-4243},
abstract = {Alzheimer's disease (AD) involves progressive cholinergic degeneration, with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) playing key enzymatic roles in its pathology. In this study, we computationally repurposed four FDA-approved quinolone antibiotics, Norfloxacin, Sparfloxacin, Gatifloxacin, and Nalidixic acid, as potential dual-site cholinesterase (ChE) inhibitors using a hybrid in vitro/in silico workflow. Enzyme inhibition assays identified Norfloxacin as the most potent AChE inhibitor (KI = 1.08 μM), while all compounds displayed non-competitive inhibition toward BChE. Molecular docking and MM-GBSA binding free energy analyses revealed key interactions within the catalytic gorge of AChE, supported by hydrogen bonding with Phe295 and Arg296, as well as π-π contacts with Tyr124. Density functional theory computations highlighted the influence of frontier orbital distribution on binding affinity, particularly for Norfloxacin and Sparfloxacin. An explicit-solvent molecular dynamics simulation of the AChE-Norfloxacin complex further confirmed the stability of the docking-derived binding mode over 100 ns. In an exploratory fashion, SHAP-based machine learning models were applied to a descriptor set derived from QikProp, SwissADME, and Jaguar outputs, suggesting that BBB-related indices and HOMO energy contribute to AChE inhibition, whereas the energy gap is more relevant for BChE; these trends, however, are constrained by the small four-compound dataset and should be regarded as hypothesis-generating. In silico ADME/Tox profiling indicated favorable oral drug-like properties, low predicted CYP450 inhibition liabilities, and physicochemical profiles compatible with CNS-oriented optimization, although passive BBB permeability was not predicted to be high. Finally, systems-level enrichment (STRING, GeneCards) provided a qualitative network context linking ACHE and BCHE to neurodegeneration. Together, these data position Norfloxacin and Sparfloxacin as computationally prioritised candidates whose ChE-related repurposing potential warrants further validation in dedicated cellular and in vivo models.},
}

@article {pmid41411732,
year = {2025},
author = {Du, Y and Zheng, X and Yue, X and Fu, P and Diao, J and Zhang, A and Cheng, H and Yang, H and Bi, J and Zhou, Q and Wang, P},
title = {IL-24 ameliorates cognitive dysfunction via the inhibition PERK-eIF2α Signaling pathway in Alzheimer's disease.},
journal = {International immunopharmacology},
volume = {169},
number = {},
pages = {116039},
doi = {10.1016/j.intimp.2025.116039},
pmid = {41411732},
issn = {1878-1705},
abstract = {The role of inflammation in the etiology and progression of Alzheimer's disease (AD) has attracted increasing attention; however, the effect of peripheral adaptive immune cells and IL-24 expression on amnestic mild cognitive impairment (aMCI)/AD remains unclear. We detected a reduction in CD4[+] central memory T cells (TCM) and an increase in effector memory T cells (TEM) in AD compared with aMCI and controls. CD4[+] T cells from patients with AD showed enhanced proliferation, reduced secretion levels of IL-24, and increased secretion levels of IFN-γ and TNF-α. The decrease in IL-24 expression in patients with AD was positively associated with cognition. IL-24 overexpression significantly ameliorated the cognitive deficits, neuropathological injury, and cytotoxicity in AD in vivo and in vitro, potentially through PERK-eIF2α pathway inhibition. Altogether, T cell subset analyses supported a shift towards senescence of the adaptive immune system in AD. IL-24 is a new therapeutic target and strategy for AD.},
}

@article {pmid41411709,
year = {2025},
author = {Fisk, D and William, T and Spiwak, R and Modirrousta, M and Ko, JH and Sareen, J},
title = {Combining repetitive transcranial magnetic stimulation with transcranial direct current stimulation in treating psychiatric conditions: A systematic review.},
journal = {Psychiatry research},
volume = {356},
number = {},
pages = {116902},
doi = {10.1016/j.psychres.2025.116902},
pmid = {41411709},
issn = {1872-7123},
abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been thoroughly explored in the treatment of various psychiatric disorders and neuropsychiatric symptoms. However, whether combining rTMS and tDCS can safely and effectively treat psychiatric conditions remains unknown. In this systematic review, we seek to summarize all existing studies that have combined rTMS and tDCS to remedy psychiatric disorders and symptoms.

METHODS: We searched four databases in addition to grey literature to identify relevant studies. All abstracts and manuscripts were independently reviewed by two reviewers. For inclusion, studies necessarily consisted of those who received both rTMS and tDCS for a psychiatric condition or symptom.

RESULTS: Fourteen studies were reviewed, which had relevance to unipolar depression (five), bipolar disorder (two), obsessive-compulsive disorder (two), Alzheimer's Disease (one), chronic insomnia (two), depressive and anxiety symptoms (one) and stress (one). In three RCTs on unipolar depression, the group receiving both rTMS and tDCS experienced significant reductions in mean Hamilton Depression Rating Scale (HDRS) scores (by 18.22, 16.59 and 20.04) as well as response rates (83.33 % and 91.7 %) and remission rates (83.3 %) - all of which were generally superior compared to treatment with rTMS or tDCS alone. For chronic insomnia, one RCT noted greater improvements in sleep quality/efficiency and depressive symptoms compared to monotherapy. The type and frequency of side effects were comparable to monotherapy, and no significant adverse events were reported.

CONCLUSION: The existing evidence suggests that combining rTMS and tDCS alone yields greater symptomatic benefit for unipolar depression compared to either treatment alone. Further studies involving additional protocols and disorders could elucidate the utility of combined treatment.},
}

@article {pmid41411702,
year = {2025},
author = {Lebkuecher, AL and Coslett, HB and Buxbaum, LJ},
title = {The cognitive neuropsychology of action semantics: A review.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {194},
number = {},
pages = {159-190},
doi = {10.1016/j.cortex.2025.11.008},
pmid = {41411702},
issn = {1973-8102},
abstract = {The conceptual knowledge that mediates our ability to use familiar objects, understand viewed actions, and engage in communication about actions is often termed "action semantics". The underlying format, cognitive organization, and neural substrates of these representations are matters of active scientific investigation. This review synthesizes the large and diverse literature on action semantics in individuals with neurological disorders characterized by prominent motor deficits (e.g., Parkinson's disease and Amyotrophic lateral sclerosis), as well as those for whom motor deficits are often less prominent (e.g., Alzheimer's disease, Frontotemporal Dementia, stroke). Research in these two groups of disorders is strikingly "siloed" and offers many contradictory findings with respect to whether action semantic representations are abstract (i.e., "disembodied") or grounded in sensory and motor features that reflect the way knowledge was acquired. Findings across these populations also disagree as to whether action semantic representations are organized somatotopically or with a semantic feature-based architecture, and mediated by anterior motor-related or relatively posterior sensory-related brain regions. Many of these disparate findings can be reconciled with consideration of a multidimensional, multimodal representational architecture mediated by a distributed left-lateralized network of brain regions. We provide suggestions for specific methodological approaches for research with neurological populations that may further our understanding of the format, organization, and neural substrates of action semantics.},
}

@article {pmid41411656,
year = {2025},
author = {Romero-Flores, IS and García-Mena, J and Perez-Cruz, C},
title = {Gut dysbiosis impacts estrogen levels in APP/PS1 transgenic female mice.},
journal = {Gut microbes},
volume = {17},
number = {1},
pages = {2599525},
doi = {10.1080/19490976.2025.2599525},
pmid = {41411656},
issn = {1949-0984},
mesh = {Animals ; *Dysbiosis/microbiology/metabolism ; Female ; *Gastrointestinal Microbiome/drug effects ; *Estrogens/metabolism ; Mice, Transgenic ; Mice ; *Alzheimer Disease/microbiology/metabolism ; Disease Models, Animal ; Feces/microbiology ; Amyloid beta-Protein Precursor/genetics/metabolism ; Presenilin-1/genetics ; Humans ; Cognition ; },
abstract = {Alzheimer's disease (AD) is the most common form of dementia, with a higher prevalence in women than in men. It has been suggested that the decline in estrogen production after menopause may increase the risk of developing dementia. Additionally, patients with AD often display dysbiosis of the gut microbiota (GM), even in the early stages of the disease. The GM plays a crucial role in modulating systemic estrogen levels through a mechanism known as the estrobolome. However, it remains unclear whether gut dysbiosis contributes to estrogen imbalance and subsequent cognitive decline in women. In this study, we aim to investigate whether alterations in the GM impact estrogen availability and cognitive function in 6-month-old female APP/PS1 (TG) mice compared to age-matched wild-type (WT) littermates. We included a group of both WT and TG mice treated with a broad-spectrum antibiotic cocktail (ABX) for one month to modify their GM composition. Our results revealed that TG mice exhibited a dysfunctional estrobolome characterized by a decreased abundance of Limosilactobacillus and Lactobacillus, an increased abundance of Ligilactobacillus, and reduced activity of the β-glucuronidase enzyme in fecal samples. Additionally, TG female mice showed low bioavailability of estradiol, disrupted estrous cycle, and cognitive impairments. Notably, WT-ABX mice displayed gut dysbiosis, marked by a decrease in the relative abundances of Limosilactobacillus and Lactobacillus, as well as reduced β-glucuronidase activity. Moreover, WT-ABX exhibited altered estradiol levels and cognitive impairments compared to WT controls. Therefore, our findings suggest that gut dysbiosis may be a contributing factor to female vulnerability in developing dementia by disrupting hormonal levels and cognitive function.},
}

Animals
*Dysbiosis/microbiology/metabolism
Female
*Gastrointestinal Microbiome/drug effects
*Estrogens/metabolism
Mice, Transgenic
Mice
*Alzheimer Disease/microbiology/metabolism
Disease Models, Animal
Feces/microbiology
Amyloid beta-Protein Precursor/genetics/metabolism
Presenilin-1/genetics
Humans
Cognition

@article {pmid41411185,
year = {2025},
author = {Bhuiya, J and Shibly, AZ and Sheikh, AM and Tabassum, S and Abdullah, FB and Fahmida, J and Tamegai, H and Aritake, S and Yano, S and Nagai, A},
title = {Deposition of aggregated cystatin C-amyloid-β complexes and reduced cathepsin B activity modulate cerebral amyloid angiopathy pathogenesis.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlaf138},
pmid = {41411185},
issn = {1554-6578},
abstract = {Cystatin C (CST3) colocalizes with amyloid-β (Aβ) around vessels in cerebral amyloid angiopathy (CAA). This study aimed to characterize CST3-Aβ interactions in CAA. Brain tissues from 12 Alzheimer disease (AD) and 5 non-AD control subjects, along with AD model mice (J20), were examined. In AD brains, immunohistochemistry revealed Aβ positivity around cortical and leptomeningeal vessels as well as in intra- and extracellular areas. Congo red-positive vessels were also present. Conversely, control brains showed only few Aβ-positive cells. CST3 was primarily intracellular in controls, but in AD, it was found both to be intracellular and perivascular, colocalizing with Aβ and Congo red in affected vessels. Vessel quantification showed a positive correlation between CST3-positive and Aβ- or Congo red-positive vessels. Moreover, most CST3-positive vessels were Cathepsin B (CatB)-negative. CatB was significantly decreased in AD and inversely correlated with CAA severity. Immunoprecipitation followed by Western blotting, dot blot, and TEM revealed oligomeric aggregates and short fibrillar CST3 bound to Aβ in both AD and J20 mice brains. In J20 mice, CST3 was only neuron-positive at 2 months, and vessel-positive, colocalizing with Aβ from 3 months. These findings suggest that aggregated CST3 binds to Aβ and accumulates around vessels, potentially contributing to CAA pathogenesis.},
}

@article {pmid41410987,
year = {2025},
author = {Nakayama, Y and Chambers, JK and Uchida, K},
title = {Phosphorylated tau aggregation in the brains of aged Artiodactyla animals.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlaf139},
pmid = {41410987},
issn = {1554-6578},
support = {22KA3003//Japanese Ministry of Health and Welfare Sciences Research/ ; JPMJSP2108//JST SPRING/ ; },
abstract = {The aggregation of amyloid-β (Aβ) and phosphorylated tau (p-tau) in the human brain is associated with Alzheimer disease (AD). Although Aβ aggregation has been reported in various mammals, significant p-tau aggregation has been reported in only a few species. We examined Aβ and p-tau aggregation in the brains of 30 animals belonging to 12 artiodactyl species. Amyloid-β aggregates were observed in 2 animals (21 and 22 years old); p-tau aggregates were observed in all animals >9 years of age (n = 12). Regarding tau pathology, mildly affected animals exhibited neuropil threads (NTs), whereas severely affected animals exhibited NTs and neurofibrillary tangles. The most severe p-tau aggregation was observed in the parahippocampal gyrus, basal ganglia, hippocampus, and cerebral cortex. Proteinase K treatment resulted in high proteinase resistance for 4-repeat tau and low resistance for 3-repeat tau. These results suggest that p-tau aggregation occurs prior to Aβ aggregation in artiodactyls, which differs from other mammalian species and human AD. Regarding the distribution, p-tau aggregated in neurites and then in the neuronal cell soma of the parahippocampal gyrus and spread to associated regions of the brain. Moreover, 4-repeat tau was the main component of proteinase-resistant p-tau aggregates in the artiodactyl brains studied.},
}

@article {pmid41410687,
year = {2025},
author = {Steward, A and Dewenter, A and Hirsch, F and Roemer-Cassiano, SN and Zhu, Z and Dehsarvi, A and Biel, D and Klonowski, M and Frontzkowski, L and Palleis, C and Gnörich, J and Dichgans, M and Höglinger, G and Brendel, M and Franzmeier, N},
title = {ApoE4 lowers the ptau217 threshold for tau aggregation and spread in an allele dose-dependent manner.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf463},
pmid = {41410687},
issn = {1460-2156},
abstract = {In Alzheimer's disease, carriage of the ApoE4 risk allele is linked to faster tau accumulation at lower amyloid-PET levels, thereby accelerating disease progression. However, it remains unclear whether this ApoE4-facilitated transition from amyloidosis to tauopathy is mechanistically promoted by increased secretion of phosphorylated (p)tau, a key intermediate that drives the amyloid-to-tauopathy transition, or alternatively by increased ptau-driven tau aggregation. Therefore, we investigated where along the amyloid-to-tau axis ApoE4 accelerates tau aggregation and assessed i) whether ApoE4 increases ptau secretion or ii) whether ApoE4 increases ptau-associated tau aggregation. To this end, we analysed two large-scale APOE-genotyped cohorts covering the full Alzheimer's disease spectrum (ADNI: n=201) as well as a preclinical cohort (A4-LEARN: n=200), integrating baseline amyloid-PET, plasma ptau217 and CSF ptau181 with longitudinal tau-PET. Using linear regression, we tested whether ApoE4-carriage moderates i) amyloid-PET-associated plasma ptau217 increases or ii) ptau217-associated tau spreading from local epicentres across patient-tailored tau spreading stages. All analyses were independently validated across both cohorts, including an additional replication in an ADNI subset (n=115) with available CSF ptau181 measures as an alternative marker of ptau secretion. Finally, we used logistic regression to determine ApoE4 allele count-stratified plasma ptau217 thresholds marking early pathological tau-PET increases. We found that ApoE4 did not facilitate amyloid-PET-associated ptau increases, suggesting that amyloid-related ptau secretion is not altered by ApoE4-carriage. Contrastingly, we found that plasma ptau217 elevations were linked to faster tau-PET spread from local epicentres across connected brain regions in an ApoE4-allele dose-dependent manner, independent of amyloid (ADNI/A4-LEARN: mean β=0.44/0.56, p<0.001/<0.001). Lastly, we found that a higher ApoE4 allele count was linked to lower ptau217 thresholds marking transition to tauopathy, i.e. early abnormal tau-PET increases, consistently across both samples (ADNI: 0/1/2 ApoE4 alleles=0.62/0.34/0.15pg/ml, representing ∼45% and ∼76% reductions from non-carriers; Fujirebio ptau217 assay; A4/LEARN: 0/1/2 ApoE4 alleles=0.31/0.23/0.18pg/ml, representing ∼26% and ∼42% reductions; Eli Lilly ptau217 assay). These findings suggest that ApoE4, i.e. the key genetic risk factor for sporadic Alzheimer's disease, facilitates amyloid-dependent tau aggregation in an allele dose-dependent manner by enhancing the ptau-driven spread of fibrillar tau, leading to an earlier transition from amyloidosis to tauopathy at lower ptau217 levels. This has implications for plasma ptau-based screening approaches and therapeutic timing of anti-amyloid drugs in ApoE4 carriers: Specifically, ApoE4 carriers may require genotype-adjusted ptau thresholds to detect Alzheimer's disease pathophysiology, as well as anti-amyloid treatment at lower ptau levels to prevent the transition to tauopathy, which ultimately drives neurodegeneration and cognitive decline.},
}

@article {pmid41410547,
year = {2025},
author = {Ni, T and Bi, K and Wang, Y},
title = {Insertion of β-barrel amyloid (25-35) oligomers in lipid bilayers: a molecular dynamics study.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/07391102.2025.2592592},
pmid = {41410547},
issn = {1538-0254},
abstract = {Amyloid β (Aβ) peptides, particularly the toxic fragment Aβ25-35, disrupt lipid bilayers by forming ion channels or inserting into the membrane, which is a key factor in the pathogenesis of Alzheimer's disease. In this study, molecular dynamics simulations were employed to investigate the insertion behavior of β-barrel Aβ25-35 oligomers in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) membrane. The results demonstrate that embedding the oligomer at a deeper position can enhance the stability of the barrel, and deprotonation of the LYS residue can notably influence its mobility within the membrane and interactions with lipids. During insertion, the protein barrel disrupts local lipid distribution and causes regional thinning of the membrane, but does not affect the overall membrane structural stability. These findings provide a deeper understanding of Aβ-induced membrane disruption mechanisms and offer insights into the membrane-associated pathogenic mechanisms of Aβ25-35 in the context of Alzheimer's disease.},
}

@article {pmid41410237,
year = {2025},
author = {Kranz, DL and de Leon Velez, O and Ulupinar, E and Ozdinler, PH and Silverman, RB and Klein, WL},
title = {Identification of a glia-associated amyloid β oligomer subtype and the rescue from reactive astrogliosis by inhibitor NU-9.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70968},
pmid = {41410237},
issn = {1552-5279},
support = {//NIH/ ; AG061708//Foundation for the National Institutes of Health/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; *Gliosis/pathology/metabolism/drug therapy ; Mice ; *Alzheimer Disease/pathology/metabolism/drug therapy ; Mice, Transgenic ; Astrocytes/metabolism/drug effects/pathology ; *Neuroglia/metabolism/drug effects ; Disease Models, Animal ; Microglia/metabolism/drug effects ; Brain/pathology/metabolism/drug effects ; Humans ; Neurons/metabolism/pathology ; },
abstract = {INTRODUCTION: Neuronal degeneration and immune cell activation occur early in Alzheimer's disease (AD), but the responsible molecules remain undetermined. While exogenous amyloid beta oligomers (AβOs) induce neuronal death and gliosis, the role of endogenous AβOs is less defined.

METHODS: Brain sections from 1- to 12-month-old 5xFAD mice were immunolabeled for AβOs, activated glia, phosphorylated transactive response DNA-binding protein 43 kDa (pTDP-43), and other AD markers. Neuropathology was analyzed following 60-day oral treatment with NU-9, a small-molecule AβO inhibitor.

RESULTS: By 8 weeks, AβOs accumulated in the subiculum alongside early reactive astrocytes and activated microglia. Clinical-stage antibody ACU193 detected AβOs in early-stage degenerating neurons, while NU4-labeled denser deposits in late-stage degenerating neurons. ACU193[+] AβOs accumulated on reactive astrocyte surfaces, which also contained pTDP-43, and later emerged inside activated microglia. NU-9 reduced astrocyte-associated ACU193[+ ]AβOs, pTDP-43, and markedly diminished glial fibrillary acidic protein.

DISCUSSION: These findings demonstrate in vivo efficacy of NU-9 and support targeting ACU193[+ ]AβOs to mitigate AD progression.

HIGHLIGHTS: ACU193[+] AβOs accumulated as puncta in neurons at an early stage of degeneration, while NU4[+] AβOs appeared as dense deposits only in late-stage degenerating neurons. The onset and progression of ACU193[+] AβOs paralleled activated microglia and reactive astrocytes. ACU193[+] AβOs significantly increased on reactive astrocyte surfaces, as NU4[+] AβOs accumulated in halos around Thio-S[+] plaque cores. In older mice, the ACU193 signal decreased on astrocytes and was found inside activated microglia. Sixty-day oral NU-9 treatment significantly reduced astrocyte ACU193[+] AβOs and markedly decreased reactive astrogliosis.},
}

Animals
*Amyloid beta-Peptides/metabolism
*Gliosis/pathology/metabolism/drug therapy
Mice
*Alzheimer Disease/pathology/metabolism/drug therapy
Mice, Transgenic
Astrocytes/metabolism/drug effects/pathology
*Neuroglia/metabolism/drug effects
Disease Models, Animal
Microglia/metabolism/drug effects
Brain/pathology/metabolism/drug effects
Humans
Neurons/metabolism/pathology

@article {pmid41409874,
year = {2025},
author = {Miyahara, R and Akiyama, O and Yoshida, N and Suzuki, M and Ashizawa, K and Kodama, T and Shimizu, Y and Kondo, A},
title = {A case of cerebral sparganosis diagnosed by surgical resection and molecular analysis.},
journal = {Surgical neurology international},
volume = {16},
number = {},
pages = {512},
pmid = {41409874},
issn = {2229-5097},
abstract = {BACKGROUND: Sparganosis is a rare parasitic infection caused by the plerocercoid larvae (spargana) of Spirometra species. Central nervous system (CNS) involvement is uncommon; cerebral sparganosis can be particularly challenging to diagnose because its clinical presentation and imaging features often mimic those of more common parasitic infections (e.g., neurocysticercosis) or neoplastic lesions.

CASE DESCRIPTION: A 74-year-old woman with slowly progressive Alzheimer's disease, who had undergone regular brain magnetic resonance imaging (MRI) examinations over the past three years, was incidentally found to have a slowly enlarging lesion with surrounding edema in the left frontal lobe on MRI of the brain. The lesion demonstrated calcification and radiological features atypical for a neoplastic process, thus prompting a left frontal craniotomy for diagnostic purposes. Intraoperatively, a whitish, linear structure was removed. Frozen section revealed granulomatous inflammation with parasitic structures. Molecular biological analysis identified the specimen as a Spirometra larva (Type I), confirming the diagnosis of cerebral sparganosis. Postoperatively, her baseline cognitive impairment persisted; however, follow-up MRI at 1 month demonstrated resolution of the enhancing lesion, and no new neurological deficits occurred.

CONCLUSION: Cerebral sparganosis should be considered in the differential diagnosis of intracranial mass lesions with a tumor-like appearance. Although the diagnosis remains challenging, molecular techniques permit definitive confirmation. Surgical resection serves a dual role, facilitating both accurate diagnosis and treatment.},
}

@article {pmid41409784,
year = {2025},
author = {Xing, D and Gong, Y and Xia, W and Tu, H and Yuan, L and Yin, Y and Wang, K},
title = {Dynamic glycosylation remodeling in neurological disorders.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1674665},
pmid = {41409784},
issn = {1662-5099},
abstract = {Glycosylation, a crucial post-translational modification, involves the covalent attachment of monosaccharides or oligosaccharides to proteins. This process significantly influences protein stability and function. Within the nervous system, glycosylation regulates key processes including neuronal differentiation, migration, synapse formation, and neurotransmitter release and signaling. Its proper functioning is essential for maintaining neuronal homeostasis and reducing the risk of neurological disorders. Understanding the specific mechanisms by which glycosylation impacts the central nervous system is therefore essential for developing novel therapeutic strategies. This review focuses on the roles of three major glycosylation types-N-glycosylation, O-glycosylation, and O-GlcNAcylation-in the pathogenesis of central nervous system disorders.},
}

@article {pmid41409742,
year = {2025},
author = {Kokkinos, P and Cheng, Y and Zamrini, E and Faselis, C and Sui, X and Morgan, CJ and Sheriff, HM and Myers, J and Franklin, B and Alderman, B and Zeng-Treitler, Q},
title = {Long-term changes in cardiorespiratory fitness and incidence of Alzheimer's disease and related dementias among US Veterans.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70171},
pmid = {41409742},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease and related dementias (ADRD) remain a leading cause of morbidity and mortality. Poor cardiorespiratory fitness (CRF) has been identified as a potential risk factor for ADRD. Since CRF is a modifiable risk factor, we evaluated the association between CRF changes over time and ADRD risk.

METHODS: Our cohort consisted of US Veterans (mean age 60.7±9.0 years; male, n = 128,749; and female, n = 5,421). All completed two standardized exercise treadmill tests (ETT) between 2000 and 2017, at least 1 year apart (mean 3.5±2.7 years), with no evidence of ADRD at the time of both ETTs. We assigned participants to one of three age- and gender-specific CRF categories based on peak metabolic equivalents (METs) achieved during the initial ETT and five categories based on CRF changes at the final ETT. Cox proportional hazard models adjusted for age, comorbidities, and medications were used to evaluate ADRD risk across CRF categories.

RESULTS: During the up to 15.0 years of follow-up (mean 7.2 years; interquartile range [IQR] 4.3-9.9 years), totaling 966,337 person-years, 10,699 ADRD cases occurred (11.1 events/1000 person-years). Compared to the Low-fit group, ADRD risk decreased progressively with increased CRF and was 22% lower (hazard ratio [HR] 0.78; 95% confidence interval [CI]: 0.75-0.81; p<0.0001) for Moderate-fit individuals and 30% lower (HR 0.70, 95% CI: 0.67-0.73; p<0.0001) for High-fit individuals. Compared to Low-fit individuals with no CRF change, an increase of 0.1-<2.0 METs was associated with a 13% lower ADRD risk (HR 0.87, 95% CI 0.79-0.95; p<0.0001), while an increase of ≥2.0 METs was associated with a 24% lower risk (HR 0.76, 95% CI 0.70-0.83; p<0.0001).

CONCLUSION: We observed an inverse and independent association between CRF and ADRD risk. An improvement in CRF of approximately ≥1.0 MET led to a lower risk of ADRD in Low-fit individuals. These findings may have considerable clinical and public health significance in reducing ADRD risk.

HIGHLIGHTS: Poor cardiorespiratory fitness (CRF) has been identified as a potential risk factor for Alzheimer's disease and related dementias (ADRD). Thus, we assessed the potential impact of changes in CRF over time on ADRD risk.CRF changes reflected inverse and proportional changes in ADRD risk.Low-fit individuals who improved their CRF by ≥0.1 metabolic equivalents (METs) had a 13%-24% lower ADRD risk. Conversely, a decline in CRF by ≥2.0 METs was associated with a 14% increased ADRD risk among Moderate-fit and a 18% increase among High-fit individuals.},
}

@article {pmid41409674,
year = {2025},
author = {Sai, I and Grill, JD and Younes, K and Winer, JR and Cody, KA and Sperling, R and Mormino, EC and Young, CB},
title = {Cognitive screening biases in a secondary prevention Alzheimer's disease clinical trial.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.11.28.25341235},
pmid = {41409674},
abstract = {INTRODUCTION: Alzheimer's disease (AD) prevention trials have multiple screening steps to identify cognitively unimpaired individuals with AD biomarker evidence. Cognitive/functional screening tests may be biased in underrepresented groups, thereby impacting trial eligibility.

METHODS: 6669 participants screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were grouped by ethnoracial background and testing language. Ethnoracial/language differences in ineligibility reason, cognitive/functional test performance, and amyloid positivity rates were examined.

RESULTS: Ethnoracial minorities were least likely to meet eligibility criteria. Patterns of incorrect Mini-Mental State Examination items and impaired Clinical Dementia Rating functional domains differed between groups excluded for impaired cognition/function, suggesting test biases. The Free and Cued Selective Reminding Test yielded more similar exclusion rates across groups than Logical Memory. Cognitive/functional screening biases may impact subsequent biomarker screening as amyloid positivity rates were lowest in ethnoracial minorities.

DISCUSSION: Biases in cognitive/functional screening tests may disproportionately exclude ethnoracial minorities in AD prevention trials.},
}

@article {pmid41409670,
year = {2025},
author = {Franklin, CE and Rosenberg, PB and Lyketsos, CG and Ismail, Z and Leoutsakos, JM},
title = {The impact of anticholinergic burden on the development of mild behavioral impairment.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.05.25341723},
pmid = {41409670},
abstract = {OBJECTIVE: Mild Behavioral Impairment (MBI) is a syndrome of late-life-onset persistent neuropsychiatric symptoms. Anticholinergic medication is commonly prescribed in older adults. Both MBI and anticholinergic exposure are associated with increased dementia risk. We sought to understand the association of anticholinergic burden (ACB) with MBI.

DESIGN SETTING PARTICIPANTS: We mapped ratings on the Neuropsychiatric Inventory Questionnaire to the MBI checklist (MBI-C) using an established algorithm to define MBI status in cognitively unimpaired individuals in the National Alzheimer's Coordinating Center database. We then assessed the association between time-varying ACB ratings and risk of incident MBI.

RESULTS: 4865 participants met inclusion criteria and were followed for a mean (SD) of 5.64 (3.92) years. ACB scores ranged from 0-11. 63.3% of participants had a score of 0, 27.7% had a score of 1-2, and 9% had a score of ≥3. Higher maximum total ACB score was associated with a higher likelihood of developing MBI (p=<0.001). When assessed as a time varying covariate, ACB score was associated with incident MBI (HR 1.12, 95% CI 1.05-1.19, p=<0.001). This association remained significant when adjusted for 10-year mortality risk.

CONCLUSIONS: MBI risk should be considered when prescribing anticholinergic medication in older adults.},
}

@article {pmid41409668,
year = {2025},
author = {Cai, M and Lei, H and Zhang, Y and Zou, J and Cao, W and Wang, Y and Wei, K and , },
title = {APOE ε 4-Associated Hippocampal Atrophy Trajectories Across the Alzheimer's Disease Continuum: A Systematic Review, Meta-Analysis, and Longitudinal Validation.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.08.25341534},
pmid = {41409668},
abstract = {BACKGROUND: The role of APOE- ε 4 in hippocampal atrophy is contested. We aimed to determine whether it functions as a static risk factor or an amyloid- β (A β)-dependent modulator of neurodegeneration.

METHODS: We integrated a systematic meta-analysis of 18 studies (N = 3, 781) with longitudinal validation using linear mixed-effects models in the NACC and ADNI cohorts (N > 5, 000), employing biomarker stratification to test for gene-pathology interactions.

RESULTS: The meta-analysis confirmed significant atrophy in APOE- ε 4 carriers but with high heterogeneity. Longitudinal analysis resolved this by identifying a crucial interaction: in A β -negative individuals, carrier atrophy rates were indistinguishable from non-carriers. However, A β positivity triggered a dramatic, dose-dependent acceleration in atrophy among carriers, with homozygotes declining over three times faster.

CONCLUSIONS: APOE- ε 4 acts as a potent, conditional accelerator of neurodegeneration, not an independent driver. Its deleterious effect is contingent on the presence of A β pathology. Clinical risk stratification should therefore integrate amyloid status with APOE genotype to accurately predict structural progression.},
}

@article {pmid41409665,
year = {2025},
author = {Marella, B and Weinisch, P and Bless, JJ and Risacher, SL and Blach, C and Karu, N and Kalecký, K and Wang, T and Huynh, K and Kueider-Paisley, A and Thompson, JW and , and , and Bottiglieri, T and Nho, K and Doraiswamy, PM and Saykin, AJ and Meikle, PJ and Kastenmüller, G and Kaddurah-Daouk, R and Arnold, M},
title = {A seven-year longitudinal study of the Alzheimer's disease blood metabolome.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.05.25341709},
pmid = {41409665},
abstract = {Metabolic dysregulation is a hallmark of Alzheimer's disease (AD), yet the temporal nature of metabolite-phenotype associations remains poorly understood. We systematically evaluated 506 serum metabolites across 4,063 longitudinal samples from 1,430 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), applying cross-sectional single-timepoint analyses, multi-timepoint meta-analysis, and time-interaction analysis. Across 15 AD-related phenotypes, we identified 311 metabolites to be significantly associated with disease. Of those, 281 emerged from the multi-timepoint meta-analysis, 243 (216 overlapping/27 additional) from cross-sectional analyses, and 19 (16 overlapping/3 additional) metabolites that showed a significant evolution of their association with AD over time. In total, 128 metabolites (41%) showed persistent associations over time, providing evidence for chronic and systemic metabolic dysregulation in the disease. This, together with the comparably small number of metabolites showing evolving changes, suggests that many metabolic alterations in AD do not change substantially anymore once they manifested. Our findings confirm impaired fatty acid and energy metabolism, disrupted neurotransmitter systems, and oxidative stress as key metabolic features of AD. We demonstrate broad replication of the reported metabolite associations in prior studies and an independent lipidomics dataset in ADNI. In summary, this work expands previous metabolomics studies in AD and provides novel leads regarding timing and persistence of metabolic alterations across the disease trajectory.},
}

@article {pmid41409662,
year = {2025},
author = {Terem, I and Younes, K and Weiss, S and Dreisbach, A and Vossler, H and Kwon, E and Cornfeld, D and Wright, J and Condron, P and L Poston, K and Mormino, E and Holdsworth, S and Setsompop, K},
title = {Pulsatile Brain Motion as a Marker of Brain Aging and Dementia: Insights from 3D q-aMRI.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.10.25341649},
pmid = {41409662},
abstract = {Heart brain interactions, including cardiac induced brain pulsatility, are thought to support brain homeostasis, yet their alteration with aging and neurodegeneration remains poorly understood. Here, we used three-dimensional quantitative amplified MRI (qaMRI) to visualize and quantify cardiac-induced pulsatile brain motion across healthy individuals and those on the Alzheimers and Lewy body disease spectra. Expert evaluations revealed consistent distinctions between normal and abnormal motion patterns, which were further characterized using strain-based biomechanical features. Principal component analysis identified interpretable signatures of abnormal motion that emerged predominantly after midlife and were closely linked to chronological age. Even after accounting for age, these biomechanical features differentiated individuals with clinical and biomarker evidence of neurodegenerative disease. Together, these findings suggest that qaMRI derived measures of cardiac-gated pulsatile brain motion may serve as imaging biomarkers of normal brain aging and dementia.},
}

@article {pmid41409616,
year = {2025},
author = {Gleerup, HS and Sanna, F and Koutarapu, S and Lantero-Rodriguez, J and Montoliu-Gaya, L and Hanrieder, J and Brinkmalm, G and Karikari, TK and Simren, J and Høgh, P and Blennow, K and Hasselbalch, SG and Zetterberg, H and Ashton, NJ and Simonsen, AH},
title = {Saliva phosphorylated tau concentration is not associated with Alzheimer's disease, cerebrospinal fluid or blood biomarkers.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1718237},
pmid = {41409616},
issn = {1662-4548},
abstract = {OBJECTIVE: One of the most challenging aims of the scientific community in the last decade, is to find an easily accessible matrix in which neurodegeneration-related biomarkers can be measured and used to diagnose Alzheimer's disease (AD) in vivo. Blood biomarkers have led the way in this regard, specifically, phosphorylated tau (p-tau) which demonstrates excellent diagnostic and prognostic properties. The recent success of the blood biomarkers for AD pathophysiology poses a new question - can p-tau be measured in other peripheral and even more accessible biofluids, and do they have relation to disease? Saliva contains biomarkers linked to neurodegeneration and it has been proposed as a potential sample type that would be minimally invasive to collect for this purpose.

METHODS: In this study, we confirmed the presence of several p-tau species in saliva fluid and saliva gland tissue by Immunoprecipitation-Mass spectrometry (IP-MS) and immunohistochemistry, respectively. Furthermore, we measured saliva and plasma p-tau181 concentrations in 125 memory clinic participants, using ultrasensitive Single molecule array (Simoa) technology.

RESULTS: Despite a weak correlation between saliva p-tau181 and CSF t-tau (rho = 0.13, p < 0.01), there were no significant differences in saliva p-tau181 concentration between the different clinical groups and the healthy controls.

INTERPRETATION: For this reason, we conclude that saliva p-tau181 is not acceptable as a biomarker for AD.},
}

@article {pmid41409615,
year = {2025},
author = {Huang, S and Wu, J and He, L},
title = {APOE ε4 allele drives female-specific Alzheimer's disease progression via vascular dysfunction and tau spreading.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1683204},
pmid = {41409615},
issn = {1662-4548},
abstract = {BACKGROUND: Apolipoprotein E (APOE) epsilon4 (ε4) is a major genetic risk factor for late-onset Alzheimer's disease (AD), with women exhibiting heightened vulnerability to APOE ε4-associated cognitive impairment. Despite recognition of this sexual dimorphism, the underlying biological mechanisms remain incompletely understood.

METHODS: We performed weighted gene co-expression network analysis (WGCNA) on RNA-seq data from the Mayo Clinic cohort (n = 277 temporal cortex samples) to identify sex- and APOE ε4-linked co-expression modules. 315 hub genes were identified within the most relevant gene modules derived from female AD patients with APOE ε4. The expression patterns of representative hub genes were then validated in female APOE ε4 carriers. Causal genes were prioritized via Summary-data-based Mendelian Randomization (SMR), and diagnostic biomarkers were identified using machine learning. Single-cell RNA-seq elucidated cell-type-specific gene expression, and Connectivity Map (CMap) screening nominated candidate therapeutics validated in a tauopathy mouse model (AAV-hTau-injected APP/PS1 mice).

RESULTS: Four co-expression modules (tan, blue2, grey60, antiquewhite4) specifically correlated with female AD patients with APOE ε4-positive and were enriched for vascular endothelial development and extracellular matrix pathways. Ten hub genes were implicated in the pathogenesis of female-specific APOE ε4 AD. LAMC1, RBMS2, TMOD3, and LRP10 were suggested as key drivers of AD progression associated with endothelial dysfunction. Single-cell analysis confirmed endothelial-specific upregulation of these genes in female APOE ε4 AD brains. Drug repositioning nominated the vasodilator vincamine, which downregulated Lrp10, Lamc1 in cortex tissue, and effectively inhibited the tau protein propagation from the medial entorhinal cortex (MEC) to the hippocampus in female AD mice.

CONCLUSION: we reveal a female-specific APOE ε4-driven molecular network linking endothelial dysfunction to tau pathology. These hub genes provide potential biomarkers, while vincamine represents a targeted prevention and therapeutic candidate for high-risk APOE ε4-positive women.},
}

@article {pmid41409512,
year = {2025},
author = {Billaud, CHA and Yu, J},
title = {Erratum: Structure-function coupling using fixel-based analysis and functional magnetic resonance imaging in Alzheimer's disease and mild cognitive impairment.},
journal = {Network neuroscience (Cambridge, Mass.)},
volume = {9},
number = {4},
pages = {i-ii},
doi = {10.1162/NETN.x.506},
pmid = {41409512},
issn = {2472-1751},
abstract = {[This corrects the article DOI: 10.1162/netn_a_00461.].},
}

@article {pmid41409494,
year = {2025},
author = {Ivanic, S and Vogel, AP and Chatterjee, P and Baird, J and Darby, D and Werden, E and Gao, L and Darzins, P and Patel, SK and Burke, I and Morris, T and Churilov, L and Bice, J and Mielke, MM and Brodtmann, A},
title = {Neurofilament light chain and voice acoustics in dementia diagnosis (NAVAIDD): Protocol for a cohort study assessing the real-world diagnostic utility of blood and digital biomarkers in clinical settings.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395325},
pmid = {41409494},
issn = {2542-4823},
abstract = {BACKGROUND: The advent of disease modifying therapies for dementia has highlighted the need for simple, accessible and low-cost diagnostic tests. Blood and digital biomarkers increase accuracy in highly selected research populations. However, their real-world applicability for diverse clinical populations remains unknown.

OBJECTIVE: We will investigate the utility of plasma neurofilament light chain (NfL) and voice acoustic analysis in a multi-ethnic and multi-lingual population. We hypothesise that NfL and voice acoustic biomarkers will discriminate between individuals with a neurodegenerative diagnosis and those with non-neurodegenerative causes; abnormal biomarker findings will have high prognostic validity for clinical progression; and shorten the time to diagnosis and reduce costs.

METHODS: All adults presenting with a cognitive concern to outpatient and inpatient settings at a community-based healthcare network in Melbourne, Australia are eligible to participate. Plasma NfL and speech sample recordings are performed at baseline and functional status (modified Rankin Scale) is recorded. Clinical diagnostic consensus meetings are convened wherein baseline diagnostic class (neurodegenerative vs non-neurodegenerative), syndrome (diagnosis), and certainty (low, moderate, high) are confirmed with the clinician prior to and following disclosure of NfL to examine effect on clinical decision-making. Participants complete cognitive, functional and mood screens and speech sampling via 12-month follow-up phone call.

DISCUSSION: Blood and digital biomarkers are transforming the landscape of dementia diagnosis. Our study design allowing inclusion of people from diverse linguistic, cultural and racial backgrounds offers an opportunity to evaluate the utility of NfL and speech markers in real-world clinical settings.

TRIAL REGISTRATION: https//www.clinicaltrials.gov (NCT06339190), Apr 2024.},
}

@article {pmid41409326,
year = {2025},
author = {Ansari, AS and Mohammadi, MS and Cattani, C and Tassaddiq, A},
title = {An advanced multimodal image fusion model for accurate detection of Alzheimer's disease using MRI and PET.},
journal = {Frontiers in medical technology},
volume = {7},
number = {},
pages = {1699821},
pmid = {41409326},
issn = {2673-3129},
abstract = {The accurate detection of Alzheimer's disease (AD), a progressive and irreversible neurodegenerative disorder, remains a critical challenge in clinical neuroscience. The research aims to develop an advanced multimodal image fusion model for the accurate detection of AD using positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques. The proposed method leverages structural MRI and functional 18-fluorodeoxyglucose PET (FDG-PET) information derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI). After preprocessing, including Gaussian filtering, skull stripping, and intensity normalization, voxel-based morphometry (VBM) is applied to extract gray matter (GM) features relevant to AD progression. A GM mask generated from MRI is used to isolate corresponding metabolic activity in the PET scans. These features are then integrated using a mask-coding strategy to construct a unified representation that captures both anatomical and functional characteristics. For classification, the model introduces a Glowworm Swarm-Optimized Spatial Multimodal Attention-Enriched Convolutional Neural Network (GWS-SMAtt-ECNN), where the optimization enhances both feature selection and network parameter tuning. The Python was implemented, and the result demonstrates that the proposed multimodal image fusion strategy outperforms traditional unimodal and basic fusion approaches in terms of F1-score (94.22%), recall (96.73%), and accuracy (98.70%). These results highlight the therapeutic usefulness of the suggested improved fusion architecture in facilitating immediate and accurate AD detection by MRI and PET.},
}

@article {pmid41409156,
year = {2025},
author = {Liu, Y and Zhang, Z and Qiu, M and Wang, S and Salim, FD and Shen, J and Chen, T and Razzak, I and Bian, J},
title = {GatorSC: Multi-Scale Cell and Gene Graphs with Mixture-of-Experts Fusion for Single-Cell Transcriptomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.03.691688},
pmid = {41409156},
issn = {2692-8205},
abstract = {Single-cell RNA sequencing (scRNA-seq) enables high-resolution characterization of cellular heterogeneity, but its rich, complementary structure across cells and genes remains underexploited, especially in the presence of technical noise and sparsity. Effectively leveraging this multi-scale structure is essentially an information fusion problem that requires integrating heterogeneous graph-based views of cells and genes into robust low-dimensional representations. In this paper, we introduce GatorSC , a unified representation learning framework that models scRNA-seq data through multi-scale cell and gene graphs and fuses them with a Mixture-of-Experts architecture. GatorSC constructs a global cell-cell graph, a global gene-gene graph, and a local gene-gene graph derived from neighborhood-specific subgraphs, and learns graph neural network embeddings that are adaptively fused by a gating network. To learn noise-robust and structure-preserving embeddings without labels, we couple graph reconstruction and graph contrastive learning in a unified self-supervised objective applied to both cell- and gene-level graphs. We evaluate GatorSC on 19 publicly available scRNA-seq datasets covering diverse tissues, species, and sequencing platforms. Across 14 benchmark datasets, GatorSC consistently outperforms state-of-the-art deep generative, graph-based, and contrastive methods for cell clustering, gene expression imputation, and cell-type annotation. The learned embeddings are used for accurate trajectory inference, recovery of canonical marker gene programs, and cell-type-specific pathway signatures in an Alzheimer's disease singlenucleus dataset. GatorSC provides a flexible foundation for comprehensive single-cell transcriptomic analysis and can be readily extended to multi-omic and spatial modalities.},
}

@article {pmid41409143,
year = {2025},
author = {Kim, MJ and Blumenfeld, J and Li, Y and Yip, O and Yao, L and Ancheta, S and De Leon, S and Platow, Z and Liang, Z and Shostak, D and Suan, K and Hao, Y and Koutsodendris, N and Ellis, C and Nguyen, J and Huang, Y},
title = {Neuronal APOE4 drives damaging lipid accumulation via contact-dependent neuron-oligodendrocyte-microglia interaction in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.04.692390},
pmid = {41409143},
issn = {2692-8205},
abstract = {Apolipoprotein E4 (APOE4) confers the greatest genetic risk for developing Alzheimer's disease (AD). With APOE4 broadly expressed in the brain, its cell-type-specific roles in AD pathogenesis are only beginning to be defined. Here, we show that neuronal APOE4 expression drives damaging lipid accumulation in hippocampal neurons, oligodendrocytes, and microglia, with preferential buildup of peroxidized lipids in microglia in a tauopathy mouse model. Neuron-specific removal of APOE4 abolished this lipid phenotype, whereas neuron-specific expression of APOE4 was sufficient to recapitulate it, demonstrating that neuronal APOE4 is both necessary and sufficient for lipid accumulation. Strikingly, the association between lipid burden, microgliosis, and neurodegeneration was strongest in mice with neuron-specific APOE4 expression. Single-nucleus RNA sequencing revealed neuronal APOE4-vulnerable neuron populations, as well as enrichment of disease-associated microglia and oligodendrocytes, all promoting lipid pathology. Primary mouse co-culture experiments showed that neuronal APOE4 drives microglial lipid accumulation via contact-dependent mechanisms involving uptake of lipids from neurons and oligodendrocytes. These findings establish neuronal APOE4 as a key driver of lipid accumulation via neuron-oligodendrocyte-microglia interactions, providing mechanistic insight into APOE4-driven lipid pathology in AD.},
}

@article {pmid41408986,
year = {2025},
author = {Liu, C and Ene, J and Lu, W and Syed, F and Sun, L and Raulin, AC and Ren, Y and Wang, X and Kanekiyo, T and Li, Y},
title = {Immuno-Regulation of Brain Region-Specific Organoids Containing Isogenic Microglia-Like Cells.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e03579},
doi = {10.1002/adhm.202503579},
pmid = {41408986},
issn = {2192-2659},
support = {2017869//NSF/ ; R01NS125016//Foundation for the National Institutes of Health/ ; R21EB033495//Foundation for the National Institutes of Health/ ; },
abstract = {Most brain organoids derived from human induced pluripotent stem cells (iPSCs) lack microglia and thus immune function. Microglia-like cells (MGCs) can be differentiated from iPSCs, while the characteristics of isogenic MGC-containing brain organoids in modeling neurodegeneration and cell-cell communications have not been well investigated. In this study, iPSC-derived MGCs are co-cultured with isogenic forebrain cortical organoids (iFCo), which are stimulated with extracellular vesicles (EVs) of brain organoids differentiated from Alzheimer's disease (AD) patient-derived iPSCs (APOE ε4/ε4 and presenilin 1). The AD EV-stimulated co-culture organoids are treated with EVs from healthy MGCs or co-culture. Differential responses of the co-cultured organoids and the MGCs to AD EVs are demonstrated. The co-cultured organoids mitigated pro-inflammatory gene expressions. EVs from healthy MGCs or co-culture reduced the expression of IL-12β, iNOS, TREM2, and CASS4, which are associated with neural inflammation and degeneration, as well as showed regulation on genes involved in microglial activation and carbon metabolism. AD EV cargo analysis by proteomics and microRNA-sequencing revealed APOE and APP proteins and microRNAs regulated pathways such as mitophagy. This study paves the way for understanding the role of microglia and brain organoids in modeling neural degeneration and the development of EV-based cell-free therapeutics for AD treatment.},
}

@article {pmid41408807,
year = {2025},
author = {Besli, N and Ercin, N and Carmena-Bargueño, M and Pérez-Sánchez, H and Celik, U},
title = {Interpreting the Conformational Dynamics Over Interaction of FAM222A Protein with Amyloid-Beta Peptides.},
journal = {Acta chimica Slovenica},
volume = {72},
number = {4},
pages = {831-845},
doi = {10.17344/acsi.2025.9340},
pmid = {41408807},
issn = {1580-3155},
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; Molecular Dynamics Simulation ; Protein Binding ; Molecular Docking Simulation ; Humans ; *Peptide Fragments/chemistry/metabolism ; Protein Conformation ; },
abstract = {Alzheimer's disease (AD), a neurological disorder with increasing prevalence worldwide, presents a significant challenge to the medical community. The molecular mechanism underpinning its neuropathology is still wholly unexplained. Recent investigations have focused on the role of the protein aggregatin (AP), encoded by FAM222A, in amyloid-beta (Aβ) aggregation via its N-terminal Aβ binding domain. The current study aims to characterize the interaction mechanisms between the AP and Aβ (1-42 and 1-28) peptides using all-atom molecular dynamics (MD) simulations. The objective is to assess whether AP is a stabilizing scaffold in Aβ peptide aggregation, validate docking outcomes from previous studies, and compare the stability and interaction profiles of different Aβ isoforms. Aβ (1-42, 1-28) peptides were converted from the α-helix to the β-sheet form to inquire better-docked formation with the AP. The selected docking poses from our previous study and the four top scoring from HADDOCK were implemented in MD simulations, resulting in relatively stable complexes as indicated by consistent RMSD/RMSF trends without major structural disruptions. However, no binding free energy or interaction network analysis was conducted, and the conclusions are thus limited to structural stability observations. Our calculations hold accurate points for further experimental AD research on designing and developing the relevant protein-peptide interactions.},
}

*Amyloid beta-Peptides/chemistry/metabolism
Molecular Dynamics Simulation
Protein Binding
Molecular Docking Simulation
Humans
*Peptide Fragments/chemistry/metabolism
Protein Conformation

@article {pmid41408633,
year = {2025},
author = {Lorenzon, G and Marseglia, A and Poulakis, K and Imbimbo, C and Rydén, L and Galaris, E and Lindberg, O and Shams, S and Mohanty, R and Ferreira, D and Kivipelto, M and Eriksdotter, M and Kern, S and Skoog, I and Westman, E},
title = {Risk and protective factors associated with brain grey matter patterns in a population-based cohort of cognitively unimpaired 70 years old.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-025-04583-0},
pmid = {41408633},
issn = {1741-7015},
abstract = {BACKGROUND: Ageing involves heterogeneous brain grey matter (GM) patterns that may overlap with dementia-related changes. We evaluated cognitively unimpaired older adults to identify specific GM patterns, their clinical and cognitive profiles, and longitudinal trajectories.

METHODS: We analysed 746 participants from the Gothenburg H70 study using random forest cross-sectional clustering based on MRI measures of cortical thickness and subcortical volume across 41 regions. Using regression-based models, we examined associations with clinical, MRI variables, biochemical, and CSF Alzheimer biomarkers (n = 286) and assessed 5-year longitudinal cognitive and brain trajectories.

RESULTS: Five clusters emerged, mainly differing in frontoparietal regions. Compared to Cluster 1 (reference), Cluster 2 showed diffuse GM loss, higher odds of diabetes (OR = 2.54, 95% CI [1.27-5.06]) and at-risk alcohol consumption (OR = 1.83, 95% CI [1.13-2.97]), poorer episodic memory (β =  - 0.19, p = 0.014) and visuospatial abilities (β =  - 0.21, p = 0.044), and greater longitudinal decline in MMSE (βslope =  - 0.45, p = 0.035) and increase in white matter hyperintensity volume (βslope = 1.84, p = 0.004). Cluster 3 showed thicker GM and lower BMI (OR = 0.57, 95% CI [0.35-0.94]). Cluster 4 had preserved GM, lower smoking habits (OR = 0.62, 95% CI [0.40-0.95]), triglyceride levels (OR = 0.55, 95% CI [0.32-0.95]) and depression (OR = 0.17, 95% CI [0.05-0.56]), higher education (OR = 2.52, 95% CI [1.08-5.87]), and better cognition in multiple domains. Cluster 5 had a mixed GM pattern and higher odds of heart disease (OR = 3.44, 95% CI [1.48-8.01]).

CONCLUSIONS: Cardiovascular and psychosocial factors influence GM integrity, which in turn relates to cognition. Targeting these risk factors may preserve brain health in late life.},
}

@article {pmid41408566,
year = {2025},
author = {Shabana, S and Hamouda, HI and Shang, A and Shao, S and Zhao, J and Yuan, H and Liu, B},
title = {Recent molecular insights and biosensor-based diagnostic technologies for hyperphosphorylated Tau in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01932-2},
pmid = {41408566},
issn = {1758-9193},
support = {No. 2023JJ11CG005//Dalian Major Basic Research Projects/ ; },
abstract = {Tau pathology is a defining feature of Alzheimer's disease (AD), with hyperphosphorylated Tau (p‑Tau) emerging as a central biomarker for early diagnosis and disease monitoring. Various p‑Tau epitopes have demonstrated superior diagnostic precision and now form the molecular basis of updated AD diagnostic frameworks. Classical immunoassays such as enzyme-linked immunosorbent assay (ELISA), chemiluminescent enzyme immunoassay (CLEIA), and single molecule array (SIMOA) remain central to fluid based detection, offering high sensitivity and clinical validation. Recent advances in tau biology, especially in post-translational modifications, have driven the development of next generation biosensors. Electrochemical, optical, and nanostructured platforms now enable real-time, label-free, and attomolar level detection of p‑Tau in biofluids and live cell models. These systems are increasingly portable and suitable for point of care or in vivo applications. This review highlights the evolution of p‑Tau detection technologies, from benchmark immunoassays to cutting edge biosensors. Special attention is given to advanced affinity reagents, including aptamers, synthetic peptides, and antibody mimetics, which enhance biosensor specificity, stability, and translational potential. Together, these innovations are redefining AD diagnostics, enabling early intervention and more effective disease monitoring.},
}

@article {pmid41408481,
year = {2025},
author = {Eimer, WA and Rodriguez, AS and DeFao, MT and Ehricke, S and Park, J and Vijaya Kumar, DK and Navalpur Shanmugam, NK and Singh, S and Sawhney, T and Moir, RD and Tanzi, RE},
title = {Phosphorylated tau exhibits antimicrobial activity capable of neutralizing herpes simplex virus 1 infectivity in human neurons.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41408481},
issn = {1546-1726},
support = {1R01AG061035-01//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Tau is a microtubule-associated cytoskeletal protein, which, when hyperphosphorylated and aggregated, can result in a myriad of different tauopathies, including Alzheimer's disease (AD). We previously showed that the principal component of senile plaques, amyloid beta (Aβ), is an antimicrobial peptide capable of binding and entrapping microbial pathogens. Here we show that tau is hyperphosphorylated in neurons in response to viral infection and can neutralize herpes simplex virus 1 (HSV-1) infectivity by directly binding to viral capsids. Our data suggest that the 'pathogenic' characteristics of tau hyperphosphorylation, microtubule destabilization and aggregation are part of an antiviral response, in which tau serves as a host defense protein in the innate immune system of the brain. The combined antimicrobial activities of Aβ and phosphorylated tau resulting in Aβ plaques and neurofibrillary tangles, along with neuroinflammation, suggest that AD neuropathology may have evolved as an orchestrated innate immune host defense response to microbial infection in the brain.},
}

@article {pmid41408378,
year = {2025},
author = {Neuharth, JI and Hernandez, KS and Bernholtz, J and Edwards, H and Stewart, A},
title = {Consideration of sex as a biological variable over the history of the 5xFAD Alzheimer's Disease mouse model.},
journal = {Biology of sex differences},
volume = {16},
number = {1},
pages = {105},
pmid = {41408378},
issn = {2042-6410},
support = {NIH T32NS007421/NH/NIH HHS/United States ; Lulu Merle Johnson Recruitment Fellowship//University of Iowa/ ; },
mesh = {Animals ; *Alzheimer Disease ; Disease Models, Animal ; Male ; Female ; Mice ; Mice, Transgenic ; *Sex Characteristics ; },
abstract = {BACKGROUND: Women are nearly twice as likely to be diagnosed with Alzheimer's Disease (AD) over their lifetime. However, historically, preclinical studies utilizing AD rodent models to define new therapeutic targets in AD treatment have neglected to consider the confounding influence of subject sex leading to a lack of mechanistic insight into the biological underpinnings of sex bias in AD.

METHODS: Here, we tracked choice of subject sex over the twenty-year history of the 5xFAD mouse, one of the most frequently cited pre-clinical AD models. We analyzed 1,330 primary research articles indexed on PubMed and recorded information provided regarding subject sex and/or as a rationale for not including datasets separated by sex, if noted. Trends were then plotted as a function of time ending in December 2024.

RESULTS: In the last 15 years, the number of published manuscripts on the 5xFAD model omitting information on subject sex has progressively declined. However, the proportion of studies utilizing either males only (29%) or combining data from both sexes (24%) far surpasses studies acknowledging sex as a biological variable (SABV) (< 12%) with no significant changes noted over time. On average, the ratio of male only: female only studies of 5xFAD mice hovered around 2:1. The most frequently cited reason for omitting sex-based analyses was either a lack of sex differences found (29%), accelerated development of plaque burden in 5xFAD females (17%), or the possibility of within- or between-sex variability (15%). Mention of SABV has steadily increased in studies utilizing 5xFAD mice peaking at ~ 30% of manuscripts published in 2024. However, two key confounds in the 5xFAD model, including the potential impact of an estrogen response element (ERE) and parental imprinting in the Thy1 promoter driving transgene expression, have been largely ignored.

CONCLUSIONS: The 5xFAD model represents a compelling example of how neglecting to recognize the impact of biological sex on neural function can compromise study design and data interpretation. Given sex-dependent Thy1 promoter regulation may skew phenotypic outcomes, investigators should judiciously interpret sex differences observed in any AD mouse utilizing the Thy1 promoter to drive transgene expression.},
}

Animals
*Alzheimer Disease
Disease Models, Animal
Male
Female
Mice
Mice, Transgenic
*Sex Characteristics

@article {pmid41408128,
year = {2025},
author = {Sharma, R and Acharya, V},
title = {Lightweight Vision Transformer with transfer learning for interpretable Alzheimer's disease severity assessment.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {44028},
pmid = {41408128},
issn = {2045-2322},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis/pathology ; Humans ; *Magnetic Resonance Imaging/methods ; *Deep Learning ; Neural Networks, Computer ; Severity of Illness Index ; *Image Interpretation, Computer-Assisted/methods ; },
abstract = {Early and reliable diagnostic tools are critical for slowing the progression of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss and cognitive decline. This study introduces, ViTTL, lightweight deep learning framework for assessing the severity of AD using MRI data. ViTTL integrates Vision Transformers (ViT) with pre-trained convolutional neural networks utilized in transfer learning mode, to extract informative features from 2D MRI slices. Among the evaluated combinations, the ViT-DenseNet201 model integrated with an artificial neural network (ANN) classifier achieved the highest classification accuracy (99.89%) on the OASIS dataset. To ensure interpretability, we incorporated LIME and GRAD-CAM method, which consistently focus on cortical and hippocampal regions known to be associated with Alzheimer's pathology. The average Dice similarity coefficient across runs was 0.85 with a standard deviation of 0.03, indicating high consistency in the model's focus regions against ground truth annotations by expert radiologists. ViTTL also achieved a substantial reduction in model size from 83.0 MB to 6.47 MB enabling deployment in resource-limited environments without compromising performance. Validation on an independent dataset (Kaggle) and comparative performance analysis against state-of-the-art methods further support the robustness and generalizability. These findings demonstrate that ViTTL is a promising tool for accurate, interpretable, and resource-efficient AD diagnosis, with strong potential for clinical translation and patient outcome improvement. The related codes are available at https://github.com/RuhikaSharma/enhanced-alzheimer-risk-assessment .},
}

*Alzheimer Disease/diagnostic imaging/diagnosis/pathology
Humans
*Magnetic Resonance Imaging/methods
*Deep Learning
Neural Networks, Computer
Severity of Illness Index
*Image Interpretation, Computer-Assisted/methods

@article {pmid41408121,
year = {2025},
author = {Lee, JW and Kim, S and Kim, S and Um, YH and Wang, SM and Kim, T and Kim, D and Lim, HK and Lee, CU and Kang, DW},
title = {Alzheimer-related individual factors modulate effects of transcranial direct current stimulation strength on white matter integrity in mild cognitive impairment.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {43985},
pmid = {41408121},
issn = {2045-2322},
support = {HI22C0467//the Korea Health Technology R&D Project through the Korea Health Industry Development Institute/ ; HI22C0467//the Korea Health Technology R&D Project through the Korea Health Industry Development Institute/ ; 2019R1C1C1007608//National Research Foundation of Korea/ ; },
mesh = {Humans ; *Cognitive Dysfunction/therapy/diagnostic imaging/pathology/physiopathology ; *White Matter/diagnostic imaging/pathology/physiopathology ; *Transcranial Direct Current Stimulation/methods ; Male ; Female ; Aged ; *Alzheimer Disease/diagnostic imaging/therapy/pathology/genetics/physiopathology ; Diffusion Tensor Imaging ; Middle Aged ; Prospective Studies ; Apolipoprotein E4/genetics ; Magnetic Resonance Imaging ; Brain-Derived Neurotrophic Factor/genetics ; },
abstract = {Transcranial direct current stimulation (tDCS) is a promising non-invasive intervention for mild cognitive impairment (MCI). This prospective study investigated the relationship between optimized electrical field (EF) strength of tDCS and white matter (WM) microstructural changes in 55 individuals with MCI. Magnetic resonance imaging (MRI)-based computational modeling was used to optimize EF strength targeting the left dorsolateral prefrontal cortex (DLPFC). Diffusion tensor imaging (DTI) assessed WM integrity through fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD). Higher EF strength was significantly associated with increased FA and reduced MD and RD in specific left-lateralized tracts, including the anterior thalamic radiation, corticospinal tract, inferior fronto-occipital fasciculus, and inferior longitudinal fasciculus. These EF-dependent WM changes were moderated by Alzheimer's disease (AD)-related factors. Greater WM plasticity was observed in Aβ-positive individuals, APOE ε4 non-carriers, and BDNF Met non-carriers. Moreover, APOE ε4 status significantly moderated the relationship between EF strength and executive function; in non-carriers, stronger EF strength was associated with improved Stroop performance, potentially reflecting enhanced WM integrity in the right superior longitudinal fasciculus. However, no significant associations were observed between EF-sensitive tracts and short-term cognitive changes in the full sample, suggesting that structural modifications may precede functional improvements or require longer follow-up. These findings emphasize the importance of individual AD-related factors in shaping neuromodulatory responses. They also support the need for longitudinal, sham-controlled studies to clarify the clinical implications of EF strength in personalized tDCS for MCI.},
}

Humans
*Cognitive Dysfunction/therapy/diagnostic imaging/pathology/physiopathology
*White Matter/diagnostic imaging/pathology/physiopathology
*Transcranial Direct Current Stimulation/methods
Male
Female
Aged
*Alzheimer Disease/diagnostic imaging/therapy/pathology/genetics/physiopathology
Diffusion Tensor Imaging
Middle Aged
Prospective Studies
Apolipoprotein E4/genetics
Magnetic Resonance Imaging
Brain-Derived Neurotrophic Factor/genetics

@article {pmid41408021,
year = {2025},
author = {Kaur, K and Kulkarni, YA and Wairkar, S},
title = {Improved Oral Bioavailability and Brain Distribution of Hesperidin via Cochleate Formulation: Statistical Optimization and Pharmacokinetic Study.},
journal = {AAPS PharmSciTech},
volume = {27},
number = {1},
pages = {59},
pmid = {41408021},
issn = {1530-9932},
mesh = {*Hesperidin/pharmacokinetics/administration & dosage/chemistry ; Animals ; Biological Availability ; Rats, Wistar ; Administration, Oral ; Liposomes/chemistry ; Rats ; *Brain/metabolism ; Male ; Particle Size ; Chemistry, Pharmaceutical/methods ; Solubility ; Tissue Distribution ; Drug Liberation ; },
abstract = {Hesperidin, a flavanone, exhibits antioxidant, anti-inflammatory, and anti-amyloidogenic properties, making it a promising candidate for the treatment of Alzheimer's disease. The hesperidin possesses poor solubility, and its oral bioavailability is < 20%. Therefore, hesperidin cochleates (HC) were prepared using the trapping method of calcium ions into preformed liposomes to improve oral bioavailability. The HC formulation was statistically optimized by applying a 3-level factorial design. Optimum cochleates were observed, with an average particle size of 398.9 nm, a zeta potential of -39.1 mV, and an entrapment efficiency of 92.2%, respectively. The in vitro release of hesperidin from cochleates (Batch 15) was 97% in phosphate buffer at pH 7.4 after 24 h. The HC formulation exhibited a 1% release at a gastric pH of 1.2, indicating its stability in the stomach, allowing the formulation to reach the absorption site. In Wistar rats, a comparative pharmacokinetic study was conducted between hesperidin liposomes and HC. Hesperidin concentration was 2.21-fold higher in plasma and 1.2-fold higher in the brain after cochleates administration than in the liposomal formulation and more than 25-fold greater than plain API. Thus, cochleates may be superior oral carriers for hesperidin, improving its oral bioavailability for the treatment of Alzheimer's disease.},
}

*Hesperidin/pharmacokinetics/administration & dosage/chemistry
Animals
Biological Availability
Rats, Wistar
Administration, Oral
Liposomes/chemistry
Rats
*Brain/metabolism
Male
Particle Size
Chemistry, Pharmaceutical/methods
Solubility
Tissue Distribution
Drug Liberation

@article {pmid41407958,
year = {2025},
author = {Mullard, A},
title = {How common is Alzheimer's? Blood-test study holds surprises.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {41407958},
issn = {1476-4687},
}

@article {pmid41407938,
year = {2025},
author = {Kalia, V and Reyes-Dumeyer, D and Dubey, S and Udhani, H and Nandakumar, R and Lee, AJ and Lantigua, R and Medrano, M and Rivera, D and Honig, LS and Mayeux, R and Miller, GW and Vardarajan, BN},
title = {Lysophosphatidylcholines are associated with amyloidosis in early stages of Alzheimer's disease.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {41407938},
issn = {2662-8465},
support = {R56AG063908, R01AG067501, RF1AG015473, R01AG072474, R01AG066107//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R56AG063908, R01AG067501, RF1AG015473, R01AG072474, R01AG066107//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG067501//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG067501//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG067501//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG067501//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R56AG063908, R01AG067501, RF1AG015473, R01AG072474, R01AG066107//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R56AG063908, R01AG067501, RF1AG015473, R01AG072474, R01AG066107//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R56AG063908, R01AG067501, RF1AG015473, R01AG072474, R01AG066107//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 5UL1TR001873//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; 5UL1TR001873//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; 5UL1TR001873//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; 5UL1TR001873//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; 5UL1TR001873//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; },
abstract = {Circulating metabolites can identify biochemical risk factors related to Alzheimer's disease (AD). We measured plasma metabolites in 1,068 participants of Caribbean Hispanic ancestry (250 patients with AD and 818 healthy controls) across 2 cohorts and analyzed their relationship with clinical AD, biomarker-supported AD and plasma biomarkers (P-tau181, P-tau217, P-tau231 and Aβ42:Aβ40). Amino acid metabolism pathways were enriched among metabolites associated with P-tau biomarkers, whereas sialic acid and N-glycan pathways were associated with Aβ42:Aβ40. Through several dimensionality reduction approaches, we identified an APOE-ε4 dependent relationship between lysophosphatidylcholines (lysoPCs) carrying polyunsaturated fatty acids and biomarker-supported AD and P-tau biomarkers. In an independent dataset of 110 postmortem brain tissues from non-Hispanic white participants, lysoPCs in the brain were also associated with AD neuropathological features. Our results show that biomarker-based diagnostic criteria identified an APOE-ε4 dependent association with lysoPCs, which play a critical role in the transport of neuroprotective polyunsaturated fatty acids into the brain, and AD.},
}

@article {pmid41407852,
year = {2025},
author = {Aarsland, D and Sunde, AL and Tovar-Rios, DA and Leuzy, A and Fladby, T and Zetterberg, H and Blennow, K and Tan, K and De Santis, G and Yakoub, Y and Arslan, B and Huber, H and Pola, I and Grötschel, L and Di Molfetta, G and Skjellegrind, HK and Selbaek, G and Ashton, NJ},
title = {Prevalence of Alzheimer's disease pathology in the community.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {41407852},
issn = {1476-4687},
abstract = {The prevalence of Alzheimer's disease neuropathological changes (ADNCs), the leading cause of cognitive impairment, remains uncertain. Recent blood-based biomarkers enable scalable assessment of ADNCs[1]. Here we measured phosphorylated tau at threonine 217 in 11,486 plasma samples from a Norwegian population-based cohort of individuals over 57 years of age as a surrogate marker for ADNCs. The estimated prevalence of ADNCs increased with age, from less than 8% in people 58-69.9 years of age to 65.2% in those over 90 years of age. Among participants aged 70 years or older, 10% had preclinical Alzheimer's disease, 10.4% had prodromal Alzheimer's disease and 9.8% had Alzheimer's disease dementia. Furthermore, among those 70 years of age or older, ADNCs were present in 60% of people with dementia, in 32.6% of those with mild cognitive impairment and in 23.5% of the cognitively unimpaired group. Our findings suggest a higher prevalence of Alzheimer's disease dementia in older individuals and a lower prevalence of preclinical Alzheimer's disease in younger groups than previously estimated[2].},
}

@article {pmid41407844,
year = {2025},
author = {Rabiei Rad, A and Nadaki, A and Khosravi, F and Nasiri, H and Ghayourvahdat, A and , },
title = {Plasma p-tau217 and p-tau217/Aβ1-42 ratios associate with medial temporal lobe subfield atrophy in normal aging and mild cognitive impairment.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-32404-0},
pmid = {41407844},
issn = {2045-2322},
abstract = {Early diagnosis of Alzheimer's disease (AD), particularly during its preclinical and prodromal phases, remains a major challenge. Plasma biomarkers such as phosphorylated tau at threonine 217 (p-tau217), amyloid-β (Aβ) isoforms, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) show promise for early detection; however, their relationships with medial temporal lobe (MTL) subfield atrophy and potential inter-biomarker pathways remain unclear. This study aimed to address this gap by investigating the associations between plasma biomarkers and MTL subfield atrophy, and by assessing potential mediation pathways. We conducted a cross-sectional study using data from 330 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively normal (CN) and mild cognitive impairment (MCI) groups. High-resolution coronal T2-weighted MRI quantified MTL subfield volumes using the ASHS protocol. Plasma biomarkers were measured using ultrasensitive immunoassays. The cohort included 209 CN participants (mean age [SD] = 69.3 [6.9] years; 64.2% women; 24.4% APOE ε4 carriers) and 121 MCI participants (mean age [SD] = 71.3 [7.3] years; 48.8% women; 27.9% APOE ε4 carriers). MCI individuals showed significantly higher plasma concentrations of p-tau217, p-tau217/Aβ1-42 ratio, NfL, and GFAP, and greater MTL atrophy. Higher plasma p-tau217 and p-tau217/Aβ1-42 were associated with reduced bilateral hippocampal and CA1 volumes in MCI (β = - 0.37 to - 0.28; FDR p < 0.02). In CN, these biomarkers were positively associated with left hippocampal volume (β ≈ 0.19; FDR p = 0.04), and GFAP correlated with larger sulcal volume (FDR p = 0.03). Mediation analysis demonstrated that in CN individuals, the relationship between p-tau217/Aβ1-42 and left sulcal volume was partially mediated by GFAP (indirect β = 0.11; FDR p = 0.048). This study reveals stage-specific plasma biomarker-MTL relationships across the Alzheimer's continuum. In MCI, plasma p-tau217 and its ratio to Aβ1-42 closely track hippocampal subfield atrophy, reflecting tau-related neurodegeneration. In CN individuals, higher p-tau217 and p-tau217/Aβ1-42 levels relate positively to hippocampal integrity, partly mediated by GFAP, suggesting early astroglial activity preceding structural loss. These findings underscore dynamic biomarker interactions and support integrating plasma and imaging markers for early AD characterization.},
}

@article {pmid41407658,
year = {2025},
author = {Xu, YQ and Sun, X and Liao, C and Li, X},
title = {A Framework for Identifying Serum Exosomal Lipid Biomarkers in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00947},
pmid = {41407658},
issn = {1948-7193},
abstract = {The escalating global burden of Alzheimer's disease (AD), projected to reach $16.9 trillion by 2050 with disproportionate impacts on low- and middle-income countries and racial minorities, underscores an urgent need for accessible early detection tools. Current therapies offer limited symptomatic relief but fail to halt neurodegeneration. Serum exosomal lipids, which reflect brain pathophysiology through blood-brain barrier crossing vesicles, present promising minimally invasive biomarkers. However, a standardized framework for their systematic development is lacking. We propose a structured three-phase approach comprising discovery, analytical validation, and clinical utility assessment. The discovery phase employs nontargeted lipidomics of serum exosomes from AD patients and controls integrated with machine learning to identify dysregulated pathways and prioritize candidate biomarkers. Analytical validation involves targeted quantification using UPLC-MS/MS to optimize sensitivity and specificity within complex matrices, with rigorous performance evaluation via receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) analysis in independent case-control cohorts establishing preliminary diagnostic cut-offs. Clinical utility assessment requires longitudinal evaluation in treated AD cohorts to correlate biomarker dynamics with disease progression or therapeutic response, refine diagnostic thresholds, and explore presymptomatic risk prediction. Implementing this framework demands multidisciplinary collaboration and strict ethical adherence. This strategy paves the way for clinically validated serum exosomal lipid biomarkers to enable presymptomatic detection and personalized risk stratification, ultimately mitigating AD's devastating socioeconomic impact.},
}

@article {pmid41407593,
year = {2025},
author = {Yan, R and Zhang, W and Wang, W and Wu, J and Zhang, J and Xu, Y and Xu, W and Yang, W},
title = {Deep learning analysis of urine-derived stem cell mitochondrial morphology as a non-invasive Alzheimer's disease biomarker.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00813},
doi = {10.1016/j.neurot.2025.e00813},
pmid = {41407593},
issn = {1878-7479},
abstract = {Alzheimer's disease (AD), closely associated with mitochondrial dysfunction, currently lacks convenient and non-invasive biomarkers for mitochondrial assessment. In this study, we developed an artificial intelligence framework leveraging live urine-derived stem cell (USC) mitochondrial fluorescence imaging to investigate differences between cognitively impaired individuals (AD and mild cognitive impairment (MCI)) and cognitively normal (CN) subjects. Mitochondrial fluorescence images from living HeLa cells were first segmented, and two binary classification models based on the ResNet-18 convolutional neural network were trained to identify mitochondrial hyperfission and hyperfusion relative to normal morphology. The models demonstrated robust performance in detecting intermediate mitochondrial states during validation. When applied to USCs, the system effectively distinguished mitochondrial patterns associated with cognitive impairment, highlighting its potential for the early detection of Alzheimer's disease and merits further validation in larger, independent cohorts.},
}

@article {pmid41407165,
year = {2025},
author = {Ghosh, N and Ghosh, J and Ghosh, S and Sinha, K and Sil, PC},
title = {Nutraceutical interventions for neuroprotection: a comprehensive review.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117637},
doi = {10.1016/j.bcp.2025.117637},
pmid = {41407165},
issn = {1873-2968},
abstract = {Nutraceuticals, bioactive compounds derived from food sources, are emerging as promising agents for neuroprotection, particularly through their modulation of gut health. Unlike conventional single-molecule therapeutics that often target isolated pathways, nutraceuticals offer a multi-targeted approach by influencing the gut-brain axis, a bidirectional communication network linking the gut microbiota and the central nervous system. Key nutraceuticals such as probiotics, prebiotics, polyphenols, omega-3 fatty acids, and vitamins have been shown to beneficially alter microbiota composition, reduce intestinal inflammation, and strengthen gut barrier integrity. These changes can significantly influence brain function by modulating neurotransmitter activity and systemic immune responses. This review compares the holistic action of nutraceuticals with the more focused effects of single-molecules, particularly in the context of neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's Disease and Motor Neuron Diseases like amyotrophic lateral sclerosis. It discusses how nutraceuticals may mitigate key pathological features of these conditions-including neuroinflammation, oxidative stress, and mitochondrial dysfunction, through gut-mediated pathways. Despite their potential, challenges remain regarding the standardization of formulations, bioavailability, dosage optimization, and long-term safety. Further clinical research is needed to validate the efficacy of nutraceuticals as complementary or alternative strategies to traditional neuroprotective agents.},
}

@article {pmid41407043,
year = {2025},
author = {Fan, B and Liang, Y and Zhi, T and Wu, L and Wu, Y and Yang, Y and Xie, Z and Wu, X},
title = {GPR55 deficiency exacerbates cognitive impairments and Alzheimer's disease-like pathology in mice.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106105},
doi = {10.1016/j.neuint.2025.106105},
pmid = {41407043},
issn = {1872-9754},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, characterized by progressive cognitive decline and neuronal damage. Although studies have indicated a link between G-protein coupled receptor 55 (GPR55) and AD-related cognitive impairment, the underlying mechanisms remain unclear. Here, we aim to further investigate the role of GPR55 in the pathogenesis of AD.

METHODS: We used viral vectors to knock down GPR55 expression in the hippocampus of normal mice. We also generated GPR55 knockout in AD mice by crossing GPR55[-/-] mice with APP/PS1 transgenic mice (APP/PS1; GPR55[-/-]). Behavioral tests were conducted to assess spatial memory deficits in 9-month-old APP/PS1; GPR55[-/-] mice. We also assessed the amyloid β (Aβ) deposition, glial cell activation, and synaptic protein expression in the hippocampus. In addition, we used AAV9 viruses to overexpress GPR55 in the hippocampus of APP/PS1; GPR55[-/-] mice to further observe its effect on cognitive function.

RESULTS: Knockdown of GPR55 in the hippocampus induces AD-like pathology, cognitive dysfunction, neuroinflammation, and synaptic plasticity damage in normal mice. This was evidenced by increased hippocampal levels of Aβ and p-Tau, enhanced glial cell activation accompanied by upregulation of proinflammatory cytokines, and aggravated synaptic plasticity damage in the normal mice. Furthermore, knockdown of GPR55 induced the reduction of P-AKT1/2/3/AKT1/2/3 and P-GSK3β/GSK3β, while increasing the expression of P-ERK1/2/ERK1/2 in the hippocampus of normal mice. In addition, GPR55 deficiency exacerbated AD-like pathology and spatial learning and memory deficits in APP/PS1 mice. Conversely, AAV9-mediated overexpression of GPR55 rescued spatial memory impairments in APP/PS1; GPR55[-/-] mice.

CONCLUSIONS: These findings underscore the critical role of GPR55 in AD progression and highlight its potential as a therapeutic target for AD treatment.},
}

@article {pmid41406951,
year = {2025},
author = {Fang, S and Cui, F and Drucker, DJ},
title = {Glucagon-like peptide-1 medicines in neurological and psychiatric disorders.},
journal = {Cell reports. Medicine},
volume = {6},
number = {12},
pages = {102511},
doi = {10.1016/j.xcrm.2025.102511},
pmid = {41406951},
issn = {2666-3791},
mesh = {Humans ; *Glucagon-Like Peptide 1/therapeutic use/metabolism ; *Mental Disorders/drug therapy ; *Nervous System Diseases/drug therapy ; Diabetes Mellitus, Type 2/drug therapy ; },
abstract = {Glucagon-like peptide-1 (GLP-1) medicines are used for the treatment of type 2 diabetes (T2D) and obesity and reduce rates of cardiovascular disease, including stroke, in people with T2D. Substantial evidence from real-world data and clinical trials highlights the therapeutic potential of GLP-1 medicines for the treatment of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Similarly, there is growing evidence for the potential utility of using GLP-1 medicines to reduce rates of smoking, or use of alcohol, tobacco, cannabis, or cocaine in individuals with substance use disorders. More limited clinical data suggest utility for GLP-1 medicines in patients with migraine or intracranial hypertension. The available data suggest that the use of GLP-1 medicines exhibits an acceptable safety profile in most individuals with neuropsychiatric disorders. Here, we review recent clinical evidence and ongoing trials exploring the efficacy and safety of GLP-1 medicines across a broad range of neurological conditions.},
}

Humans
*Glucagon-Like Peptide 1/therapeutic use/metabolism
*Mental Disorders/drug therapy
*Nervous System Diseases/drug therapy
Diabetes Mellitus, Type 2/drug therapy

@article {pmid41406948,
year = {2025},
author = {Lan, G and Li, B and Wang, M and Barve, A and Colin, M and Buée, L and Zhang, L and Jiang, M and Yang, J and Li, A and He, Z and Zhou, X and Zhu, Y and Cai, Y and Sun, P and Liu, L and Li, J and Chen, L and Fang, L and Wang, Y and Li, M and Chen, X and Shi, D and Ye, C and Fan, X and Wang, Q and Zhou, L and Liu, Z and Han, Y and Wang, L and Cheng, G and Guan, Y and Ni, R and Richetin, K and Xie, F and Guo, T},
title = {Plasma growth-associated protein 43 correlates with synaptic loss in Alzheimer's disease.},
journal = {Cell reports. Medicine},
volume = {6},
number = {12},
pages = {102508},
doi = {10.1016/j.xcrm.2025.102508},
pmid = {41406948},
issn = {2666-3791},
mesh = {Humans ; *Alzheimer Disease/blood/pathology/metabolism/diagnostic imaging ; Male ; Female ; Aged ; Biomarkers/blood/cerebrospinal fluid ; *Synapses/pathology/metabolism ; *GAP-43 Protein/blood/cerebrospinal fluid/metabolism ; tau Proteins/metabolism ; Positron-Emission Tomography ; Brain/pathology/metabolism/diagnostic imaging ; Aged, 80 and over ; Magnetic Resonance Imaging ; Middle Aged ; Cognitive Dysfunction/blood ; },
abstract = {Synaptic loss is a hallmark of Alzheimer's disease (AD) but lacks robust blood-based biomarkers. We investigate growth-associated protein 43 (GAP-43), previously identified as a synaptic candidate in the cerebrospinal fluid (CSF). Postmortem proteomic profiling of brain-derived extracellular vesicles (n = 21) highlights GAP-43 as a central hub within synaptic protein networks co-depleted in AD and closely linked with proteins enriched in immune-, metabolic-, and synaptic-related modules. In two well-characterized Chinese AD cohorts (n = 785), we measure plasma GAP-43, including subgroups with CSF biomarkers (n = 72), SV2A-PET (positron emission tomography) (n = 85), tau-PET (n = 280), and magnetic resonance imaging (MRI) (n = 595). Plasma GAP-43 correlates with CSF GAP-43, neurofilament light, and both baseline and longitudinal synaptic PET. Elevated plasma GAP-43 is associated with greater tau aggregation, faster brain atrophy, and accelerated cognitive decline, particularly among cognitively unimpaired individuals. These findings support plasma GAP-43 as a promising biomarker of early synaptic degeneration and a potential tool for identifying individuals at risk of AD progression.},
}

Humans
*Alzheimer Disease/blood/pathology/metabolism/diagnostic imaging
Male
Female
Aged
Biomarkers/blood/cerebrospinal fluid
*Synapses/pathology/metabolism
*GAP-43 Protein/blood/cerebrospinal fluid/metabolism
tau Proteins/metabolism
Positron-Emission Tomography
Brain/pathology/metabolism/diagnostic imaging
Aged, 80 and over
Magnetic Resonance Imaging
Middle Aged
Cognitive Dysfunction/blood

@article {pmid41406907,
year = {2025},
author = {Chen, C and Chen, Q and Zou, H and Zhao, C and Wang, X},
title = {Research Trends in Periodontitis and Alzheimer's Disease: A Bibliometric Analysis Based on Web of Science and Scopus.},
journal = {International dental journal},
volume = {76},
number = {1},
pages = {109327},
doi = {10.1016/j.identj.2025.109327},
pmid = {41406907},
issn = {1875-595X},
abstract = {INTRODUCTION AND AIMS: This study aimed to conduct a comprehensive bibliometric analysis to identify global research trends, key contributors and emerging hot spots in the field investigating the association between periodontitis and Alzheimer's disease (AD).

METHODS: Scientific publications from 2002 to 2025 were retrieved from the Web of Science Core Collection (WoSCC) and Scopus databases. The data were analysed using VOSviewer, CiteSpace and the R package 'bibliometrix' to perform co-authorship, co-occurrence and citation analyses.

RESULTS: A total of 262 articles from WoSCC and 272 from Scopus were included in the analysis. China was the leading contributing country, and Shanghai Jiao Tong University was the most productive institution. The Journal of Alzheimer's Disease was identified as the most influential journal in this domain. Keyword co-occurrence analysis identified central research themes, including 'dementia', 'tooth loss', and 'Porphyromonas gingivalis'. Citation burst analysis indicated that 'oral microbiome' and 'oral health' are currently emerging research frontiers.

CONCLUSION: This is the first bibliometric study to systematically map the intellectual structure and evolution of research linking periodontitis and AD. The findings underscore the strengthening link between oral inflammatory conditions and neurodegeneration.

CLINICAL RELEVANCE: The analysis highlights a shifting focus towards mechanisms such as the oral microbiome and systemic inflammation, pointing to promising directions for future research aimed at novel preventive strategies and therapeutic interventions for AD.},
}

@article {pmid41406783,
year = {2025},
author = {Ioannidou, E and Vavilis, T and Bourtzos, Z and Stamoula, E},
title = {Corrigendum to "A review of the TGF-β1 pathway in Alzheimer's disease and depression: Possible restoration potential of antidepressants" [Neuroscience 585 (2025) 429-440].},
journal = {Neuroscience},
volume = {593},
number = {},
pages = {170},
doi = {10.1016/j.neuroscience.2025.12.006},
pmid = {41406783},
issn = {1873-7544},
}

@article {pmid41406583,
year = {2025},
author = {Yıldızbaş, A and Taslimi, P and Tüzün, B and Sadeghian, N and Kurt, R and İstek, A},
title = {Chemical composition and bioactivity of Sideritis taurica Stephan ex Wild. (Lamiaceae) leaves: GC/MS analysis, antioxidant and enzyme inhibition activities, and in silico studies.},
journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences},
volume = {1270},
number = {},
pages = {124894},
doi = {10.1016/j.jchromb.2025.124894},
pmid = {41406583},
issn = {1873-376X},
abstract = {Since ancient times, Sideritis taurica and other Sideritis species have been used in traditional medicine in Türkiye and beyond for treating a variety of ailments, including coughs, sore throats, gastrointestinal, respiratory, and urogenital disorders, as well as wounds, colds, and flu, and are believed to possess numerous therapeutic properties such as antispasmodic, analgesic, antibacterial, anti-inflammatory, and antioxidant effects. This study aimed to evaluate the enzyme inhibition and antioxidant activities of various extracts from S. taurica leaves collected from Kurucaşile, Bartın, Türkiye. The extracts were prepared using ethanol, methanol, and hot/cold water extraction methods from leaves that were dried at room temperature and stored in a freezer. Enzyme inhibition activities were assessed against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-glucosidase, and α-amylase, with IC50 values calculated. Antioxidant activities were measured using DPPH, ABTS, and CUPRAC assays. Furthermore, ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) and molecular docking calculations were performed on the phytochemical components of S. taurica to investigate their effects and interactions with human metabolism. These calculations were performed on a number of proteins, including alpha-amylase protein (PDB ID: 1HNY), AChE protein (PDB ID: 4M0E), and BChE protein (PDB ID: 5NN0). The purpose of these calculations was to investigate the interaction between these substances and human metabolism. The results indicated that the ethanol and methanol extracts exhibited the highest inhibition on AChE and BChE (IC50 values of 73.99 μg/mL and 5.04 μg/mL, respectively). The methanol extracts also demonstrated potent inhibition against α-glucosidase (IC50 value of 25.81 μg/mL) and α-amylase (IC50 value of 70.42 μg/mL). Regarding antioxidant activity, the methanol extracts showed the highest radical scavenging activity in the DPPH (87.88 %) and ABTS (99.97 %) tests. Additionally, the methanol extracts stored in the freezer exhibited the best-reducing power in the CUPRAC assay (2.436 ± 0.1669). These findings underscore the potential of S. taurica as a source of natural antioxidants and enzyme inhibitors, suggesting its applicability in the treatment of neurodegenerative diseases such as Alzheimer's disease. In conclusion, extracts obtained from S. taurica leaves, particularly those derived from room temperature-dried leaves, demonstrate significant enzyme inhibition and antioxidant properties. Also, the findings support the consideration of S. taurica as a natural therapeutic source for neurodegenerative diseases and emphasize for further investigation into its active components and health benefits.},
}

@article {pmid41406575,
year = {2025},
author = {Quadir, A and Tanveer, M},
title = {TRKM: Twin restricted kernel machines for classification and regression.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {197},
number = {},
pages = {108449},
doi = {10.1016/j.neunet.2025.108449},
pmid = {41406575},
issn = {1879-2782},
abstract = {Restricted kernel machines (RKMs) have significantly advanced machine learning by integrating kernel functions with least squares support vector machines (LSSVM), adopting an energy function akin to restricted Boltzmann machines (RBM) to enhance generalization performance. Despite their strengths, RKMs face challenges in handling unevenly distributed or complexly clustered data and incur substantial computational costs when scaling to large datasets due to the management of high-dimensional feature spaces. To address these limitations, we propose the twin restricted kernel machine (TRKM), a novel framework that synergizes the robustness of RKM with the efficiency of twin hyperplane methods, inspired by twin support vector machines (TSVM). TRKM leverages conjugate feature duality based on the Fenchel-Young inequality to reformulate classification and regression problems in terms of dual variables, establishing a bound on the objective function and introducing a new methodology within the RKM framework. By incorporating an RBM-inspired energy function with visible and hidden variables corresponding to both classes, TRKM effectively captures complex data patterns. The kernel trick is employed to project data into a high-dimensional feature space, where an optimal separating hyperplane is identified using a regularized least squares approach, enhancing both performance and computational efficiency. Extensive experiments on 36 diverse datasets from UCI and KEEL repositories demonstrate TRKM's superior accuracy and scalability compared to baseline models. Additionally, TRKM's application to the brain age estimation dataset underscores its efficacy in predicting brain age, a critical biomarker for early Alzheimer's disease detection, highlighting its potential for real-world medical applications. To the best of our knowledge, TRKM is the first twin variant of the RKM framework, offering a robust and efficient solution for complex classification and regression tasks. The source code of the proposed TRKM model is available at https://github.com/mtanveer1/TRKM.},
}

@article {pmid41406552,
year = {2025},
author = {Moazzam, F and Hatamian-Zarmi, A and Sabaghian, M and Khezri, K and Hosseinzadeh, BE and Khodagholi, F and Shahmansouri, MJ and Rashidi, FS},
title = {Frankincense-loaded lactoferrin-conjugated solid lipid nanoparticles for targeted brain delivery and neuroprotection in a scopolamine-induced Alzheimer's model.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {260},
number = {},
pages = {115370},
doi = {10.1016/j.colsurfb.2025.115370},
pmid = {41406552},
issn = {1873-4367},
abstract = {Central nervous system (CNS) disorders remain a major field with substantial unmet therapeutic needs. This study aimed to address the critical challenge of brain drug delivery by employing solid lipid nanoparticles (SLNs) surface-functionalized with lactoferrin (Lf) ligands, from the transferrin family, to facilitate transport across the blood-brain barrier. Frankincense (F), a natural compound with well-documented neuroprotective properties and minimal adverse effects, was encapsulated within (SLNs) using a microemulsion approach. The optimal formulation resulted in nanoparticles (NPs) with an average size of 103.1 ± 0.9 nm, an encapsulation efficiency of 95.2 ± 0.8 %, a drug loading capacity of 8.6 ± 0.1 %, a polydispersity index (PDI) of 0.3 ± 0.08, and a zeta potential of -29.2 ± 0.5 mV. The optimized NPs showed a sustained drug release profile, and ATR-FTIR spectra confirmed the conjugation of lactoferrin to the nanoparticles. To establish translational relevance, the neuroprotective effectiveness of (F-Lf-SLNs) was investigated using a scopolamine-induced Alzheimer's disease animal model. Behavioral tests, along with biochemical and histological analyses, were conducted. The findings demonstrated that (F-Lf-SLNs) significantly improved the brain delivery of frankincense, highlighting their promise as a neuroprotective strategy for CNS disorders. They also effectively protected neurons compared to the scopolamine-induced group. Overall, these results emphasize the key role of drug delivery systems and ligand-targeting methods in enhancing the therapeutic effectiveness of drugs.},
}

@article {pmid41406490,
year = {2025},
author = {Shin, J and Kang, HW and Kim, S},
title = {Nanoscale Structural and Immunological Remodeling of the Primo Vascular System in Alzheimer's Disease: Mast Cell Activation Along the Gut-Brain Axis.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00637},
pmid = {41406490},
issn = {1948-7193},
abstract = {The primo vascular system (PVS) is a fine-scale circulatory network composed of nanoscale tissues that are closely associated with biological signal transmission pathways, such as the gut-brain axis, and that harbor immune and regenerative cells. Mast cells (MCs), critical mediators of gut-brain axis communication, have been implicated in the pathogenesis of Alzheimer's disease (AD). Characterized by a high MC density, the PVS is increasingly recognized as a potential modulator of immune responses and tissue regeneration. However, its pathological alterations in neurodegenerative conditions remain poorly understood. This study aimed to investigate the nanoscale structural and immunological characteristics of the organ surface and meningeal PVS (OS-PVS and M-PVS) in APP/PS2 transgenic mice, a well-established model of AD. Behavioral testing in APP/PS2 mice confirmed cognitive impairments characteristic of AD. Atomic force microscopy revealed irregular alignment of primo subvessels and interstitial spaces, along with increased surface roughness and loss of spatial periodicity. Scanning electron microscopy showed a significant increase in the density and diameter of primo pores, as well as reduced fiber structure diameter, suggesting ultrastructural remodeling. Toluidine blue and immunofluorescence staining demonstrated elevated MC density and degranulation ratio within the PVS. These findings suggest that the OS-PVS and M-PVS undergo coordinated nanoscale structural and immunological remodeling in AD, reflecting shared pathological features within the PVS. MC activity within the PVS may contribute to the neuroimmune dysregulation underlying disease progression, supporting its role as an anatomical conduit for immune communication along the gut-brain axis.},
}

@article {pmid41406402,
year = {2026},
author = {Du, Y and Borné, Y and Samuelsson, J and Glans, I and Hu, X and Nägga, K and Palmqvist, S and Hansson, O and Sonestedt, E},
title = {High- and Low-Fat Dairy Consumption and Long-Term Risk of Dementia: Evidence From a 25-Year Prospective Cohort Study.},
journal = {Neurology},
volume = {106},
number = {2},
pages = {e214343},
doi = {10.1212/WNL.0000000000214343},
pmid = {41406402},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Middle Aged ; *Dairy Products ; Prospective Studies ; *Dementia/epidemiology ; Sweden/epidemiology ; Aged ; Risk Factors ; Cohort Studies ; *Dietary Fats ; Cheese ; *Diet, High-Fat ; Alzheimer Disease/epidemiology ; },
abstract = {BACKGROUND AND OBJECTIVES: The association between dairy intake and dementia risk remains uncertain, especially for dairy products with varying fat contents. The aim of this study was to investigate the association between high-fat and low-fat dairy intake and dementia risk.

METHODS: This study used data from a prospective cohort in Sweden, the Malmö Diet and Cancer cohort, which consisted of community-based participants who underwent dietary assessment at baseline (1991-1996). Dietary intake was evaluated using a comprehensive diet history method that combined a 7-day food diary, a food frequency questionnaire, and a dietary interview. Dementia cases were identified through the Swedish National Patient Register until December 31, 2020, and cases diagnosed until 2014 were further validated. The primary outcome of the study was all-cause dementia, and the secondary outcomes were Alzheimer disease (AD) and vascular dementia (VaD). Cox proportional hazard regression models were used to estimate hazard ratio (HR) and 95% CI.

RESULTS: This study included 27,670 participants (mean baseline age 58.1 years, SD 7.6; 61% female). During a median of 25 years of follow-up, 3,208 incident dementia cases were recorded. Consumption of ≥50 g/d of high-fat cheese (>20% fat) was associated with a reduced risk of all-cause dementia (HR 0.87; 95% CI, 0.78-0.97) and VaD (HR 0.71, 95% CI 0.52-0.96) compared with lower intake (<15 g/d). An inverse association between high-fat cheese and AD was found among APOE ε4 noncarriers (HR 0.87, 95% CI 0.76-0.99, p-interaction = 0.014). Compared with no consumption, individuals consuming ≥20 g/d of high-fat cream (>30% fat) had a 16% lower risk of all-cause dementia (HR 0.84, 95% CI 0.72-0.98). High-fat cream consumption was inversely associated with the risk of AD and VaD. Consumption of low-fat cheese, low-fat cream, milk (high-fat and low-fat), fermented milk (high-fat and low-fat), and butter showed no association with all-cause dementia.

DISCUSSION: Higher intake of high-fat cheese and high-fat cream was associated with a lower risk of all-cause dementia, whereas low-fat cheese, low-fat cream, and other dairy products showed no significant association. APOE ε4 status modified the association between high-fat cheese and AD. Our study's observational design limits causal inference.},
}

Humans
Female
Male
Middle Aged
*Dairy Products
Prospective Studies
*Dementia/epidemiology
Sweden/epidemiology
Aged
Risk Factors
Cohort Studies
*Dietary Fats
Cheese
*Diet, High-Fat
Alzheimer Disease/epidemiology

@article {pmid41406216,
year = {2025},
author = {Liu, A and Citu, C and Enduru, N and Chen, X and Tung, CH and Sinha, T and Sepulveda, SE and Manuel, AM and Gorski, D and Fernandes, BS and Yu, M and Schulz, PE and Simon, LM and Soto, C and Zhao, Z},
title = {Single-nucleus multiomics reveals the disrupted regulatory programs in three brain regions of sporadic early-onset Alzheimer's disease.},
journal = {Science advances},
volume = {11},
number = {51},
pages = {eadw4917},
pmid = {41406216},
issn = {2375-2548},
mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/pathology ; *Brain/metabolism/pathology ; Male ; Female ; Transcriptome ; Gene Expression Regulation ; Transcription Factors/metabolism/genetics ; Aged ; Hippocampus/metabolism/pathology ; Entorhinal Cortex/metabolism/pathology ; Multiomics ; },
abstract = {Sporadic early-onset Alzheimer's disease (sEOAD) represents a substantial but less-studied subtype of Alzheimer's disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type-specific transcriptomic changes and linked candidate cis-regulatory elements (cCREs) across brain regions. We prioritized eight conservative transcription factors in glial cells in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in regulating sEOAD-associated genes. Moreover, we identified the top 25 altered intercellular signaling between glial cells and neurons, highlighting their regulatory potential on gene expression in receiver cells. We reported 33 cCREs linked to sEOAD-associated genes overlapped with late-onset AD risk loci, and found that, in addition, sEOAD cCREs are enriched for neuropsychiatric disorder risk variants. This atlas helps dissect transcriptional and chromatin dynamics in sEOAD, providing a key resource for AD research.},
}

Humans
*Alzheimer Disease/genetics/metabolism/pathology
*Brain/metabolism/pathology
Male
Female
Transcriptome
Gene Expression Regulation
Transcription Factors/metabolism/genetics
Aged
Hippocampus/metabolism/pathology
Entorhinal Cortex/metabolism/pathology
Multiomics

@article {pmid41406173,
year = {2025},
author = {Tanjin, R and Al-Amin, M and Etee, JM and Siddika, A and Siddiki, A and Mahi, SI and Toma, SN and Akter, N and Uddin, MH and Bristy, NA and Mowlee, SI and Rafa, EK and Hossen, MF},
title = {An evaluation of Roluperidone as a promising repurposing candidate for Alzheimer's Disease: A Computational Investigation.},
journal = {PloS one},
volume = {20},
number = {12},
pages = {e0338211},
pmid = {41406173},
issn = {1932-6203},
mesh = {*Alzheimer Disease/drug therapy ; *Drug Repositioning/methods ; Humans ; Molecular Docking Simulation ; Support Vector Machine ; Blood-Brain Barrier/metabolism ; Machine Learning ; Donepezil ; },
abstract = {Alzheimer's disease (AD) is the most dominant and prevalent form of dementia. The therapeutic agents for AD are not sufficient. Drug repurposing (i.e., also called drug repositioning or therapeutic switching of drugs) could contribute to adding novel therapeutic agents in AD discovery pipeline. Blood-brain barrier (BBB) is a crucial factor, for brain's diseases related drug discovery. Since, CNS active compounds have BBB crossing property, in this study this category of compounds was re-evaluated as repurposing potential candidate for AD by integrated machine learning algorithm, cheminformatics analysis, molecular Docking and simulation-based approach. We builded three machine learning model such as Support Vector Machine (SVM), Random Forest (RF), Extreme Gradient Boosting (XGB) for the prediction of AD potential repurposing candidates. The SVM classification model performed better than others. The SVM classification model achieved an Area Under the Curve of the Receiver Operating Characteristics (ROC-AUC) of 0.81, along with higher precision, recall, and F1 scores. The support vector machine (SVM) was implemented to classify 500 CNS active compounds as AD drug potential and non-AD drug potential. Using the SVM model, 60 compounds were predicted as AD repurposing potential from 500 CNS active compounds. Structural similarity analysis of 60 compounds with Donepezil as a reference drug was performed using 5 different types of fingerprints such as 'substructure', 'extended', 'circular', 'EState', 'MACCS'. 9 compounds from them obtained as structurally most similar to the reference drug. After the molecular docking performance of 9 compounds into the active site & peripheral anionic site of human acetylcholinesterase (hAChE), it was revealed that Roluperidone' had binding affinity of -12 kcal/mol, and 'Napitane' had binding affinity of -11.9 kcal/mol whereas the reference drug Donepezil had a binding affinity of -11.8 Kcal/mol. Molecular dynamics simulation revealed that Roluperionde had better binding integrity to hAChE. This study laid out computational reinvestigation of 500 CNS active drugs for therapeutic switching to AD, and 'Roluperidone' is found as an AD repurposing potential candidate. However, in-vitro and in-vivo studies are further needed to fully elucidate the compound's potential as AD repurposing drugs.},
}

*Alzheimer Disease/drug therapy
*Drug Repositioning/methods
Humans
Molecular Docking Simulation
Support Vector Machine
Blood-Brain Barrier/metabolism
Machine Learning
Donepezil

@article {pmid41405898,
year = {2025},
author = {Knopman, DS},
title = {Valacyclovir and Symptomatic Alzheimer Disease-No Evidence for Benefit.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2025.20795},
pmid = {41405898},
issn = {1538-3598},
}

@article {pmid41405876,
year = {2025},
author = {},
title = {Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: Research Summary.},
journal = {JAMA},
volume = {},
number = {},
pages = {e2522830},
doi = {10.1001/jama.2025.22830},
pmid = {41405876},
issn = {1538-3598},
}

@article {pmid41405855,
year = {2025},
author = {Devanand, DP and Wisniewski, T and Razlighi, Q and Qian, M and Wei, R and Andrews, HF and Acosta, EP and Bell, KL and Pelton, GH and Deliyannides, D and Perrin, AC and Caccappolo, E and Gershon, AA and Prasad, KM and Kreisl, WC and Mintz, A and Huey, ED},
title = {Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2025.21738},
pmid = {41405855},
issn = {1538-3598},
abstract = {IMPORTANCE: Neuroscientific, epidemiological, and electronic health record studies implicate herpes simplex virus (HSV) as potentially etiological for Alzheimer disease (AD).

OBJECTIVE: To compare the efficacy and adverse effects of valacyclovir vs placebo in participants with early symptomatic AD and HSV seropositivity (HSV-1 or HSV-2).

This randomized clinical trial included adults with a clinical diagnosis of probable AD or a clinical diagnosis of mild cognitive impairment with positive biomarkers for AD, a positive serum antibody test (IgG or IgM) for HSV-1 or HSV-2, and a Mini-Mental State Examination score of 18 to 28. The trial was conducted at 3 US outpatient clinics specializing in memory disorders. Recruitment occurred from January 2018 to May 2022; the last follow-up occurred in September 2024.

INTERVENTION: Either 4 g/d of valacyclovir (n = 60) or matching placebo (n = 60).

MAIN OUTCOMES AND MEASURES: The primary outcome was least-squares mean (LSM) change at 78 weeks in the 11-item Alzheimer's Disease Assessment Scale Cognitive (ADAS-Cognitive) Subscale score (range, 0-70; higher scores indicate greater impairment). The secondary outcomes were LSM change in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scale score; LSM change in the 18F-florbetapir amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR; higher scores indicate higher amyloid levels) for 6 brain regions (medial orbitofrontal, anterior cingulate, parietal lobe, posterior cingulate, temporal lobe, and precuneus); and LSM change in 18F-MK-6240 tau PET medial temporal SUVR (higher scores indicate higher tau levels) for 4 brain regions (amygdala, hippocampus, entorhinal, and parahippocampus). The frequency of adverse events was the safety outcome.

RESULTS: Of the 120 participants (mean age, 71.4 [SD, 8.6] years; 55% were female), 93 (77.5%) completed the trial. At 78 weeks, the LSM change in the 11-item ADAS-Cognitive Subscale score was 10.86 (95% CI, 8.80 to 12.91) in the valacyclovir group vs 6.92 (95% CI, 4.88 to 8.97) in the placebo group, indicating greater cognitive worsening with valacyclovir than placebo (between-group difference, 3.93 [95% CI, 1.03 to 6.83]; P = .01). The LSM change in the ADCS-ADL Scale score at 78 weeks was -13.78 (95% CI, -17.00 to -10.56) in the valacyclovir group vs -10.16 (95% CI, -13.37 to -6.96) in the placebo group (between-group difference, -3.62 [95% CI, -8.16 to 0.93]). At 78 weeks, the LSM change in the 18F-florbetapir amyloid PET SUVR was 0.03 (95% CI, -0.04 to 0.10) in the valacyclovir group vs 0.01 (95% CI, -0.06 to 0.08) in the placebo group (between-group difference, 0.02 [95% CI, -0.08 to 0.12]). The LSM change in the 18F-MK-6240 tau PET medial temporal SUVR at 78 weeks was 0.07 (95% CI, -0.06 to 0.19) in the valacyclovir group vs -0.04 (95% CI, -0.15 to 0.07) in the placebo group (between-group difference, 0.11 [95% CI, -0.06 to 0.28]). The most common adverse events were elevated serum creatinine level (5 participants [8.3%] in the valacyclovir group vs 2 participants [3.3%] in the placebo group) and COVID-19 infection (3 [5%] vs 2 [3.3%], respectively).

CONCLUSIONS AND RELEVANCE: Valacyclovir was not efficacious with cognitive worsening for the primary outcome and it is not recommended to treat individuals with early symptomatic AD and HSV seropositivity.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03282916.},
}

@article {pmid41405805,
year = {2025},
author = {Blair, HA},
title = {Sublingual Cyclobenzaprine: First Approval.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {41405805},
issn = {1179-1918},
abstract = {TONMYA[™] is a sublingual eutectic formulation of cyclobenzaprine being developed by Tonix Pharmaceuticals for the treatment of various conditions, including fibromyalgia, post-traumatic stress disorder (PTSD), acute stress disorder, major depressive disorder, post-acute COVID-19 syndrome, alcohol use disorder, and agitation in Alzheimer's disease. The sublingual formulation was designed for rapid transmucosal absorption to produce diurnal variation in peak-to-trough drug concentrations, making it suitable for long-term bedtime use. On 15 August 2025, sublingual cyclobenzaprine was approved for the treatment of fibromyalgia in adults in the USA. This article summarizes the milestones in the development of sublingual cyclobenzaprine leading to this first approval for fibromyalgia.},
}

@article {pmid41405795,
year = {2025},
author = {Ekström, I and Vetrano, DL and Valletta, M and Ruane, R and Larsson, M and Fredolini, C and Winblad, B and Grande, G and Laukka, EJ},
title = {Blood-based biomarkers of Alzheimer's disease and olfactory decline over 15 years in older adults.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41405795},
issn = {2509-2723},
support = {2021-00178//Vetenskapsrådet/ ; 2020-01030//Vetenskapsrådet/ ; 2024-00721//Vetenskapsrådet/ ; P22-0785 2023//Riksbankens Jubileumsfond/ ; },
abstract = {Olfactory impairment is common in older age and is a known early feature of several dementia diseases. Blood-based biomarkers of Alzheimer's disease (AD) now offer a scalable method for detecting pathophysiological mechanisms related to olfactory decline in the general population. However, few studies have examined how these biomarkers relate to long-term olfactory trajectories. Most existing work has been limited to cross-sectional settings. In this population-based study, we used biomarker data collected at baseline and followed participants for up to 15 years, enabling us to test whether early biological changes are temporally linked to subsequent olfactory decline. Data came from the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study with baseline assessments from March 21, 2001, through August 30, 2004. We included participants without prevalent neurodegenerative diseases who completed olfactory assessment at baseline. The 15-year follow-up was finished in December 2019. Data were analysed from December 2023 to April 2024. Serum-derived biomarkers of tau phosphorylated at threonine 217 (p-tau217) and at theorine181 (p-tau181), total tau (t-tau), amyloid-β ratio (Aβ42/Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were obtained at baseline. Linear mixed models examined associations between biomarker quartiles and Sniffin' Sticks odor identification performance over 15 years, adjusting for demographics, health conditions, and semantic knowledge. We included 1868 participants (mean [SD] age 71.3 [9.9] years; 1122 females [60.1%]). In fully adjusted models, higher quartiles of p-tau217, p-tau181, NfL, and GFAP, and lower quartiles of Aβ42/Aβ40, were associated with steeper olfactory decline, with the steepest decline among participants in the highest quartiles (β for Q4 vs Q1: -0.20 [95% CI: -0.26 to -0.15] for p-tau217; -0.19 [95% CI: -0.25 to -0.13] for p-tau181; -0.23 [95% CI: -0.29 to -0.17] for NfL; β = -0.17 [95% CI: -0.23 to -0.11] for GFAP. Participants in the lowest Aβ42/Aβ40 quartile declined more steeply than those in the highest (β = -0.09 [95% CI: -0.14 to -0.04]). Associations appeared stronger in the oldest participants, in APOE ε4 carriers for p-tau181, in non-carriers for NfL and GFAP, and among former smokers for NfL. Blood-based biomarkers of AD were consistently associated with faster olfactory decline in older adults, particularly in the highest biomarker quartiles. These results provide large-scale longitudinal evidence, across up to 15 years of follow-up, that olfactory decline in the general population is linked to AD-related blood biomarkers, supporting the hypothesis that common olfactory losses in ageing partly reflect dementia-related processes.},
}

@article {pmid41405782,
year = {2025},
author = {Afifi, I and Elgendy, M and Abdelfatah, M and El-Sappagh, S},
title = {Vision and convolutional transformers for Alzheimer's disease diagnosis: a systematic review of architectures, multimodal fusion and critical gaps.},
journal = {Brain informatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40708-025-00286-7},
pmid = {41405782},
issn = {2198-4018},
abstract = {Alzheimer's disease (AD), a significant public health challenge, requires accurate early diagnosis to improve patient outcomes. Vision Transformers (ViTs) and Convolutional Vision Transformers (CViTs) have emerged as powerful Deep Learning architectures for this task. Following PRISMA guidelines, this systematic review analyzes 68 studies selected from 564 publications (2021-2025) across five major databases: Scopus, Web of Science, ScienceDirect, IEEE Xplore, and PubMed. We introduce novel taxonomies to systematically categorize these works by model architecture, data modality, fusion strategy, and diagnostic objective. Our analysis reveals key trends, such as the rise of hybrid CViT frameworks, and critical gaps, including a limited focus on Mild Cognitive Impairment-to-AD progression. Critically, we also assess practical implementation details, revealing widespread challenges in algorithmic reproducibility. The discussion culminates in a forward-looking analysis of Large Vision Models and proposes future directions emphasizing the need for robust multimodal integration, lightweight transformer designs, and Explainable AI to advance AD research and bridge the critical gap between high-performance modeling and clinical applicability.},
}