@article {pmid41399730,
year = {2025},
author = {Zhang, Y and Chen, S and Yan, G and Zhang, Z and Amina, and Wang, T and Wang, S and Zhang, C and Sun, Y},
title = {MAPT mutation-induced behavioral variant frontotemporal dementia in an Asian patient: a multimodal biomarker case report resolving diagnostic challenges with Alzheimer's disease.},
journal = {Frontiers in genetics},
volume = {16},
number = {},
pages = {1645068},
pmid = {41399730},
issn = {1664-8021},
abstract = {BACKGROUND: The clinical phenotypic overlap between frontotemporal dementia (FTD) and Alzheimer's disease (AD) frequently leads to misdiagnosis, while biomarkers (e.g., Aβ-PET) and genetic testing provide critical differential diagnostic evidence. Although MAPT gene mutations represent common genetic etiologies of FTD, their occurrence in Asian populations remains underreported. Specifically, FTD caused by the MAPT IVS10 + 16C>T mutation shows limited documentation in Asian populations, with its phenotypic heterogeneity and treatment responses remaining poorly characterized.

METHODS: We present a case of FTD manifesting progressive memory decline, compulsive behaviors, and apathy. MRI revealed bilateral frontoparietotemporal atrophy with prominent medial temporal lobe and hippocampal involvement, initially misdiagnosed as AD. Subsequent Aβ-PET negativity emerged as a pivotal diagnostic turning point, and identification of a heterozygous MAPT mutation (IVS10 + 16C>T) confirmed behavioral variant FTD (bvFTD) diagnosis. Partial improvement in compulsive behaviors and verbal fluency was observed following memantine treatment. A literature review summarizes clinical characteristics of FTD associated with IVS10 + 16C>T mutations.

RESULTS: Comprehensive neuropsychological assessment, cranial MRI, and negative Aβ-PET excluded AD pathology. Genetic confirmation of MAPT IVS10 + 16C>T mutation established bvFTD diagnosis. Three-month memantine treatment reduced compulsive behaviors without cognitive improvement. Literature analysis indicates this mutation's rarity in Asian populations, typically presenting with behavioral abnormalities frequently misdiagnosed as AD.

CONCLUSION: This study rectified misdiagnosis of MAPT IVS10 + 16C>T-associated bvFTD through multimodal diagnostics, emphasizing the synergistic value of genetic testing and neuroimaging. Memantine's partial behavioral symptom alleviation suggests potential mutation-specific therapeutic efficacy requiring further validation. Future directions should optimize diagnostic protocols (e.g., cost-effective genetic screening) and address barriers to early diagnosis in Asian populations.},
}

@article {pmid41399728,
year = {2025},
author = {Zhang, Y and Chen, S and Yan, G and Zhang, Z and Amina, and Wang, T and Wang, S and Zhang, C and Sun, Y},
title = {Correction: MAPT mutation-induced behavioral variant frontotemporal dementia in an Asian patient: a multimodal biomarker case report resolving diagnostic challenges with Alzheimer's disease.},
journal = {Frontiers in genetics},
volume = {16},
number = {},
pages = {1749030},
doi = {10.3389/fgene.2025.1749030},
pmid = {41399728},
issn = {1664-8021},
abstract = {[This corrects the article DOI: 10.3389/fgene.2025.1645068.].},
}

@article {pmid41399578,
year = {2025},
author = {Gassull, A},
title = {Ethical Challenges in Managing a Displaced Neer III Humeral Head Fracture in an Undocumented Immigrant With Early Alzheimer's Disease: A Case Report.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e96805},
pmid = {41399578},
issn = {2168-8184},
abstract = {This report describes an 82-year-old undocumented Peruvian female immigrant presenting to the ED with right elbow pain and limited shoulder mobility, diagnosed with a displaced Neer III right humeral head fracture sustained two days prior. She had not clearly communicated shoulder pain to her family for two days post-injury, possibly due to early Alzheimer's disease, which may have impaired her ability to recognize or articulate the severity of her injury, illustrating the clinical-ethical intersection. Radiographic imaging confirmed the fracture with medial displacement, necessitating surgical intervention. Due to her undocumented status and lack of health insurance, she was required to pay the full cost of a reverse shoulder prosthesis (€24,000), which she could not afford. Her Alzheimer's-related dependency and absence of family support in Peru prevented seeking treatment abroad, resulting in discharge with a sling. Comprehensive blood tests ruled out metabolic contributors to her fall. This case highlights ethical challenges in healthcare access for undocumented immigrants, compounded by Alzheimer's-related communication and dependency issues, underscoring disparities and the need for equitable care. This case exemplifies how clinical vulnerability and legal status can intersect to create barriers in emergency and trauma care.},
}

@article {pmid41399419,
year = {2025},
author = {Chen, HW},
title = {Axial Spinal Traction as a Potential Modulator of Cerebrospinal and Glymphatic Circulation in Neurodegenerative Diseases: A Technical Report and Biomechanical Hypothesis.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e99153},
pmid = {41399419},
issn = {2168-8184},
abstract = {Impairment of glymphatic function contributes to the accumulation of metabolic and proteinaceous waste products implicated in neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and certain spinocerebellar ataxias. Pelvis-stabilized axial spinal traction (PSAST) is a biomechanical technique designed to produce brief, controlled cranio-caudal elongation of the vertebral column and spinal dural sac, potentially generating transient pressure gradients capable of influencing cerebrospinal fluid (CSF) dynamics and glymphatic circulation. The technique has been applied in the author's musculoskeletal practice for more than eight years without observed persistent or treatment-related adverse effects, although such practice-based experience does not constitute a formal safety evaluation. Improved sleep quality has been the most consistently reported patient-perceived response to PSAST, a clinically notable observation given the dependence of glymphatic function on consolidated slow-wave sleep. These practice-based observations provide preliminary, hypothesis-generating support for exploring whether controlled axial elongation may modulate cerebrospinal and glymphatic physiology. To the best of the author's knowledge, this report presents the first peer-reviewed technical description of a reproducible, whole-axis axial spinal traction procedure with defined force parameters intended to examine potential modulation of CSF and glymphatic circulation. The report outlines the PSAST protocol and its biomechanical rationale and safety considerations and proposes its potential relevance as a noninvasive, investigational approach for conditions associated with impaired glymphatic function.},
}

@article {pmid41399254,
year = {2025},
author = {Raeesi, S and Zeighami, Y and Moqadam, R and Morrison, C and Dadar, M},
title = {Vascular risk factors mediate the relationship between education and white matter hyperintensities.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70972},
doi = {10.1002/alz.70972},
pmid = {41399254},
issn = {1552-5279},
support = {U24 AG072122/AG/NIA NIH HHS/United States ; //Canadian Institutes of Health Research (CIHR)/ ; //Fonds de Recherche du Québec-Santé/ ; //Natural Sciences and Engineering Research Council of Canada (NSERC), and Brain Canada/ ; },
mesh = {Humans ; Male ; *White Matter/pathology/diagnostic imaging ; Female ; Risk Factors ; *Educational Status ; Aged ; Magnetic Resonance Imaging ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Education can protect against cognitive decline and dementia through cognitive reserve and reduced vascular risk. This study examined whether vascular risk mediated the relationship between education and white matter hyperintensity (WMH) burden.

METHODS: Data from 1443 older adults from the National Alzheimer's Coordinating Center were analyzed. A composite vascular score was created using diabetes, hypertension, hypercholesterolemia, smoking, alcohol abuse, body mass index, and blood pressure. Linear regressions and mediation analyses examined associations and indirect effects between education, vascular risk, and WMHs, adjusting for age, sex, and diagnosis.

RESULTS: Higher education was associated with lower vascular risk (p < 0.001) and WMH burden (p = 0.004). Mediation analysis showed an indirect effect of education on WMH via vascular risk (a*b = -0.02, p < 0.001), accounting for 27% of the total effect.

DISCUSSION: Education influences cerebrovascular health by reducing vascular risk. Addressing vascular health may reduce WMH burden.

HIGHLIGHTS: Education is associated with lower WMH burden in aging adults. Vascular risk factors mediate the education-WMH relationship. Higher education predicts better vascular profiles and less WMH accumulation.},
}

Humans
Male
*White Matter/pathology/diagnostic imaging
Female
Risk Factors
*Educational Status
Aged
Magnetic Resonance Imaging
Aged, 80 and over

@article {pmid41399206,
year = {2025},
author = {Guo, D and Cai, M and Xian, Y and Chen, Y and Feng, Y and Hu, C and Zeng, L and Shi, L and Zhang, S},
title = {Transient Receptor Potential Channels as Key Regulators of Neuroinflammation in Neurological Disorders: Mechanistic Insights, Therapeutic Potentials, and Future Directions.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {12},
pages = {e70700},
doi = {10.1002/cns.70700},
pmid = {41399206},
issn = {1755-5949},
support = {2022ZD0214400//The STI2030-Major Projects/ ; 82371175//National Natural Science Foundation of China/ ; U24A20804//National Natural Science Foundation of China/ ; 2023A0505050121//the International Science and Technology Cooperation Projects of Guangdong Province/ ; 2022B1515130007//Guangdong Basic and Applied Basic Research Foundation/ ; 2023B1515040015//Guangdong Basic and Applied Basic Research Foundation/ ; 2023A1515030012//Guangdong Basic and Applied Basic Research Foundation/ ; 202102070001//the Science and Technology Program of Guangzhou/ ; },
mesh = {Humans ; *Nervous System Diseases/metabolism/drug therapy ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Animals ; *Transient Receptor Potential Channels/metabolism ; },
abstract = {BACKGROUND: Transient receptor potential (TRP) ion channels, a ubiquitous family of nonselective cation channels, are extensively expressed across the nervous system, immune system, and peripheral tissues. These channels serve as critical sensors for detecting temperature, mechanical forces, and chemical stimuli, thereby regulating numerous physiological and pathological processes. Over the past decade, their pivotal role in neuroimmune crosstalk and inflammatory signaling has emerged as a key focus within neuroscience research.

METHODS: A comprehensive literature review was conducted in PubMed using key terms "TRP channel," "neuroinflammation," and each of the following neurological disorders: neuropathic pain, migraine, stroke, multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), autism spectrum disorder (ASD), epilepsy, and psychiatric disorders.

RESULTS: This review synthesizes the current evidence to elucidate the dual-edged contributions of TRP channels as mediators of inflammation in neuropathic pain, migraine, stroke, MS, AD, PD, ASD, epilepsy, and psychiatric disorders. Furthermore, we also evaluate emerging therapeutic strategies targeting TRP channels, encompassing both nonpharmacological approaches and pharmacological interventions.

CONCLUSIONS: By integrating mechanistic insights with translational perspectives, this review highlights TRP channels as promising targets for precision medicine and underscores their potential in the development of novel, mechanism-based therapies for complex neurological disorders, thereby advancing a new era of targeted neuroimmunomodulation.},
}

Humans
*Nervous System Diseases/metabolism/drug therapy
*Neuroinflammatory Diseases/metabolism/drug therapy
Animals
*Transient Receptor Potential Channels/metabolism

@article {pmid41399190,
year = {2025},
author = {Zhang, B and McEvoy, LK and Nguyen, S and Espeland, MA and Rapp, SR and Horvath, S and Lu, AT and LaCroix, AZ and Nievergelt, CM and Maihofer, AX and Resnick, SM and Mielke, MM and Beckman, K and Li, D and Silver, B and Manson, JE and Ferrucci, L and Shadyab, AH},
title = {Epigenetic clocks and longitudinal plasma biomarkers of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70983},
doi = {10.1002/alz.70983},
pmid = {41399190},
issn = {1552-5279},
support = {R01AG074345/AG/NIA NIH HHS/United States ; R01AG079149/AG/NIA NIH HHS/United States ; K99AG082863/AG/NIA NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/HL/NHLBI NIH HHS/United States ; 75N92021D00004/HL/NHLBI NIH HHS/United States ; 75N92021D00005/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/blood/genetics ; Female ; *Amyloid beta-Peptides/blood ; Longitudinal Studies ; Aged ; tau Proteins/blood ; *Aging/genetics ; *Epigenesis, Genetic ; Neurofilament Proteins/blood ; Aged, 80 and over ; Peptide Fragments/blood ; Cohort Studies ; },
abstract = {INTRODUCTION: Chronological age is the strongest risk factor for Alzheimer's disease and related dementias (ADRD). However, the association of accelerated biological aging relative to chronological age with ADRD pathology is unclear.

METHODS: In a cohort of 2366 (873 with longitudinal data) cognitively unimpaired older women, we examined associations of seven baseline measures of epigenetic age acceleration (EAA) and pace of aging with 15-year changes in plasma ADRD biomarkers.

RESULTS: At baseline, higher AgeAccelHorvath and AgeAccelPheno were associated with lower amyloid beta (Aβ) 42 to Aβ40 (Aβ42:Aβ40) ratio, and higher AgeAccelGrim2, PCPhenoAge, and PCGrimAge were associated with elevated neurofilament light (NfL). Longitudinally, higher baseline DunedinPACE - capturing the pace of biological aging - was associated with faster increases in tau phosphorylated at threonine 181 (p-tau181), p-tau217, NfL, and glial fibrillary acidic protein (GFAP) over 15 years.

DISCUSSION: Accelerated biological aging, particularly DunedinPACE, was associated with increasing levels of plasma ADRD biomarkers over time.

HIGHLIGHTS: We studied 2366 older women from the Women's Health Initiative Memory Study. AgeAccelHorvath and AgeAccelPheno were linked to lower plasma Aβ42:Aβ40 at baseline. AgeAccelGrim2, PCPhenoAge, and PCGrimAge were linked to higher plasma NfL at baseline. DunedinPACE was associated with faster increases in p-tau181, p-tau217, NfL, and GFAP.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/blood/genetics
Female
*Amyloid beta-Peptides/blood
Longitudinal Studies
Aged
tau Proteins/blood
*Aging/genetics
*Epigenesis, Genetic
Neurofilament Proteins/blood
Aged, 80 and over
Peptide Fragments/blood
Cohort Studies

@article {pmid41399181,
year = {2025},
author = {Zhang, Y and Li, Z and Guan, H and Qiu, Z and Zou, C},
title = {Engineering exosomes for Alzheimer's disease: Multi-target therapeutic strategies from pathogenesis to clinical translation.},
journal = {Clinical and translational medicine},
volume = {15},
number = {12},
pages = {e70548},
doi = {10.1002/ctm2.70548},
pmid = {41399181},
issn = {2001-1326},
support = {2025GXNSFAA069384//The Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation/ ; GuikeAB23026023//Guangxi Key Technologies R&D Program/ ; },
mesh = {*Alzheimer Disease/therapy/drug therapy ; *Exosomes/metabolism ; Humans ; Blood-Brain Barrier/metabolism ; Drug Delivery Systems/methods ; Animals ; },
abstract = {The complex pathogenesis of Alzheimer's disease (AD), combined with the presence of the blood‒brain barrier (BBB), severely limits the effectiveness of conventional therapeutic approaches. Engineered exosomes-nanoscale extracellular vesicles of natural origin-have emerged as a promising platform for innovative AD therapy due to their excellent biocompatibility, low immunogenicity and intrinsic ability to cross the BBB. This review provides a systematic overview of the synthetic and structural biological characteristics of exosomes, with a focus on their functionalisation through physical, chemical and genetic modifications. These approaches enable the targeted loading of therapeutic cargo and the conjugation of brain-targeting peptides, thereby facilitating precise delivery to specific brain regions and offering a multi-target therapeutic strategy for AD. We further examine the potential of engineered exosomes in modulating core AD pathological pathways, including amyloid-beta deposition, tau hyperphosphorylation, neuroinflammation and synaptic dysfunction, and highlight their utility as an integrated delivery system for the co-delivery of multiple therapeutic agents to achieve synergistic therapeutic effects. Finally, key challenges in clinical translation are addressed, such as scalable production, standardised drug loading protocols and comprehensive assessment of safety and immunogenicity. Unlike previous reviews that primarily focus on general engineering techniques, this article emphasises a rational design strategy tailored for multi-target synergistic therapy and presents a comprehensive roadmap from basic research to clinical application, thereby providing both theoretical insights and practical guidance for the development of next-generation AD treatments. KEY POINTS: A multidimensional approach combining physical, chemical, and genetic modifications equips exosomes with brain-targeted peptides, enhancing their capability for precise brain delivery in Alzheimer's disease (AD) Engineered exosomes are designed to cross the blood-brain barrier and provide stimuli-responsive release of therapeutic agents, enabling simultaneous clearance of amyloid-beta plaques and neurofibrillary tangles, and inhibition of neuroinflammation. The transition from preclinical success to early-phase human trials is underway, with intranasal administration emerging as a promising, non-invasive method for brain drug delivery. A well-defined plan for clinical translation includes scalable Good Manufacturing Practice (GMP) production, rigorous safety assessments, and biomarker-guided clinical trial design to facilitate clinical application.},
}

*Alzheimer Disease/therapy/drug therapy
*Exosomes/metabolism
Humans
Blood-Brain Barrier/metabolism
Drug Delivery Systems/methods
Animals

@article {pmid41399123,
year = {2025},
author = {Tabrizi, Z and Lim, XR and Chakraborty, S and Harraz, OF and Bracko, O},
title = {Systemic Piezo1 activation improves cerebrovascular function in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71016},
doi = {10.1002/alz.71016},
pmid = {41399123},
issn = {1552-5279},
support = {R01HL169681/HL/NHLBI NIH HHS/United States ; R21AG082193/AG/NIA NIH HHS/United States ; R21AG075798/AG/NIA NIH HHS/United States ; P20GM135007/GM/NIGMS NIH HHS/United States ; R01NS141137/NS/NINDS NIH HHS/United States ; 20CDA35310097//American Heart Association/ ; //Bloomfield Early Career Professorship in Cardiovascular Research/ ; //Totman Medical Research Trust/ ; //Cardiovascular Research Institute of Vermont/ ; AARG-22-974437/ALZ/Alzheimer's Association/United States ; //Provost Award from the University of Miami/ ; 23A12//Florida Department of Health/ ; 2024-338506//Chan Zuckerberg Initiative, the Silicon Valley Community Foundation/ ; },
mesh = {Animals ; *Alzheimer Disease/physiopathology ; *Cerebrovascular Circulation/drug effects/physiology ; *Ion Channels/metabolism/agonists ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Hyperemia ; *Benzoxazoles/pharmacology ; Vibrissae ; Male ; Humans ; Brain/blood supply ; Pyrazines ; Thiadiazoles ; },
abstract = {INTRODUCTION: Cerebral blood flow (CBF) reductions and impaired functional hyperemia (FH) are early features of Alzheimer's disease (AD) that contribute to disease progression. Here, we investigated whether systemic activation of the mechanosensitive ion channel Piezo1 affects cerebrovascular deficits in an AD mouse model.

METHODS: Using two-photon in vivo imaging and laser-speckle imaging, we determined CBF, capillary stalling, and FH in the 5xFAD model of AD.

RESULTS: We observed increased capillary stalling and reduced CBF and FH to whisker stimulation in 5xFAD mice compared to wild-type controls. The systemic administration of the Piezo1 agonist Yoda1 led to a ≈ 65% reduction in capillary stalls, increased CBF, and significantly improved FH in response to whisker stimulation, restoring CBF responses in 5xFAD mice to levels comparable to controls.

DISCUSSION: These results suggest that Piezo1 activation improves microvascular flow and neurovascular coupling in AD, highlighting Piezo1 as a promising therapeutic target for early cerebrovascular dysfunction during AD.

HIGHLIGHTS: An Alzheimer's disease (AD) animal model demonstrates reduced brain capillary blood flow and impaired neurovascular coupling. Pharmacological activation of Piezo1 at the systemic level improves blood flow and functional hyperemia during AD. Piezo1 is involved in cerebrovascular dysfunction associated with AD.},
}

Animals
*Alzheimer Disease/physiopathology
*Cerebrovascular Circulation/drug effects/physiology
*Ion Channels/metabolism/agonists
Disease Models, Animal
Mice
Mice, Transgenic
Hyperemia
*Benzoxazoles/pharmacology
Vibrissae
Male
Humans
Brain/blood supply
Pyrazines
Thiadiazoles

@article {pmid41399037,
year = {2025},
author = {Di Donna, MG and Motta, C and Bonomi, CG and Bernocchi, F and Ricci, F and Poli, M and Koch, G and Martorana, A},
title = {Reframing TDP-43 in Alzheimer's disease: From co-pathology to neurovascular culprit.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70988},
doi = {10.1002/alz.70988},
pmid = {41399037},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; *Blood-Brain Barrier/metabolism/pathology ; Astrocytes/metabolism/pathology ; Endothelial Cells/metabolism/pathology ; *Brain/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD) is widely recognized as a multifactorial disorder involving neurovascular and glial dysfunction beyond amyloid-β and tau pathology. In this Perspective, we synthesize recent evidence to propose a conceptual framework linking transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) to neurovascular unit (NVU) disruption in AD. Traditionally considered a neuronal co-pathology, TDP-43 also aggregates in astrocytes and endothelial cells, impairing blood-brain barrier (BBB) integrity, glymphatic clearance, and metabolic homeostasis. Endothelial TDP-43 loss disrupts β-catenin signaling and fibronectin, triggering vascular breakdown and neuroinflammation. Astrocytic perivascular aggregates correlate with reduced aquaporin-4 (AQP4) and CD146, further compromising clearance pathways. These vascular-glial mechanisms may accelerate AD progression and help explain clinical heterogeneity and limited therapeutic response in TDP-43-positive patients. We argue for the reclassification of TDP-43 as a potential upstream driver of disease progression. Such a shift would support the development of integrative biomarkers and precision treatment strategies targeting NVU dysfunction. HIGHLIGHTS: Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) may act as a driver of neurovascular dysfunction in Alzheimer's disease (AD). We propose reclassifying TDP-43 from co-pathology to upstream contributor. TDP-43 affects endothelial cells and astrocytes, disrupting blood-brain barrier (BBB) and clearance. Neurovascular unit (NVU) dysfunction links TDP-43 to inflammation, hypoperfusion, and cognitive decline. A vascular-glial model of AD opens new therapeutic and biomarker opportunities.},
}

Humans
*Alzheimer Disease/pathology/metabolism
*DNA-Binding Proteins/metabolism
*Blood-Brain Barrier/metabolism/pathology
Astrocytes/metabolism/pathology
Endothelial Cells/metabolism/pathology
*Brain/pathology/metabolism

@article {pmid41399016,
year = {2025},
author = {Hale, JM and Lorenti, A and Cunningham, SA},
title = {Disentangling social isolation, loneliness, and later-life cognitive function for older adults in the United States: Evidence from causal inference modeling.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbaf254},
pmid = {41399016},
issn = {1758-5368},
abstract = {OBJECTIVES: Older adults are at high risk of the negative health impacts of social isolation and loneliness. One of those possible negative health impacts is Alzheimer's disease, a leading cause of death for adults in the United States and many high-income countries. Taking a life course perspective, we explore whether there is a direct causal effect of social isolation on later-life trajectories of cognitive function, the extent to which any effect of social isolation on cognitive impairment operates indirectly through loneliness, who may be most vulnerable, and the potential efficacy of a statistical intervention for those living alone.

METHODS: We use a counterfactual approach, the g-formula, with the U.S. Health and Retirement Study, analyzing data from 30,421 individuals with 137,653 observations across 2004-2018.

RESULTS: We find a consistent pattern of social isolation having a detrimental direct causal effect on cognitive function, with only 6% of this effect operating through loneliness. Reducing social isolation has a protective effect on cognitive function for all subpopulations regardless of gender, race/ethnicity, and educational level, with only minor differences among social categories. Our statistical intervention shows that targeting social isolation in those living alone may be one viable public health strategy for protecting against cognitive decline.

DISCUSSION: Our results suggest that addressing social isolation-and, by extension, its effects on health-requires both a broad understanding of its heterogenous impacts on the general population and a nuanced approach to targeting public health interventions where they can be most effective.},
}

@article {pmid41398960,
year = {2025},
author = {Papavergi, MT and Bathini, P and Singh, B and Lemere, CA},
title = {The complement cascade in Alzheimer's disease: modern implications of an ancient immune protagonist.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-025-00916-y},
pmid = {41398960},
issn = {1750-1326},
}

@article {pmid41398876,
year = {2025},
author = {Zhong, S and Feng, C and Li, S and Lin, Y and Zhu, J and Liang, X and Qin, C},
title = {Impact of rheumatoid arthritis on Alzheimer's disease: A two-sample bidirectional Mendelian randomization study.},
journal = {Medicine},
volume = {104},
number = {50},
pages = {e46518},
doi = {10.1097/MD.0000000000046518},
pmid = {41398876},
issn = {1536-5964},
support = {Grant No.82060226//National Natural Sciences Foundation of China/ ; GuikeAA22096030//Guangxi Science and Technology Major Project/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/epidemiology ; *Arthritis, Rheumatoid/genetics/epidemiology/complications ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; Risk Factors ; Genetic Predisposition to Disease ; },
abstract = {Controversial relationship of rheumatoid arthritis (RA) with Alzheimer disease (AD) risk has been reported in previous research. However, epidemiological studies are susceptible to confounding factors and reverse causality. This study aimed to explore the causal relationship between RA and AD by using a 2-sample bidirectional Mendelian randomization (MR) study. Genetic data for RA and AD were extracted from published genome-wide association study databases and the FinnGen project. The primary statistical method was inverse variance weighted, which was supplemented by MR Egger regression, weighted median, simple mode, and weighted mode methods. In addition, Cochran Q test, MR Egger intercept, and MR-PRESSO global test were used to detect heterogeneity and pleiotropy. Further sensitivity analyses were conducted using leave-one-out method and funnel plots, to evaluate the robustness of the results. Genetically predicted RA had a positive casual effect on the risk of AD development (inverse variance weighted odds ratio [OR] = 1.062, 95% confidence interval [CI] = 1.019-1.107, P = .004; weighted median OR = 1.073, 95% CI = 1.021-1.126, P = .005; weighted mode OR = 1.077, 95% CI = 1.025-1.131, P = .007). Notably, reverse MR analysis indicated no significant effect of AD on RA (all P > .05). No pleiotropy or heterogeneity was identified in the bidirectional MR analysis. And leave-one-out analysis and funnel plots confirmed the robustness and reliability of the findings. This study provides new evidence for the causal relationship between RA and the increased risk of AD. Early screening of cognitive function in patients with RA may be beneficial in preventing future AD progression.},
}

Humans
*Alzheimer Disease/genetics/epidemiology
*Arthritis, Rheumatoid/genetics/epidemiology/complications
Mendelian Randomization Analysis
Genome-Wide Association Study
Risk Factors
Genetic Predisposition to Disease

@article {pmid41398677,
year = {2025},
author = {Wang, B and Wang, Y and Yang, F and Han, F and Li, K and Sun, K and Liang, P},
title = {The effect of repetitive transcranial magnetic stimulation on immediate and long-term cognitive functions in Alzheimer's dementia and mild cognitive impairment: a meta-analysis.},
journal = {Journal of neuroengineering and rehabilitation},
volume = {22},
number = {1},
pages = {262},
pmid = {41398677},
issn = {1743-0003},
support = {LGKCYLWS2022034//Key Project of Medical and health technology of Longgang District, Shenzhen/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Cognitive Dysfunction/therapy/psychology ; *Transcranial Magnetic Stimulation/methods ; *Cognition/physiology ; Randomized Controlled Trials as Topic ; Neuropsychological Tests ; Treatment Outcome ; Aged ; },
abstract = {BACKGROUND: Alzheimer's dementia (AD) and mild cognitive impairment (MCI) are characterized by progressive cognitive decline. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technology, has been widely used to improve cognition in AD and MCI. However, the impact of rTMS on immediate and long-term cognitive functions in AD and MCI, as well as the optimal stimulating parameters, need further clarification.

METHOD: Thirty-one randomized controlled trials were included to examine the effects of rTMS on immediate cognition (post-treatment cognition), while nine trials were specifically used to assess its impact on long-term cognition (follow-up cognition). All participants were tested on at least one of the neuropsychological scales of the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Alzheimer's disease Assessment Scale-Cognitive Section (ADAS-Cog) to evaluate global cognitive outcomes of rTMS. The study followed the guidelines for meta-analysis of intervention studies and assessed the risk of bias of the included studies. Moderator analysis was used to examine factors that might affect treatment effect. Sensitivity analysis was used to evaluate stability of results. Meta-regression analysis was used to assess the interpretability of heterogeneity. Begg's and Egger's test and funnel plot were applied to assess publication bias.

RESULTS: The results demonstrated that rTMS significantly improved immediate cognition (SMD = 0.93, 95% CI = 0.64 to 1.22, p < 0.001) and long-term cognition (SMD = 0.42, 95% CI = 0.13 to 0.70, p = 0.004) across all patients (including AD and MCI). Moderator analysis revealed that targeting dorsolateral prefrontal cortex (DLPFC), using intensities of 80% or less of the motor threshold, total time of 800 min or more and stimulation sessions greater than 20 significantly enhanced immediate cognitive performance than their counterparts. In contrast, stimulation frequency, duration/session and patient type showed no significant impact on immediate cognition. For long-term cognition, differences in stimulation protocols had no influence on treatment effect for all patients.

CONCLUSION: rTMS had a positive effect on immediate and long-term cognition in AD and MCI, stimulation region, intensity, total time and number of sessions significantly improve immediate cognition. These findings suggest that rTMS has potential as a promising adjunctive treatment for AD and MCI.},
}

Humans
*Alzheimer Disease/therapy/psychology
*Cognitive Dysfunction/therapy/psychology
*Transcranial Magnetic Stimulation/methods
*Cognition/physiology
Randomized Controlled Trials as Topic
Neuropsychological Tests
Treatment Outcome
Aged

@article {pmid41398494,
year = {2025},
author = {Bekena, S and Singh, RK and Zhu, Y and Carr, DB and Babulal, GM},
title = {Sensorimotor function as an early marker of cognitive decline and alzheimer's biomarker burden.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41398494},
issn = {2509-2723},
support = {R01 AG068183/AG/NIA NIH HHS/United States ; R01 AG067428/AG/NIA NIH HHS/United States ; R01 AG074302/AG/NIA NIH HHS/United States ; },
abstract = {Early identification of markers of cognitive decline in cognitively normal older adults is essential for dementia prevention strategies. Sensorimotor measures, such as gait speed, grip strength, and reaction time, may provide sensitive indicators of current and future impairment. This study examined associations between baseline sensorimotor function and cognitive decline in cognitively normal older adults. In this prospective cohort, 246 cognitively normal older adults from the DRIVES Project completed baseline assessments of grip strength, gait speed, simple reaction time, and the Preclinical Alzheimer Cognitive Composite (PACC). Participants were followed for a mean of 4 years. Linear mixed-effects models adjusted for demographics, APOE ε4 status, and neighborhood deprivation. Cross-sectional analyses evaluated the associations between sensorimotor measures and cerebrospinal fluid (CSF) biomarkers of amyloid, tau, and plasma neurofilament light chain (NfL). Participants (mean age: 74.9 ± 5.17 years; 48.8% female) had a mean baseline PACC score of 1.06 ± 0.50. Cross-sectionally, slower gait speed was associated with higher CSF tau/Aβ42 ratio (p = 0.027), CSF tTau/Aβ42 ratio (p = 0.009), and plasma NfL (p = 0.024). A slower reaction time was associated with lower baseline PACC scores (p = 0.028). Longitudinally, low grip strength (p = 0.002) and slow gait speed (p < 0.001) were predictive of lower cognitive performance, with slow gait speed also predicting a faster decline (p = 0.015). Sensorimotor function measures are associated with current and future cognitive performance, supporting their role in early identification of older adults at risk for cognitive decline.},
}

@article {pmid41398493,
year = {2025},
author = {Li, R and Rudd, K and Roccati, E and Goldberg, LR and Bindoff, AD and Lawler, K and Aiyede, M and Simonet, C and Mulisa, D and King, AE and Vickers, JC and Bai, Q and Alty, J},
title = {Smartphone self-testing of hand and speech motor functions: a study of reliability and usability in older adults.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41398493},
issn = {2509-2723},
abstract = {Scalable remote-monitoring tools of motor function are vital for early detection and tracking of neurodegenerative diseases. This study evaluated the reliability and usability of TapTalk, a 2-min validated smartphone-based self-assessment of hand and speech motor function, in older adults. Community-dwelling adults aged 50 + completed TapTalk daily for 7 days: once in the research center and six consecutive days at home. Motor features were extracted using validated algorithms. Test-retest reliability was analyzed using intraclass correlation coefficient (ICC) and usability via descriptive analysis of user-experience questionnaires. Four-hundred and twenty-five sessions of TapTalk were completed by 68 participants (68.6 ± 6.6 years; range 57-80; 75% female) across 43 smartphone models. All tests had features with ICC > 0.5 except for one, indicating acceptable reliability for a self-administered in-home test. Usability scores averaged 95.9% reflecting high satisfaction with ease-of-use, clarity, and performance. Findings support TapTalk's potential for scalable longitudinal monitoring. Establishing reliability and usability in older adults is a critical step toward TapTalk's broader use by those with neurodegenerative diseases.},
}

@article {pmid41398452,
year = {2025},
author = {Ghahremani, M and Smith, EE and Ismail, Z},
title = {Persistent Functional Impairment as an Early Indicator of Alzheimer Disease Pathology and Progression.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70247},
pmid = {41398452},
issn = {1532-5415},
support = {//NIHR Exeter Biomedical Research Centre/ ; //Gordie Howe CARES/ ; BCA527734/CAPMC/CIHR/Canada ; },
abstract = {BACKGROUND: Functional impairment (FI) is a key criterion for diagnosing dementia. However, subtle functional changes may occur during preclinical and prodromal phases but may not be accurately characterized. Furthermore, research linking FI to Alzheimer disease (AD) biofluid biomarkers is limited. Here we examined cross-sectional associations between cerebrospinal fluid (CSF) AD biomarkers and persistent versus transient FI in dementia-free older adults, and the longitudinal association of FI with incident dementia.

METHODS: Data from 1000 participants (age 72.9 ± 7.0; 45.2% female; 62.8% MCI) from the Alzheimer's Disease Neuroimaging Initiative were analyzed. CSF biomarkers included p-tau181, Aβ42, and ptau-181/Aβ42 ratio. Three Functional Activities Questionnaire items of "preparing a hot beverage," "preparing a balanced meal," and "shopping alone" were identified by factor analysis as assessing function rather than cognition directly. Persistent-FI was operationalized as FI present at> two-thirds of pre-dementia visits. Comparator groups included Transient-FI and No-FI. Linear regression modeled the association between FI status and baseline biomarker levels, while Cox regression assessed the association between FI and incident dementia. Models adjusted for age, sex, education, APOE-ε4 status, and MMSE.

RESULTS: Compared to No-FI, Persistent-FI was associated with lower Aβ42 (Beta = -8.93; 95% CI: -13.56 to -4.03; p < 0.001), higher p-tau181 (Beta = 10.81; 95% CI: 0.44-22.26; p = 0.041), and ptau181/Aβ42 ratio (Beta = 21.66; 95% CI: 7.02-38.31; p = 0.003). In contrast, Transient-FI showed no significant associations. APOE-ε4 carrier status was more prevalent in the Persistent-FI group compared to No-FI (p = 0.009), but not in Transient-FI (p = 0.931). Compared to No-FI, Persistent-FI had a 6.66-fold greater dementia incidence rate (95% CI: 4.98-8.91, p < 0.001), while Transient-FI had a 1.72-fold greater incidence rate (95% CI: 1.09-2.72, p = 0.021).

CONCLUSIONS: Findings extend the limited research on the association of FI with CSF AD biomarkers in dementia-free populations. Operationalizing FI-related risk by persistence enhances prognostication, identifying individuals with greater AD pathology and progression risk. This approach could enhance screening, early detection, and risk stratification, informing timely interventions before dementia onset.},
}

@article {pmid41398374,
year = {2025},
author = {Li, S and Chen, Y and Song, T and Liu, D and Wu, R and Yang, X and Wu, Q and Lei, L and Yu, X and Zhang, J and Li, L and Jiang, Y and Gu, J and Miao, J and Gu, JH and Shi, J and Wu, F and Liu, F and Chu, D},
title = {Ganglioside sialylation modulates tau internalization and pathology spread.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41398374},
issn = {1476-5578},
support = {81872853//National Natural Science Foundation of China (National Science Foundation of China)/ ; 31970968//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Gangliosides serve as receptors for proteins, bacteria, and viruses, with sialylation at the termini of their glycan chains playing a crucial role in ligand recognition and endocytosis. The internalization of proteopathic tau aggregates by neurons is integral to the propagation of tau pathology in Alzheimer's disease (AD). However, the influence of gangliosides and their sialylation modifications on the uptake of proteopathic tau aggregates and the subsequent impact on AD pathology remains unclear. This study investigates the roles of the four mammalian sialidases (Neu1-Neu4) in modulating tau aggregation in cellular models. Our findings demonstrate that Neu3 significantly inhibits tau aggregation induced by proteopathic tau derived from the brains of AD patients (AD P-tau). Overexpressing Neu3 or administering ganglioside GM1, which results from Neu3-catalyzed removal of one sialic acid from GD1a, in the mouse model decreases the GD1a/GM1 ratio in mouse brain, effectively blocks the spread of tau pathology and improves recognition in AD P-tau-injected mice. Both Neu3 and GM1 reduce the internalization of tau aggregates, while GD1a enhances tau uptake, showing a positive correlation with the level of internalized tau. Moreover, the internalization of tau mediated by GD1a dependent on low-density lipoprotein receptor-related protein 1 (LRP1) and compensates for heparin-inhibited tau uptake. In vitro assays demonstrate that GD1a exhibits a higher binding avidity for tau filaments than GM1. These findings indicate that GD1a may directly bind to tau aggregates via the sialic acid moiety, facilitating LRP1-mediated tau uptake. This study proposes a novel mechanism for tau internalization and posits that reducing ganglioside sialylation may be a promising strategy for hindering the spread of tau pathology in AD.},
}

@article {pmid41398371,
year = {2025},
author = {Yoon, J and Ha, H and Lee, HW and Kim, S and Yu, YM and Chun, H},
title = {Potential beneficial effects of PD-1/PD-L1 blockade in Alzheimer's disease: a systematic review and meta-analysis of preclinical and clinical studies.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41398371},
issn = {1476-5578},
abstract = {BACKGROUND: Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) are crucial in cancer immune evasion and in modulating neuroinflammation. Although PD-1/PD-L1 signaling is believed to modulate immune and neuronal responses, its role in AD pathophysiology remains unclear, with existing studies reporting inconsistent findings.

METHOD: This systematic review and meta-analysis investigated the effects of PD-1/PD-L1 blockade on AD-related pathology and cognitive behavior in preclinical studies. Additionally, we evaluated the impact of PD-1/PD-L1 inhibitors on cognitive outcomes in clinical studies involving cancer patients. Relevant research was systematically identified using the MEDLINE, Embase, CENTRAL, and Web of Science databases from their inception until July 31, 2025. Overall, 40 studies were included in this meta-analysis, conducted using R software.

RESULTS: Preclinical studies revealed that blockade of PD-1 signaling reduces amyloid-beta plaque burden, tau phosphorylation, and astrocyte reactivity in AD mouse models. These pathological improvements were accompanied by enhanced cognitive performance, whereas wild-type mice showed no significant cognitive changes under the same treatment, whereas wild-type mice showed no significant cognitive changes under the same treatment. Furthermore, clinical studies demonstrated the beneficial effect of PD-1 signaling inhibitors on cognitive function in patients with cancer.

CONCLUSIONS: PD-1/PD-L1 inhibition impacts AD pathology and cognitive function, suggesting its potential as a therapeutic development strategy for AD. Further studies are warranted to clarify the exact mechanisms, opening avenues for future therapies that modulate the PD-1/PD-L1 pathway for AD.},
}

@article {pmid41398345,
year = {2025},
author = {Akbar, F and Alkhrijah, Y and Usman, SM and Khalid, S and Ihsan, I and Alawad, MA},
title = {NeuroFusionNet: a hybrid EEG feature fusion framework for accurate and explainable Alzheimer's Disease detection.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {43742},
pmid = {41398345},
issn = {2045-2322},
support = {IMSIU-DDRSP2501//Deanship of Scientific Research, Imam Mohammed Ibn Saud Islamic University/ ; },
mesh = {*Alzheimer Disease/diagnosis/physiopathology ; Humans ; *Electroencephalography/methods ; Neural Networks, Computer ; Deep Learning ; Principal Component Analysis ; Female ; Male ; Aged ; Signal Processing, Computer-Assisted ; },
abstract = {Alzheimer's Disease (AD) is a very common neurodegenerative disorders and early detection using electroencephalography (EEG) can enable timely intervention, however, existing computational models often lack robustness, interpretability, and clinical scalability. This study proposes NeuroFusionNet, a hybrid deep learning framework for accurate, explainable, and efficient EEG-based classification of Alzheimer's Disease and related dementias. The model fuses handcrafted spectral, statistical, wavelet, and entropy features with latent temporal embeddings extracted from a customized one-dimensional convolutional neural network (1D-CNN). Feature selection is performed using Pearson Correlation Coefficient (PCC) and Particle Swarm Optimization (PSO), Principal Component Analysis (PCA)-based dimensionality reduction, and SMOTE-based class balancing has been performed to enhance discriminative learning. Comprehensive preprocessing including bandpass filtering, Artifact Subspace Reconstruction (ASR), and Independent Component Analysis (ICA) improves signal quality prior to classification through a five-layer deep neural network optimized via adaptive learning rate scheduling. Proposed method has been validated on three public EEG datasets including OpenNeuro ds004504 (eyes-closed), ds006036 (eyes-open), and the independent OSF dataset. Our method demonstrates state-of-the-art accuracy and macro F-1 score of 94.27% and 0.94 respectively. Cross-validation yielded minimal variance (SD <0.3%) that confirms the robustness and reproducibility. Model interpretability was ensured using Shapley Additive Explanations (SHAP) and Gradient-weighted Class Activation Mapping (Grad-CAM), which revealed physiologically consistent biomarkers such as posterior alpha attenuation and frontal-theta enhancement patterns well aligned with established AD pathophysiology. Demographic fairness analysis showed negligible bias (<0.6% difference) across gender and age subgroups. Despite its high accuracy, NeuroFusionNet remains lightweight (0.94M parameters, 4.1 MB footprint) and computationally efficient (6.5 ms inference per sample), enabling real-time deployment on standard clinical CPUs without GPU support.},
}

*Alzheimer Disease/diagnosis/physiopathology
Humans
*Electroencephalography/methods
Neural Networks, Computer
Deep Learning
Principal Component Analysis
Female
Male
Aged
Signal Processing, Computer-Assisted

@article {pmid41398199,
year = {2025},
author = {Maurice, OR and Jones, C and Harris, CB},
title = {Selective cognitive effects of multilingualism emerge in visuospatial working memory in later life.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-32091-x},
pmid = {41398199},
issn = {2045-2322},
abstract = {Epidemiological literature suggests that speaking multiple languages can delay the onset of neurodegenerative conditions such as Alzheimer's disease. Cognitive and neuroscientific explanations, however, remain inconclusive. While some studies have found behavioural and neural effects of being multilingual (compared to monolingual) for working memory, inhibitory control, and attention across the lifespan, others have found no such evidence. An emerging focus on nuanced, dimensional measures of language experience, direct comparison of tasks within the same experiment, and a direct comparison of stimulus modality (visuospatial versus auditory processing) could potentially resolve these mixed findings. The present study investigated whether multilingual experience, measured continuously via the Language History Questionnaire (LHQ-3), was associated with domain-specific cognitive performance in both auditory and visuospatial modalities in a lifespan sample (N = 94, aged 18-83). Participants completed working memory (N-back), inhibitory control (Simon), and attention (Attention Network and Dichotic Listening) tasks in both auditory and visuospatial formats. Generalised additive models revealed no significant associations between multilingual experience and cognitive performance for auditory and most visuospatial tasks. However, a significant interaction between multilingual language diversity and age was found for visuospatial working memory, with older multilingual adults demonstrating higher accuracy and faster response times. These findings suggest that the cognitive effects of multilingualism may be age-, domain-, and modality-specific rather than universal. Neuroprotective associations observed in epidemiological and neuroimaging studies may therefore reflect mechanisms beyond direct behavioural performance, such as neural reserve or compensation.},
}

@article {pmid41398131,
year = {2025},
author = {Song, Y and Ma, Y and Huang, Y and Song, D and Hu, C and Zhang, X and Chen, Y and Zhang, L and Lu, L},
title = {Neurotoxicity and Potential Mechanisms of Exposure to Per- and Polyfluoroalkyl Substances (PFASs).},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {297},
pmid = {41398131},
issn = {1559-1182},
mesh = {Humans ; *Fluorocarbons/toxicity ; Animals ; Blood-Brain Barrier/drug effects/metabolism/pathology ; *Neurotoxicity Syndromes/metabolism/pathology/etiology ; Brain/drug effects/metabolism/pathology ; *Environmental Exposure/adverse effects ; },
abstract = {Per- and polyfluoroalkyl substances (PFAS), a group of persistent organic pollutants characterized by C-F bonds, have been detected in various human samples and tend to accumulate in the brain, posing potential neurotoxic risks. Gaining insights into PFAS-induced neurotoxicity and its underlying molecular mechanisms is crucial for assessing health risks associated with human exposure, however, research in this area remains limited. This review summarizes studies on the processes of PFAS uptake, accumulation, and mechanisms within the brain: disruption of the blood-brain barrier (BBB) via tight junction interference and reliance on transporter proteins located at the BBB. Accumulation of PFAS in the brain has been linked to neurotoxic effects in the central nervous system (CNS), including attention-deficit/hyperactivity disorder (ADHD) in children and Parkinson's or Alzheimer's disease in older adults. Mechanistic investigations into neurotoxicity have focused on alterations in neurotransmitter levels, mitochondrial dysfunction, neuronal damage, and thyroid hormone signaling pathways. This study offers foundational support for a broader understanding of adverse neurological toxicity, mechanisms of brain penetration, and increased risks of behavioral and cognitive disorders due to PFAS exposure in humans.},
}

Humans
*Fluorocarbons/toxicity
Animals
Blood-Brain Barrier/drug effects/metabolism/pathology
*Neurotoxicity Syndromes/metabolism/pathology/etiology
Brain/drug effects/metabolism/pathology
*Environmental Exposure/adverse effects

@article {pmid41398125,
year = {2025},
author = {Huang, FW and Bello, ST},
title = {Role of Neuronal Cholecystokinin Receptor: An Emerging Therapeutic Target for Ameliorating Neurological Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {296},
pmid = {41398125},
issn = {1559-1182},
support = {11103220, 11101521, 11102422//Hong Kong Research Grants Council/ ; },
mesh = {Animals ; Humans ; *Receptors, Cholecystokinin/metabolism/antagonists & inhibitors ; *Nervous System Diseases/metabolism/drug therapy ; *Neurons/metabolism ; Cholecystokinin/metabolism ; },
abstract = {Neuronal cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain and serves as a critical neuromodulator regulating the physiological states of animals. Previous research on CCK primarily focused on its roles in digestive function, satiety regulation, and emotional modulation, while its involvement in the development of brain diseases remains largely unexplored. Interestingly, recent studies have revealed that CCK-2 receptor antagonists have significant effects on neural modulation, suggesting a potential strategy for the treatment of brain disorders such as Alzheimer's disease, depression, and motor neuron disease, among others. To elucidate the neural effects of CCK on the progression of neurological disorders, we review the available evidence on the neuropeptide CCK in brain diseases at multiple levels and propose novel and complementary approaches to the treatment of brain diseases based on recent developments.},
}

Animals
Humans
*Receptors, Cholecystokinin/metabolism/antagonists & inhibitors
*Nervous System Diseases/metabolism/drug therapy
*Neurons/metabolism
Cholecystokinin/metabolism

@article {pmid41398079,
year = {2025},
author = {Márquez, F and Tarraf, W and Kuwayama, S and Valencia, DF and Stickel, AM and Lipton, RB and Testai, FD and Anita, NZ and Gonzalez, KA and Kaplan, R and Isasi, CR and Talavera, GA and Daviglus, M and Cai, J and Zhou, H and Galasko, D and Gallo, LC and DeCarli, C and Thyagarajan, B and González, HM},
title = {Alzheimer's disease plasma biomarkers are associated with cognitive performance among Hispanic/Latino adults.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-025-01295-7},
pmid = {41398079},
issn = {2730-664X},
abstract = {BACKGROUND: Blood-based biomarkers hold promise as a minimally invasive tool for identifying early signs of Alzheimer's disease pathology and neurodegeneration. We investigated associations between plasma biomarkers of amyloid-beta, tau, neuroaxonal injury, and glial activation with cognitive performance among community-dwelling Hispanic/Latino adults in the United States.

METHODS: We analyzed cross-sectional data from 5730 adults aged 50 years and older (unweighted; mean [SD], 63.5 [8.2] years) in the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA; 2016-2018). Plasma concentrations of amyloid-beta (Aβ42/40), phosphorylated tau-181 (pTau-181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were quantified (Quanterix Simoa HD-X) and log-transformed (ln). Cognitive performance was assessed across domain-specific scores (learning, memory, verbal fluency, and executive functioning/processing speed) used to calculate global cognitive performance. Survey-weighted linear regression models were used to examine associations between plasma biomarkers and cognitive performance, adjusting for sociodemographic, cardiometabolic, kidney, and APOE ε4 covariates.

RESULTS: Here we show higher ln(pTau-181) and ln(NfL) are associated with lower global cognitive performance (bpTau-181 = -0.06; 95%CI = [-0.12;-0.01]; p = 0.022; bNfL = -0.07; 95%CI = [-0.12;-0.02]; p = 0.005). Lower ln(Aβ42/40) is associated with poorer verbal fluency, higher ln(pTau-181) is associated with poorer learning and memory, and higher ln(NfL) is associated with learning and executive functioning/processing speed. We find ln(GFAP) is not significantly associated with cognitive performance.

CONCLUSIONS: Plasma biomarkers related to Alzheimer's disease pathophysiology and broader neurodegenerative processes are associated with cognitive performance among Hispanic/Latino adults. These findings highlight the potential utility of blood-based biomarkers for identifying early cognitive vulnerability in this population.},
}

@article {pmid41398046,
year = {2025},
author = {Heron, R and Amato, C and Monteiro-Black, B and Williams, RJ and Wood, W},
title = {Amyloid-beta induces distinct forms of cell death in different neuronal populations.},
journal = {Cell death and differentiation},
volume = {},
number = {},
pages = {},
pmid = {41398046},
issn = {1476-5403},
support = {22460/Z/21/Z//Wellcome Trust (Wellcome)/ ; 218627/Z/19/Z//Wellcome Trust (Wellcome)/ ; 218627/Z/19/Z//Wellcome Trust (Wellcome)/ ; MR/W019264/1//RCUK | Medical Research Council (MRC)/ ; 894935//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Skłodowska-Curie Actions (H2020 Excellent Science - Marie Skłodowska-Curie Actions)/ ; },
abstract = {Recent FDA approval for treating Alzheimer's disease (AD) with amyloid-beta (Aβ) immunotherapy is a historic breakthrough, which has rekindled widespread interest in understanding the molecular basis of Aβ toxicity. In this study, we developed a novel Drosophila model to investigate Aβ42-induced pathologies in vivo and in real time. Strikingly, we unveiled compelling evidence that secreted Aβ42 affects different neurons in distinct ways-both in susceptibility to Aβ42 deposition and in the mode of cell death triggered. Additionally, we observed altered larval crawling behaviour which-remarkably-could be recovered by inhibiting ferroptotic cell death with small molecule inhibitors. Collectively these findings showcase this as a powerful new model for investigating Aβ toxicity in AD and identifying novel treatment strategies.},
}

@article {pmid41397735,
year = {2025},
author = {Zong, G and Li, R and Jiang, Y and Chen, Z and Yan, S and Yi, Z and Ren, X and Jia, B},
title = {[Two cases of urinary retention in patients with Alzheimer's disease with agitation treated by acupuncture].},
journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion},
volume = {45},
number = {12},
pages = {1822-1824},
doi = {10.13703/j.0255-2930.20250804-k0002},
pmid = {41397735},
issn = {0255-2930},
mesh = {Humans ; *Alzheimer Disease/complications/therapy/psychology ; *Acupuncture Therapy ; *Urinary Retention/therapy/etiology ; Male ; Female ; Aged ; Acupuncture Points ; *Psychomotor Agitation/therapy/complications ; },
abstract = {This article reports 2 cases of urinary retention in Alzheimer's disease with agitation treated by acupuncture. Based on patients' clinical symptoms, the etiology and pathogenesis were determined, and acupuncture was applied to Baihui (GV20), Sishencong (EX-HN1), Shenting (GV24), and bilateral Ciliao (BL32), Zhongliao (BL33), Fengchi (GB20), Taiyang (EX-HN5), etc. to regulate the mind and promote water metabolism. The positive and negative electrodes of the SDZ-Ⅴ type electroacupuncture device were attached to ipsilateral Ciliao (BL32), Zhongliao (BL33) respectively, with continuous wave, at the frequency of 15 Hz, and the current of 3 to 10 mA, depending on patients' tolerance. The needles were retained for 20 min. The treatment was delivered once every other day, 3 interventions a week and 12 interventions as 1 course. Both patients reported the micturition desire after 1 intervention with acupuncture and the catheter was removed on the same day. The urination was ameliorated without dysuresia after 1-2 courses of treatment, and the agitated behavior was alleviated. It can be the reference for the clinical treatment of urinary retention in patients with Alzheimer's disease with agitation.},
}

Humans
*Alzheimer Disease/complications/therapy/psychology
*Acupuncture Therapy
*Urinary Retention/therapy/etiology
Male
Female
Aged
Acupuncture Points
*Psychomotor Agitation/therapy/complications

@article {pmid41397578,
year = {2025},
author = {Wang, X and Wang, X and Zhao, C and Zhao, H and Wang, P and Song, T},
title = {Enhancement of cognitive behavior and hippocampal neural oscillations by rhythmic unipolar pulsed magnetic stimulation in 5xFAD Alzheimer's disease mice.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115995},
doi = {10.1016/j.bbr.2025.115995},
pmid = {41397578},
issn = {1872-7549},
abstract = {Alzheimer's disease (AD) imposes a heavy burden on families and society. Rhythmic magnetic stimulation has emerged as a promising non-invasive therapy to mitigate AD-related cognitive decline. In this study, we applied a rhythmic unipolar compound pulsed magnetic field (cPMF; carrier frequency: 40Hz, repetition rate: 5Hz, magnetic flux density: 0-20 mT) incorporating both theta and gamma rhythms to evaluate its effects on behavior and neural oscillations in AD mice and to explore the underlying mechanisms. 5xFAD mice received unipolar cPMF stimulation for 1h/d over 8 consecutive weeks. Learning and memory were assessed using the novel object recognition (NOR) and the Morris water maze (MWM) tests. In NOR test, unipolar cPMF-treated mice showed a higher cognitive index in test phase 2, and in MWM test, exhibited shorter escape latencies in the training trial and spent less time to first cross the precise former platform location with a higher crossing frequency over this target area in the probe trial. Local field potentials (LFPs) in the hippocampal CA1 area were recorded via in vivo electrophysiology. LFP analysis showed that unipolar cPMF treatment enhanced power of cognitive-related neural oscillations and strengthened theta-gamma phase-amplitude coupling. RNA sequencing analysis further indicated that unipolar cPMF-treated mice exhibited differential gene expression in molecular function and multiple neurotransmitter synaptic signaling pathways. In conclusion, unipolar cPMF might improve cognitive function in 5xFAD mice by modulating cognitive-related neural oscillations. These findings could provide experimental support for the low-intensity pulsed magnetic stimulation as a potential therapeutic strategy for AD.},
}

@article {pmid41397331,
year = {2025},
author = {Gomha, SM and Al-Hussain, SA and Riyadh, SM and Farag, B and Abolibda, TZ and Alrehaili, MM and Alakhdhari, HM and Zaki, MEA},
title = {Novel bis-Thiazolidinone -based chalcones with pyridine linker: Eco-friendly synthesis, cholinesterase and beta-amyloid inhibition potency, and molecular docking studies.},
journal = {Bioorganic chemistry},
volume = {168},
number = {},
pages = {109372},
doi = {10.1016/j.bioorg.2025.109372},
pmid = {41397331},
issn = {1090-2120},
abstract = {The grinding technique is a mechanochemical method that avoids the use of solvents in the reaction mixture, thereby reducing the detrimental effects of vapour and affording an environmentally and economically efficient process. This technique was utilized to prepare a novel series of 2,2'-[(2,6-dimethylpyridine-3,5-diyl)bis(ethan-1-yl-1-ylidene)bis(hydrazin-1-yl-2-ylidene)]bis[(5-arylidine)thiazol-4(5H)-one] via condensation of 2,2'-[(2,6-dimethylpyridine-3,5-diyl)bis(ethan-1-yl-1-ylidene)bis(hydrazin-1-yl-2-ylidene)]bis(thiazol-4(5H)-one) and carbonyl compounds. The structures of the newly synthesized chalcones were confirmed by FT-IR, [1]H NMR, [13]C NMR, and MS (ESI) data. These spectroscopic results verified the successful formation of the target bis-thiazolidinone framework. To highlight the significance of the synergistic biological potency of the target products as fundamental frameworks for the development of Alzheimer's treatments, molecular docking analyses were performed to investigate the potential binding configurations of the tested ligands. The molecular docking studies were in good agreement with the in vitro biological results, including acetylcholinesterase (AChE) and beta-amyloid (Aβ1-42) inhibition activities. In the docking analysis, compounds 5b, 5d, 5e, 5f, 5 l, and 5n demonstrated strong molecular interactions with 7AIS as the target protein. These findings highlight compounds that could be used as adjuvants in the management of AD. Additionally, in silico investigations of these newly synthesized substances were successfully conducted. The ADMET profiles of the studied compounds indicated favorable bioavailability characteristics.},
}

@article {pmid41397211,
year = {2026},
author = {Satyadev, N and Piura, YD and Tipton, PW and Dunham, SR and Morris, JC and Geschwind, MD and Brier, M and Graff-Radford, NR and Day, GS},
title = {Standardizing "Rapid": Applying the Clinical Dementia Rating to Define Rapidly Progressive Dementia.},
journal = {Neurology},
volume = {106},
number = {1},
pages = {e214439},
doi = {10.1212/WNL.0000000000214439},
pmid = {41397211},
issn = {1526-632X},
mesh = {Humans ; Female ; Male ; Disease Progression ; Aged ; *Dementia/diagnosis ; Aged, 80 and over ; Retrospective Studies ; Middle Aged ; *Mental Status and Dementia Tests/standards ; },
abstract = {BACKGROUND AND OBJECTIVES: Rapidly progressive dementia (RPD) accounts for 3%-4% of dementia cases yet presents a disproportionate clinical challenge given the wide differential diagnosis and the need to quickly identify potentially treatment-responsive causes. The lack of a standardized definition of RPD challenges generalization of published findings and precludes multisite studies. We sought to determine whether a standardized definition, based on the Clinical Dementia Rating (CDR), could reliably distinguish individuals with a broad spectrum of causes of RPD early in the symptomatic course.

METHODS: RPD was defined as dementia (global CDR ≥1) developing within 1 year or incapacitation (global CDR ≥2) within 2 years of symptom onset. Patients with suspected RPD were referred from inpatient and outpatient settings at Mayo Clinic in Florida (Jacksonville, FL) and Washington University in St. Louis (Saint Louis, MO) and prospectively evaluated (RaPID cohort). Retrospective data from participants assessed across 46 research centers were also analyzed (National Alzheimer's Coordinating Center [NACC] data set). Characteristics and rates of progression (main outcome) were compared between typically progressive and RPD. Univariable and multivariable analyses were performed using Mann-Whitney U/Kruskal-Wallis (continuous) and Fisher exact/χ[2] tests (binary), respectively. Our definition of RPD was compared against definitions identified through a scoping review conducted using a validated 6-stage approach.

RESULTS: In the RaPID cohort, 185 of 248 (74.6%) patients met our CDR-based RPD definition (median [range] age-at-symptom onset: 68.8 years [22.0-90.7]; 45.4% female). Autoimmune (55/185, 29.7%), neurodegenerative (51/185, 27.6%), and prion diseases (35/185, 18.9%) predominated. Among 20,418 NACC participants with cognitive impairment, 836 (4.1%) met our RPD definition (median [range] age-at-symptom onset: 74 years [24-103]; 57.1% female). Neurodegenerative diseases predominated, especially Alzheimer disease (485/836, 58.0%). Individuals with RPD declined substantially faster (ΔCDR sum-of-boxes/year: RaPID, 14.4 ± 5.3 vs 4.3 ± 4.3, p < 0.001; NACC, 6.7 ± 3.1 vs 1.7 ± 1.4, p < 0.001). Our scoping review identified 22 studies that applied 10 distinct definitions of RPD. Uniquely, our CDR-based definition clearly distinguished individuals with a broad spectrum of causes of RPD, assessed across multiple sites/settings, supporting early diagnosis with minimal resource requirements.

DISCUSSION: The CDR-based definition of RPD effectively identified individuals with a broad spectrum of causes of RPD early in the symptomatic course. The need for training and time to reliably administer the CDR may limit application of the proposed definition of RPD. Validation in additional cohorts is required to support generalizability.},
}

Humans
Female
Male
Disease Progression
Aged
*Dementia/diagnosis
Aged, 80 and over
Retrospective Studies
Middle Aged
*Mental Status and Dementia Tests/standards

@article {pmid41397029,
year = {2025},
author = {Sengupta, N and Luebke, JI and Weaver, CM},
title = {Axon collateralization and focal myelin dystrophy alter action potential propagation in multicompartment pyramidal neuron models.},
journal = {PLoS computational biology},
volume = {21},
number = {12},
pages = {e1013733},
doi = {10.1371/journal.pcbi.1013733},
pmid = {41397029},
issn = {1553-7358},
abstract = {Action potentials (APs) propagate along axons to enable precise and rapid neuronal communication. Axon collaterals extend a given neuron's range by distributing signals to multiple targets, but also increase its electrical demands. Myelination facilitates saltatory conduction, dramatically enhancing transmission speed and ensuring conduction fidelity over long distances. The interplay between myelin dystrophy and axonal arborization remains largely unexplored, despite their role in the impairment of AP conduction in brain circuits. Here we used cohorts of biophysically detailed, multicompartmental models of rhesus monkey dorsolateral prefrontal cortex (dlPFC) layer 3 pyramidal neurons to investigate how axon collateralization, myelin dystrophy, and other structural and biophysical perturbations affect AP conduction velocity (CV). We identified core diameter and branch point location, particularly its distance from the soma, as key structural determinants of CV. Under pathological conditions, branch points emerged as sites of heightened vulnerability, where even focal myelin damage markedly impaired conduction. The efficacy of remyelination to restore CV depended on the number of segments that replaced each demyelinated region. Effective length constant and focal input resistance largely predicted CV reductions caused by structural changes. In addition to demyelination, CV was highly sensitive to variations in axoplasmic and membrane resistivities, the formation of myelin balloons, and ion channel redistribution. These findings offer a mechanistic framework for understanding AP conduction in myelinated axons with complex topologies, while also pointing to potential factors underlying individual differences in vulnerability to cognitive impairments. This work thus provides an important building block for multiscale modeling of network and behavioral effects of aging, as well as axonopathies such as multiple sclerosis, Alzheimer's disease, and traumatic brain injury.},
}

@article {pmid41396874,
year = {2025},
author = {Zu, J and Li, C and Cui, M and Liu, X and Pan, Z and Li, X and Zhang, F and Gentz, J and Mitteregger-Kretzschmar, G and Herms, J and Shi, Y},
title = {Pioglitazone attenuates complement-mediated microglial synaptic engulfment in an Alzheimer's disease model.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf462},
pmid = {41396874},
issn = {1460-2156},
abstract = {Synaptic loss is an early hallmark of Alzheimer's disease (AD), predominantly driven by aberrant microglial reactivity. Pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist with anti-diabetic properties, has been shown to suppress microglial activity and improve cognitive performance in both AD models and clinical studies. However, whether its neuroprotective effects involve direct modulation of synaptic architecture remains unclear. Here, using longitudinal in vivo two-photon imaging, multi-channel immunohistochemistry, super-resolution confocal microscopy, and 3D reconstruction techniques in an AD mouse model, we analysed synaptic and microglial interactions. We show that a 4-week pioglitazone treatment preserves dendritic spine density and enhances spine stability over time. Mechanistically, pioglitazone reduces synaptic C1q deposition, thereby limiting complement-mediated microglial synaptic engulfment and attenuating synapse loss. These findings identify pioglitazone as a modulator of complement-dependent microglial synaptic pruning and support its therapeutic potential in preserving synaptic integrity during early AD pathogenesis.},
}

@article {pmid41396689,
year = {2026},
author = {Simão, S and Santos, DF and Teixeira, M and Agostinho, RR and Rodrigues, J and Vitorino, M and Araújo, IM},
title = {Unraveling the potential of gasotransmitters as neurogenic and neuroprotective molecules: focus on Alzheimer's and Parkinson's diseases.},
journal = {Redox report : communications in free radical research},
volume = {31},
number = {1},
pages = {2592413},
doi = {10.1080/13510002.2025.2592413},
pmid = {41396689},
issn = {1743-2928},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Parkinson Disease/metabolism/drug therapy ; *Gasotransmitters/metabolism/therapeutic use ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Neurogenesis/drug effects ; Hydrogen Sulfide/metabolism ; Animals ; Carbon Monoxide/metabolism ; Nitric Oxide/metabolism ; Oxidative Stress ; },
abstract = {Alzheimer's disease and Parkinson's disease are the two most prevalent neurodegenerative disorders worldwide, both characterized by progressive neuronal loss. Despite distinct pathophysiological features, they share cellular dysfunctions such as abnormal protein aggregation, oxidative stress, and neuroinflammation, research into which might be beneficial for developing novel therapeutic strategies that could tackle both conditions. This review highlights the emerging role of the gasotransmitters nitric oxide, carbon monoxide and hydrogen sulfide as modulators of adult neurogenesis and neuroprotection in Alzheimer's disease and Parkinson's disease. We have gathered recent evidence demonstrating that these endogenous gases exert anti-inflammatory, antioxidant, and anti-apoptotic effects, and, critically, promote neurogenesis - suggesting a dual neuroprotective and neuroregenerative therapeutic potential. The unique physicochemical features of these gasotransmitters, including their ability to cross the blood-brain barrier and diffuse rapidly throughout the neural tissue, further support their suitability as candidates for innovative neuroregenerative treatments. While clinical translation remains challenging, harnessing the neurogenic and neuroprotective actions of these gasotransmitters may offer transformative avenues for addressing the increasing burden of Alzheimer's disease and Parkinson's disease.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
*Parkinson Disease/metabolism/drug therapy
*Gasotransmitters/metabolism/therapeutic use
*Neuroprotective Agents/therapeutic use/pharmacology
*Neurogenesis/drug effects
Hydrogen Sulfide/metabolism
Animals
Carbon Monoxide/metabolism
Nitric Oxide/metabolism
Oxidative Stress

@article {pmid41396652,
year = {2025},
author = {Mellott, JG and Dellaria, LM and Guy, M and Hergenrother, SR and Tokar, NJ and Smallridge, DZ and Terzic, M and Young, JW and Dengler-Crish, CM},
title = {Ultrastructural Synaptic Differences in the Central Inferior Colliculus in the 3xTG Mouse Across Three Disease Stages.},
journal = {The Journal of comparative neurology},
volume = {533},
number = {12},
pages = {e70120},
pmid = {41396652},
issn = {1096-9861},
support = {R01 DC017708/DC/NIDCD NIH HHS/United States ; NIH/NIA//NIH/NIDCD/ ; R03 AG087423/AG/NIA NIH HHS/United States ; R01 DC017708/DC/NIDCD NIH HHS/United States ; NIH/NIA//NIH/NIDCD/ ; R03 AG087423/AG/NIA NIH HHS/United States ; //American Academy of Neurology Medical Student Research Program/ ; R01 DC017708/DC/NIDCD NIH HHS/United States ; R03 AG087423/AG/NIA NIH HHS/United States ; //American Academy of Neurology/ ; },
mesh = {Animals ; *Inferior Colliculi/ultrastructure/pathology ; *Synapses/ultrastructure/pathology ; Mice ; Mice, Transgenic ; *Alzheimer Disease/pathology/genetics ; Disease Models, Animal ; Microscopy, Electron, Transmission ; Male ; Humans ; Female ; Disease Progression ; },
abstract = {Numerous studies support a mechanistic link between hearing loss and increased risks of cognitive decline and dementia. Hearing loss is widely viewed as a modifiable risk factor for Alzheimer's disease (AD). During normal aging the inferior colliculus (IC), a large auditory midbrain nucleus, undergoes numerous changes to neurotransmission, and these changes contribute to the development of central gain and presbycusis. Recent reports also implicate the IC as a nucleus that undergoes processing changes during AD. We used transmission electron microscopy (EM) to examine the synaptic ultrastructure of the central IC (ICc) in 3xTG mice during presymptomatic, emerging, and established disease stages. Synapses were identified by a collection of presynaptic vesicles, a clear synaptic cleft, and a postsynaptic density. Symmetric synapses had pre and postsynaptic membranes of similar thickness, whereas asymmetric synapses had postsynaptic densities were conspicuously thicker than the presynaptic densities. We also quantified the presynaptic profile areas, active zone lengths, and presynaptic mitochondria. The data demonstrate a significant loss of symmetric and asymmetric synapses in the emerging disease stage. In particular, the density of symmetric synapses in the ICc was reduced by ∼50%. As inhibitory neurotransmitters gamma-aminobutyric acid (GABA), glycine, and neuropeptide Y are released from neurons that form symmetric synapses in the IC, the robust loss of these synapses may contribute to central gain and presbycusis during AD. Furthermore, as these synapses were lost well before the established disease stages, perhaps alterations in ICc represent an early biomarker for Alzheimer's progression.},
}

Animals
*Inferior Colliculi/ultrastructure/pathology
*Synapses/ultrastructure/pathology
Mice
Mice, Transgenic
*Alzheimer Disease/pathology/genetics
Disease Models, Animal
Microscopy, Electron, Transmission
Male
Humans
Female
Disease Progression

@article {pmid41396614,
year = {2025},
author = {Brown, CA and Mundada, NS and Cousins, KAQ and Sadeghpour, N and Lyu, X and McGrew, E and Korecka, M and Chen-Plotkin, A and Xie, L and Wisse, LEM and Detre, JA and McMillan, CT and Lee, EB and Nasrallah, IM and Das, SR and Mechanic-Hamilton, D and Yushkevich, PA and Shaw, LM and Wolk, DA and , },
title = {Evaluation of Copathology and Clinical Trajectories in Individuals With Tau-Clinical Mismatch.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.4974},
pmid = {41396614},
issn = {2168-6157},
abstract = {IMPORTANCE: Even within individuals who are amyloid positive, clinical symptoms can be impacted by Alzheimer pathology, other pathologic proteins, and cognitive reserve or resilience. Understanding how each of these factors contributes to a patient's clinical presentation is crucial for prognosis and treatment decisions in the era of disease-modifying therapies.

OBJECTIVE: To evaluate tau-clinical mismatch as a means to identify those more likely to harbor copathology and/or exhibit resilience to Alzheimer pathology.

This was a longitudinal, observational cohort study conducted from 2004 to 2024. The setting included multiple academic medical centers in the US participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI) or Penn Alzheimer's Disease Research Center (Penn-ADRC). Included in the analysis were individuals with clinical assessment and measures of either tau positron emission tomography (tau-PET) or phosphorylated tau 217 (p-tau217) who were selected from individuals positive for amyloid β (Aβ+) in the ADNI cohort (aged 55-95 years) and the Penn-ADRC cohort (aged 54-92 years).

EXPOSURES: Clinical assessment (Clinical Dementia Rating Sum of Boxes [CDR-SB]) and tau burden (tau-PET or p-tau217) for mismatch group classification.

MAIN OUTCOMES AND MEASURES: Cross-sectional measures of neurodegeneration (medial temporal lobe volume and thickness, cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature), α-synuclein cerebrospinal fluid seed-amplification assay, and longitudinal CDR-SB.

RESULTS: A total of 365 participants (mean [SD] age, 75.4 [7.9] years; 192 female [52.6%]) in the ADNI tau-PET group and 524 participants (mean [SD] age, 77.1 [7.9] years; 268 male [51.1%]) in the ADNI p-tau217 group were selected from the 998 individuals who were Aβ+ in the ADNI cohort and used to generate tau-clinical mismatch models with 55.6% to 57.1% classified as canonical (CDR-SB commensurate to tau), 23.7% to 24.7% as resilient (CDR-SB < tau), and 19.3% to 19.7% as vulnerable (CDR-SB > tau). Vulnerable groups had evidence of greater likelihood of copathology, with TDP-43 neurodegeneration patterns and α-synuclein positivity. Mismatch groups showed diverging clinical trajectories with earlier cognitive impairment in vulnerable groups and later impairment in resilient individuals. Similar findings were seen when applied to an independent dataset of 244 individuals (mean [SD] age, 73.7 [6.8] years; 139 female [57.0%]) of the 248 who were Aβ+ in Penn-ADRC cohort. Finally, these models were applied to a cohort receiving antiamyloid therapy to show the utility of this method for predicting individual cognitive trajectories during therapy.

CONCLUSION AND RELEVANCE: Results of this cohort study suggest that tau-clinical mismatch identified individuals more likely to have an accelerated disease course due to the presence of copathology and those exhibiting greater cognitive resilience to disease pathology. These models provide an important tool that can be implemented in clinical practice to provide improved individualized prognosis and, potentially, monitoring of response to disease-modifying therapy.},
}

@article {pmid41396454,
year = {2025},
author = {Petersen, RC and Zetterberg, H},
title = {A Test of the Alzheimer Disease Framework-Did It Pass?.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.4966},
pmid = {41396454},
issn = {2168-6157},
}

@article {pmid41396413,
year = {2025},
author = {Zuliani, G and Brombo, G and Romagnoli, T and Polastri, M and Dario, FDP and Zuin, M},
title = {Effectiveness of acetylcholinesterase inhibitors and memantine in patients affected by severe dementia.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41396413},
issn = {2509-2723},
abstract = {The efficacy of acetylcholinesterase inhibitors (AChEI) and memantine (ME) in severe dementia remains uncertain, and real world data are limited. We evaluated the progression of cognitive decline and mortality rates in a cohort of outpatients with severe dementia treated with AChEI and/or ME or not treated, from the National Alzheimer's Coordinating Center Uniform Data Set (NACC-UDS). Overall, 703 patients (mean age:78.3 ± 7.2 years; females:56.1%) with severe dementia (Mini-Mental State Examination-MMSE ≤ 10/30) were included [407 late-onset Alzheimer's disease (LOAD), 126 Lewy body dementia (LBD), 170 vascular dementia (VD)]. Patients were grouped by treatment status: untreated (AChEI - /ME - ; n.70), AChEI only (AChEI + ; n.294), ME only (ME + ; n.215), combined therapy (AChEI + /ME + ; n.124). During follow-up (mean:1.7 ± 0.3 years; range:0.2-2.9 years) the mean MMSE scores declined by - 1.7 points (Standard Deviation: -1.55 to -1.9) in AChEI - /ME - (p for trend:0.001), - 1.5 points (-1.55 to -1.9) in AChEI + (p:0.001), - 0.7 points (-0.5 to -0.9) in ME + (p:0.09), while it increased by + 0.7 points (+ 0.4 to + 1.0) in AChEI + /ME + (p:0.001). Survival rates were 8% in AChEI - /ME - , 10% in AChEI + , 28% in ME + , and 49% in AChEI + /ME + . In Cox proportional hazards analysis (age and sex adjusted), AChEI + /ME + exhibited a 39% reduction in total mortality compared with no treatment (HR:0.61; 95%CI:0.49-0.77; p < 0.001), ME + displayed a 22% reduction (HR:0.78; 95%CI:0.65-0.94; p:0.007), while AChEI + showed no association (HR:0.97; 95%CI:0.80-1.18; p:0.75). When the Cox proportional hazards models were stratified by dementia subtype, consistent significant patterns were observed in LOAD and LBD. In this real-world cohort of older adults with severe dementia, the combination therapy (ME + AchEI) seems to be associated with the best outcomes, including a stabilization of cognitive function and reduced total mortality.},
}

@article {pmid41396167,
year = {2025},
author = {Robinson, L and Bray, J and Melis, V and Harrington, CR and Wischik, CM and Riedel, G},
title = {Effects of hydromethylthionine mesylate and rivastigmine in a pharmacological mouse model of Alzheimer's disease.},
journal = {Behavioural pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1097/FBP.0000000000000865},
pmid = {41396167},
issn = {1473-5849},
support = {PAR 1577//WisTa Laboratories Ltd/ ; },
abstract = {The results from clinical trials have indicated that the tau aggregation inhibitor hydromethylthionine mesylate (HMTM) produces disease-modifying effects in Alzheimer's disease (AD) patients when administered alone, but less of an effect when administered in conjunction with cholinesterase inhibitors (ChEIs). The use of ChEIs for AD has been supported by their ability to reverse scopolamine-induced cognitive impairments in rodents reminiscent of those seen in AD patients. We have previously shown that another tau aggregation inhibitor, methylthionine chloride (MTC), is able to reverse scopolamine-induced deficits in spatial learning and memory. The objective here was to determine the symptomatic efficacy of HMTM and rivastigmine, alone or in combination, in a scopolamine model of AD. Female NMRI mice were treated systemically with scopolamine (0.5 mg/kg) or vehicle in combination with ChEI rivastigmine (0.5 mg/kg) or HMTM (5 or 15 mg/kg) daily before assessment of spatial learning and memory performance in a reference memory task in the water maze. Systemic administration of scopolamine induced significant impairments in the spatial learning of the mice compared to vehicle treatment. These deficits were reversed by treatment with HMTM at both doses and with rivastigmine when given alone. Furthermore, coadministration of rivastigmine with HMTM ameliorated the impairments induced by scopolamine. These findings extend our previous observations with MTC and confirm that HMTM also has a dual mode of action, disease modification through tau aggregation inhibition, but also having symptomatic effects through its normalisation of cholinergic activity.},
}

@article {pmid41396015,
year = {2025},
author = {Leng, L and Liao, Z and Lu, P and Sun, Y and Weng, Q and Fan, W and Zhu, H and Wu, W and Liu, P and Liu, X and Zhang, K and Wang, W and Luo, B and Wang, Z and Peng, G},
title = {Real-world experience with baseline characteristics and safety of lecanemab for Alzheimer's disease in Eastern China.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406619},
doi = {10.1177/13872877251406619},
pmid = {41396015},
issn = {1875-8908},
abstract = {BackgroundLecanemab reduces amyloid levels and modestly slows cognitive decline in a large cohort of early Alzheimer's disease (AD) but lacks real-world safety data in Chinese population.ObjectiveThe real-world study aims to analyze baseline characteristics and preliminary safety of lecanemab for AD in Zhejiang Province, and to evaluate the efficacy of plasma biomarkers for patient screening.MethodsThis multi-center study included 190 patients with AD in Zhejiang Province, who completed baseline assessments and received lecanemab treatment with follow-up.ResultsThe study included 176 participants with early AD and 14 moderate. In the early AD (mean age 68.04 years, Mini-Mental State Examination 20.03 and Montreal Cognitive Assessment 14.93), 124 (70.5%) participants were female, and 127 (72.1%) were junior high school education level or less. APOE4 heterozygote was predominant (48.9%). Logistic regression for distinguishing early AD from the Aβ negative cognitively unimpaired populations showed that p-Tau 217 independently provided better classification efficacy (area under the curve = 0.9983, p < 0.0001). In the early AD, 29 (16.5%) participants experienced infusion-related reactions (IRR) after the first-dose lecanemab, and amyloid-related imaging abnormalities (ARIA) were identified in 17 patients (9.7%), while 3 (21.4%) with IRR and none ARIA observed in the moderate AD.ConclusionsThe real-world lecanemab cohort had more females, lower educational level, and higher disease burden compared with the clinical trial cohort. Overall lecanemab exhibited a manageable short-term safety profile with no measurable cognitive efficacy. Extensive monitoring and management are required for ARIA of clinically importance. The plasma p-Tau 217 showed high accuracy for early AD screening.},
}

@article {pmid41396005,
year = {2025},
author = {Ahmed, A and Khan, H and Shen, Y and Xu, S and Zhao, Y and Lv, J and Zhu, X and Fu, X and Li, P},
title = {Neuroprotective potential of Rhus coriaria: Insights into acetylcholinesterase inhibition and amyloid-β modulation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251404020},
doi = {10.1177/13872877251404020},
pmid = {41396005},
issn = {1875-8908},
abstract = {Sumac (Rhus coriaria) is a spice and a medicinal plant that has been indicated to exert favorable effects in the management of different diseases, and it also possesses high anti-inflammatory and antioxidant properties. A plant known to be rich in bioactive molecules, including polyphenols, tannins, and flavonoids, sumac showed potent free radical scavenging activity. It thus may fight oxidative stress, which is recognized as the main cause of neurodegenerative ailments. In addition, recent investigations have also demonstrated during in vitro assays that Rhus coriaria might exert acetylcholinesterase inhibition activities, of interest in the context of therapeutic approaches for Alzheimer's disease (AD) associated with an increase of cholinergic neurotransmission supporting the cognitive processes. Furthermore, the sumac's neuroprotective activity may regulate amyloid-β (Aβ) aggregation, an important phenomenon in the AD diseased brain. Sumac may preserve neurons and synapses by blocking Aβ plaque production and neurotoxicity. That makes its anti-inflammatory activity additionally involve neuroprotective activity, largely because it reduces the pro-inflammatory cytokines level and restrains the microglial activation in the progression of AD. Given the multitarget activities, Rhus coriaria may be a potent natural candidate for preventing and treating AD. In vitro and in vivo studies are necessary to isolate its bioactive compounds, as well as preclinical and clinical studies for its effects on neurodegenerative and cognitive disorders. Dietary or medicative incorporation of sumac can supply an adjuvant choice for AD and its correlated pathogenicity.},
}

@article {pmid41395817,
year = {2025},
author = {Krejčí, M and Matušková, V and Saari, TT and Horáková, H and Borovská, Š and Laczó, J and Hort, J and Vyhnálek, M},
title = {Comparing self and informant perspectives on neuropsychiatric symptoms in older adults in a memory clinic.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251401620},
doi = {10.1177/13872877251401620},
pmid = {41395817},
issn = {1875-8908},
abstract = {BackgroundIn individuals with cognitive deficit, neuropsychiatric symptoms (NPS) are typically assessed through informant-based reports. In contrast, affective symptoms in cognitively normal individuals are typically evaluated using self-report measures, leveraging their sufficient insight. Comparison of these assessments in previous studies indicated differences in their perspectives.ObjectiveWe aimed to analyze differences between self- and informant-reported NPS using the Mild Behavioral Impairment-Checklist (MBI-C) and their relationship with cognitive deficit.MethodsThe study included 127 participant-informant dyads from a memory clinic cohort, classified as subjective cognitive decline (SCD; N = 38) or mild cognitive impairment (MCI; N = 89) based on comprehensive neuropsychological assessment; MCI group was diagnosed according to core clinical criteria for MCI due to Alzheimer's disease. A control group consisted of 26 cognitively healthy individuals. Participants and their informants completed the MBI-C, evaluating five symptom domains.ResultsBoth self- and informant-rated MBI-C scores were higher in the SCD and MCI groups compared to controls. Informant ratings correlated more strongly with objective cognitive deficit, particularly in memory and executive function domains, whereas self-ratings showed only one association (higher apathy with worse attention). In MCI, informants reported more severe impulse dyscontrol symptoms. Correlations between self and informant ratings were weak to moderate.ConclusionsThis study highlights discrepancies between self- and informant-rated NPS assessments, with informant ratings more strongly linked to cognitive deficits in older adults without dementia. Therefore, we suggest using both assessments to capture informants' and patients' subjective experiences and facilitate early identification of neurodegenerative diseases.},
}

@article {pmid41395729,
year = {2025},
author = {Njamnshi, WY and Chiotis, K and Tsoy, E and Blazhenets, G and Maiti, P and Zhang, J and Allen, IE and Rocha, S and Shankar, RP and Amuiri, A and Lawson, M and Aisen, P and Beckett, L and Eloyan, A and Hammers, DB and Kirby, K and Koeppe, R and Kukull, WA and Toga, AW and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, I and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, J and Mendez, MF and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, SJ and Turner, RS and Wingo, TS and Wolk, DA and Womack, K and Kramer, JH and Touroutoglou, A and Brickhouse, MJ and Jack, CR and Vemuri, P and Taurone, A and Thangarajah, M and Nudelman, K and Carrillo, MC and Dickerson, BC and Apostolova, LG and Possin, KL and Rabinovici, GD and La Joie, R and , },
title = {Tablet-based Cognitive Assessment Tool (TabCAT) in a multisite study of early-onset Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71012},
pmid = {41395729},
issn = {1552-5279},
support = {U01 NS128913/NS/NINDS NIH HHS/United States ; R35 AG072362/AG/NIA NIH HHS/United States ; R21AG080410//from NIH/ ; UG3AG090679//from NIH/ ; U01AG057195//from NIH/ ; R56AG057195//from NIH/ ; U24AG072122//from NIH/ ; U24AG021886//from NIH/ ; P30AG072976//from NIH/ ; P30AG062422//from NIH/ ; P30AG066462//from NIH/ ; P30AG066507//from NIH/ ; P30AG062421//from NIH/ ; P30AG072977//from NIH/ ; P30AG066444//from NIH/ ; P30AG066515//from NIH/ ; P30AG062677//from NIH/ ; P30AG072980//from NIH/ ; P30AG072979//from NIH/ ; P30AG066511//from NIH/ ; AARG-22-926940//from the Alzheimer's Association/ ; LDRFP-21-818464//from the Alzheimer's Association/ ; LDRFP-21-824473//from the Alzheimer's Association/ ; LEADSGENETICS-19-639372//from the Alzheimer's Association/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology/diagnostic imaging ; Female ; Male ; *Neuropsychological Tests ; *Cognitive Dysfunction/diagnosis ; *Computers, Handheld ; Aged ; Longitudinal Studies ; Executive Function/physiology ; Positron-Emission Tomography ; Middle Aged ; Reproducibility of Results ; },
abstract = {INTRODUCTION: Brief digital cognitive measures may be a valuable and scalable alternative to traditional tests for improving early detection and disease monitoring in patients with early-onset Alzheimer's disease (EOAD).

METHODS: We examined the convergent, diagnostic, and neuroanatomical validity of Tablet-based Cognitive Assessment Tool (TabCAT) tests in the multisite Longitudinal Early-Onset Alzheimer's Disease Study. Four hundred seventy-five participants from 16 sites (83 cognitively unimpaired participants, 146 individuals diagnosed with mild cognitive impairment [MCI], and 246 with mild dementia) underwent TabCAT testing, including two executive/attentional tasks (Match and Flanker) and two visuospatial tasks (Line Length and Line Orientation).

RESULTS: TabCAT tests showed good convergent validity with traditional pen-and-paper tests. Match was the most accurate TabCAT test in differentiating among clinical groups (controls vs. MCI vs. dementia) and predicting amyloid positron emission tomography (PET) positivity in clinically impaired participants. TabCAT tests were associated with regional tau PET patterns.

DISCUSSION: TabCAT digital measures have promise for frontline identification of patients with EOAD.

HIGHLIGHTS: Four hundred seventy-five participants from 16 US sites underwent tablet-based cognitive assessment. Digital tests assessed executive function and visuospatial abilities. Digital tests correlated with traditional pen-and-paper cognitive tests. Match (test of executive function) differentiated clinical groups. Digital tests were associated with amyloid positron emission tomography (PET) status and regional tau PET patterns.},
}

Humans
*Alzheimer Disease/diagnosis/psychology/diagnostic imaging
Female
Male
*Neuropsychological Tests
*Cognitive Dysfunction/diagnosis
*Computers, Handheld
Aged
Longitudinal Studies
Executive Function/physiology
Positron-Emission Tomography
Middle Aged
Reproducibility of Results

@article {pmid41395714,
year = {2025},
author = {Kang, KM and Park, C and Nam, H and Byun, MS and Yi, D and Jung, JH and Jung, G and Ahn, H and Lee, JY and Lee, YS and Kim, YK and Sohn, CH and Lee, DY and , },
title = {Intracranial stenosis and longitudinal progression of Alzheimer's disease pathologies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71010},
pmid = {41395714},
issn = {1552-5279},
support = {HI18C0630//Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea/ ; HI19C0149&HU23C0140//Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea/ ; U01AG072177//National Institute on Aging, United States of America/ ; 03-2023-0330//SNUH Research Fund/ ; //New Faculty Startup Fund from Seoul National/ ; RS-2025-00518633//National Research Foundation of Korea (NRF), the Ministry of Science, ICT, and Future Planning, Republic of Korea/ ; 2021R1C1C1006407//National Research Foundation of Korea (NRF), the Ministry of Science, ICT, and Future Planning, Republic of Korea/ ; 2014M3C7A1046042//National Research Foundation of Korea (NRF), the Ministry of Science, ICT, and Future Planning, Republic of Korea/ ; 2020R1G1A1099652//National Research Foundation of Korea (NRF), the Ministry of Science, ICT, and Future Planning, Republic of Korea/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; Male ; Female ; Aged ; tau Proteins/metabolism ; Disease Progression ; *Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; Longitudinal Studies ; Constriction, Pathologic/diagnostic imaging/pathology ; Prospective Studies ; *Brain/pathology/diagnostic imaging/metabolism ; Magnetic Resonance Angiography ; Cognitive Dysfunction/diagnostic imaging/pathology ; Aged, 80 and over ; Aniline Compounds ; Thiazoles ; },
abstract = {INTRODUCTION: The relationship between intracranial stenosis (ICS) and Alzheimer's disease (AD) pathologies remains unclear. We investigated whether baseline ICS is associated with longitudinal changes in amyloid beta (Aβ) and tau deposition.

METHODS: We prospectively followed 180 older adults (mean age 70.06 ± 7.40 years), including cognitively normal (CN) and cognitively impaired (CI) individuals. ICS was assessed with magnetic resonance angiography. Aβ and tau deposition were measured using Pittsburgh compound B positron emission tomography (PET) and AV-1451 PET, respectively. Participants were classified into Aβ and tau analysis groups, each including both CN and CI individuals, and separate models were constructed to evaluate associations between ICS and longitudinal changes in each biomarker.

RESULTS: The presence of any ICS was significantly associated with greater Aβ accumulation over 4 years, while ICS in two or more arteries predicted greater tau deposition over 2 years.

DISCUSSION: ICS may accelerate both Aβ and tau accumulation, supporting a vascular contribution to AD pathogenesis.

HIGHLIGHTS: Intracranial stenosis at baseline predicts 4-year increase in amyloid beta deposition. Two or more stenotic intracranial arteries are linked to 2-year tau accumulation. Associations remain after adjusting for apolipoprotein E ε4 status and cognitive impairment. Intracranial atherosclerosis may accelerate both amyloid and tau accumulation.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
Male
Female
Aged
tau Proteins/metabolism
Disease Progression
*Amyloid beta-Peptides/metabolism
Positron-Emission Tomography
Longitudinal Studies
Constriction, Pathologic/diagnostic imaging/pathology
Prospective Studies
*Brain/pathology/diagnostic imaging/metabolism
Magnetic Resonance Angiography
Cognitive Dysfunction/diagnostic imaging/pathology
Aged, 80 and over
Aniline Compounds
Thiazoles

@article {pmid41395713,
year = {2025},
author = {Liu, Y and Zhu, H and Wang, Y and Luan, X and Chen, J and Qian, J and Shen, J and Liu, Y and Wen, C and Cao, L and Tang, B and Ko, H and Kwapong, WR and Wang, Z},
title = {Apolipoprotein E ε4 homozygosity exacerbates retinal and cerebral microvascular dysfunction in Alzheimer's disease: A mediation analysis of vascular contributions to cognitive decline.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71000},
doi = {10.1002/alz.71000},
pmid = {41395713},
issn = {1552-5279},
support = {2022YFC2406500//National Key R&D Program of China/ ; CXTD202501044//Zhejiang Clinovation Pride Code/ ; },
mesh = {Humans ; Male ; *Alzheimer Disease/genetics/complications ; Female ; *Apolipoprotein E4/genetics ; *Cognitive Dysfunction/genetics ; Homozygote ; Aged ; *Retinal Vessels/diagnostic imaging/pathology ; *Microvessels/diagnostic imaging ; Tomography, Optical Coherence ; Magnetic Resonance Imaging ; Biomarkers/blood ; Middle Aged ; },
abstract = {INTRODUCTION: Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD), with homozygous carriers (ε4/ε4) experiencing accelerated cognitive decline. While its role in amyloid and tau pathology is established, its impact on retinal and cerebral microvasculature remains underexplored.

METHODS: A total of 107 AD (46 non-carriers, 42 heterozygotes, 19 homozygotes) underwent optical coherence tomography angiography (OCTA) to assess retinal microvasculature and magnetic resonance imaging (MRI) -derived peak width of skeletonized mean diffusivity (PSMD) to evaluate cerebral small vessel disease. Plasma biomarkers (Aβ42, p-tau217, glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and cognitive scores were also analyzed.

RESULTS: Homozygous APOE ε4 carriers exhibited the most severe reduction in retinal microvascular density and higher PSMD (p < 0.001). Superficial retinal vessels and PSMD partially mediated APOE ε4's association with cognitive impairment.

DISCUSSION: APOE ε4 homozygosity exacerbates retinal and cerebral microvascular dysfunction, which partially mediates cognitive impairment in AD.

HIGHLIGHTS: Apolipoprotein E (APOE) ε4 homozygosity is associated with the most severe reductions in retinal microvascular densities and elevated cerebral small vessel disease (peak width of skeletonized mean diffusivity [PSMD]) in Alzheimer's disease (AD). Vascular dysfunction (retinal and cerebral) correlates with lower Aβ42, higher p-tau217/Aβ42, and worse cognitive scores (Mini-Mental State Examination [MMSE], Montreal Cognitive Assessment [MoCA]). Mediation analysis reveals that retinal (superficial vascular complex [SVC]) and cerebral (PSMD) microvascular changes partially explain the link between APOE ε4 and cognitive decline. Findings highlight vascular pathways as potential therapeutic targets in APOE ε4 carriers to mitigate cognitive impairment.},
}

Humans
Male
*Alzheimer Disease/genetics/complications
Female
*Apolipoprotein E4/genetics
*Cognitive Dysfunction/genetics
Homozygote
Aged
*Retinal Vessels/diagnostic imaging/pathology
*Microvessels/diagnostic imaging
Tomography, Optical Coherence
Magnetic Resonance Imaging
Biomarkers/blood
Middle Aged

@article {pmid41395411,
year = {2025},
author = {Zhao, F and Yang, H and Gao, Z and Liu, H and Wu, P and Li, B and Yu, H and Shao, J},
title = {Retraction notice to "Novel fabrication of Cu(II)-incorporated chiral d-penicillamine-chitosan nanocomposites enantio-selectively inhibit the induced amyloid β aggregation for Alzheimer's disease therapy" [Heliyon 10 (2024) e23563].},
journal = {Heliyon},
volume = {11},
number = {16},
pages = {e44134},
doi = {10.1016/j.heliyon.2025.e44134},
pmid = {41395411},
issn = {2405-8440},
abstract = {[This retracts the article DOI: 10.1016/j.heliyon.2023.e23563.].},
}

@article {pmid41394741,
year = {2025},
author = {Tung, TH and Babu, S and Tang, X and Sciutto, A and Romer, M and Racha, P and Fisler, V and Saha, A and Saito, T and Saido, TC and Grinspan, JB and Mathys, H and Kozai, TDY and Cambi, F},
title = {Fus depleted oligodendrocytes reduce neuronal damage and attenuate AD progression in the App [NL-G-F] mouse.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.24.689041},
pmid = {41394741},
issn = {2692-8205},
abstract = {Oligodendrocytes (OL) and myelin abnormalities have emerged as important contributors to the pathogenesis of Alzheimer's Disease (AD). OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. To gain insight on how OL and myelin may improve neuronal deficits associated with AD, we have generated a novel mouse model (AD/cKO) by crossing the App [NL-G-F] mouse which carries three human AD mutations in the mouse App gene with the Fus [OL] cKO, which has thicker myelin associated with greater cholesterol biosynthesis. The spatial working memory deficits manifested by the aged AD mouse were fully rescued by the Fus [OL] cKO. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the plaque niches and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Single cell transcriptomics of AD/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in protecting neurons and affecting microglia state in AD pathology.},
}

@article {pmid41394728,
year = {2025},
author = {Wang, Z and Veerareddy, V and Eberts, PM and Azarin, SM and Kandimalla, KK},
title = {Endothelial-pericyte interactions activate insulin signaling and its implications for blood-brain barrier dysfunction in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.24.690270},
pmid = {41394728},
issn = {2692-8205},
abstract = {PURPOSE: This study aimed to investigate how pericyte degeneration contributes to BBB disruption in Alzheimer's disease, focusing on the roles of insulin signaling and the imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs).

METHODS: We employed an in vitro BBB model by co-culturing brain-specific microvascular endothelial-like cells (iBMECs) differentiated from human induced pluripotent stem cells (hiPSCs) and primary human brain vasculature pericytes (hBVPs). Protein expression under solo- versus co-culture conditions was assessed by western blot. MMP enzymatic activity in the culture media was measured by fluorometric assay. Exosomes were isolated from conditioned media and brain derived neurotrophic growth factor (BDNF) concentrations were determined using ELISA assays.

RESULTS: TIMP1 and collagen-IV expression was significantly increased in co-cultured BBB endothelial cells and pericytes compared to solo-cultures. However, a greater effect was observed in cells co-cultured for 2 days than 7 days. Elevated TIMP1 in co-culture media significantly inhibited MMP activity. The AKT and ERK pathways were activated in both cell types after 7 days of co-culture, and the ERK signaling mediated TIMP1 upregulation in endothelial cells. BDNF was significantly enriched in exosomes isolated from co-culture media on the abluminal side compared to the solo-cultures. Endothelial cells also protected pericytes from accumulation of toxic amyloid-beta 42 by downregulating low density lipoprotein receptor-related protein 1 (LRP1) expression.

CONCLUSIONS: These findings provide mechanistic insights into BBB disruption due to pericyte degeneration and highlight the important role of BBB insulin resistance in causing cerebrovascular dysfunction in AD.},
}

@article {pmid41394696,
year = {2025},
author = {Houmam, S and Siodlak, D and Seshadri, M and Hallum, GB and Pezant, NP and Stanford, DR and Salinas-Salinas, C and Thomason, YM and Montgomery, CG and Rice, HC},
title = {Oligodendrocytes show enriched expression of amyloid precursor protein and GABA B receptor isoform 1a.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.25.690528},
pmid = {41394696},
issn = {2692-8205},
abstract = {Amyloid precursor protein (APP) is a type I transmembrane protein that undergoes proteolytic processing to generate amyloid-β, the main component of amyloid plaques found in brains with Alzheimer's disease. The proteolytic processing of APP also generates soluble APP alpha (sAPPα) which can modulate synaptic transmission and neurite outgrowth through the γ-aminobutyric acid type B receptor (GABA B R). Whether GABA B R mediates functions of sAPPα in other neural cell types such as glia remains unknown. sAPPα binds the R1a subunit isoform of GABA B R1 which contains two sushi domains absent in R1b. It is unclear whether both GABA B R1 isoforms are expressed equally across brain cell types. We determined relative RNA levels of the GABA B R1a and 1b isoforms in oligodendrocytes, microglia, endothelial cells, astrocytes, and neurons in adult mice using two approaches. We developed a GABA B R1 isoform-specific RNAseq analysis workflow to probe a publicly available dataset. We also isolated five cell types from a single mouse brain and performed RT-qPCR. We show that the GABA B R1a and 1b isoforms are differentially expressed among cell types. GABA B R1a expression was highest in oligodendrocytes and GABA B R1b expression was highest in astrocytes, suggesting that sAPPα-mediated GABA B R signaling may be most prominent in oligodendrocytes. We also confirmed that APP is expressed in all five cell types and showed that APP RNA levels are highest in oligodendrocytes. Together, our findings uncover cell type-specific expression of GABA B R isoforms and highlight oligodendrocytes as a principal cell type for GABA B R1a-mediated APP signaling, providing a foundation for future mechanistic studies.},
}

@article {pmid41394684,
year = {2025},
author = {Montesinos, J and Yun, TD and Salomón-Cruz, ID and Agudelo-Castrillón, SC and Uceda, M and Ferre, AC and Anton-Barros, C and Gomez-Lopez, N and Agrawal, RR and Larrea, D and Velasco, KR and Fernàndez-Bernal, A and Benitez, E and Zhu, X and Schon, EA and Lopera, F and Cardona-Gomez, GP and Area-Gomez, E},
title = {Upregulation of MAM by C99 disrupts ACSL4 activity and phospholipid homeostasis in Alzheimer's disease models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.25.690197},
pmid = {41394684},
issn = {2692-8205},
abstract = {The structure and function of cellular and intracellular membranes are critically governed by the fatty acid (FA) composition of phospholipids (PLs), which is dynamically regulated by a network of enzymes that fine-tune lipid species according to cellular demands. In this study, we identify a mechanism through which the formation of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) modulates the activity of the acyl-CoA synthetase long-chain family member 4 (ACSL4), an enzyme that channels polyunsaturated fatty acids (PUFAs) into phosphatidylcholine (PC) via the Lands cycle. Through integrated biochemical, proteomic, and lipidomic analyses in both cellular and animal models, we demonstrate that MAM formation enhances ACSL4 activity, promoting arachidonic acid (AA) activation and its preferential incorporation into PC in concert with the MAM-localized lysophospholipid acyltransferase 4 (LPCAT4). Our findings further uncover an unexpected link between this pathway and the pathogenesis of Alzheimer's disease (AD). We show that elevated levels of C99-the β-secretase cleavage product of amyloid precursor protein (APP)-induce MAM remodeling through cholesterol clustering, which in turn activates ACSL4 and alters PC composition. This effect is mirrored in AD models as well as in fibroblasts, neurons, and immune cells derived from both familial and sporadic AD patients, all of which exhibit chronically increased C99 levels, heightened ACSL4 activity, and enrichment of PUFA-containing PC species, leading to lipid imbalance and membrane dysfunction. Together, these results establish MAMs as dynamic lipid-regulatory hubs that coordinate ACSL4-dependent membrane remodeling and highlight the contribution of MAM dysregulation to lipid abnormalities observed in AD.},
}

@article {pmid41394664,
year = {2025},
author = {Philippe, TJ and Avey, DR and Kearns, NA and Vyas, H and Tissera, S and Xu, J and Ng, B and Saunders, DM and Lagrimas, AK and Duong, D and Seyfried, NT and Bennett, DA and Wang, Y},
title = {A Multi-omic Atlas of Human Choroid Plexus in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.23.690014},
pmid = {41394664},
issn = {2692-8205},
abstract = {The choroid plexus (CP) regulates barrier integrity, cerebrospinal-fluid (CSF) dynamics, and immune surveillance, yet its role in Alzheimer's disease (AD) remains poorly defined. We performed snRNA-seq on CP samples from 69 ROSMAP participants spanning normal cognition, mild cognitive impairment, and AD dementia, and integrated these data with spatial transcriptomics, snATAC-seq, and proteomics from CP tissue and CSF. We identified 17 CP cell states and uncovered widespread disease-associated transitions that converged into three major phenotypic axes. Along the inflammatory axis, epithelial cells and border-associated macrophages (BAMs) showed progressive immune activation, with BAMs shifting from inflammatory to stress-dominant states. In the barrier axis, epithelial cells, fibroblasts, and endothelial cells exhibited reduced junction-related gene expression and broad alterations in transport pathways. Epithelial cells also showed late-stage cilia loss and CSF-regulatory pathway impairment, indicating a breakdown in epithelial polarity and CSF sensing, consistent with abnormal CSF proteomic signatures. Along the remodeling axis, fibroblasts showed bidirectional ECM alterations, while epithelial and stromal cells demonstrated aberrant cell-matrix adhesion pathways. Spatial neighborhood analysis revealed a multicellular signaling hub, with epithelial-rich niches showing the strongest dysregulation in AD. Together, these findings define a unified model of CP dysfunction in AD and position the CP as an active, multicellular contributor to AD pathophysiology.},
}

@article {pmid41394641,
year = {2025},
author = {Blumenfeld, J and Li, Y and Kim, MJ and Yip, O and Yao, L and De Leon, S and Fulthorpe, R and Shostak, D and Platow, Z and Suan, K and Hao, Y and Koutsodendris, N and Ellis, C and Nguyen, J and Huang, Y},
title = {Neuronal APOE4 alone is sufficient to drive tau pathology, neurodegeneration, and neuroinflammation in an Alzheimer's disease mouse model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.25.690488},
pmid = {41394641},
issn = {2692-8205},
abstract = {Apolipoprotein E4 (APOE4), the strongest genetic risk factor for late-onset Alzheimer's disease (AD), exacerbates tau tangles, amyloid plaques, neurodegeneration, and neuroinflammation-the pathological hallmarks of AD. While astrocytes are the primary producers of APOE in the CNS, neurons increase APOE expression under stress and aging. Prior work established that neuronal APOE4 is essential for AD pathogenesis, but whether it is sufficient to drive disease remained unknown. We generated a PS19 tauopathy mouse model selectively expressing APOE4 in neurons. Neuronal APOE4 alone proved sufficient to promote pathological tau accumulation and propagation, neurodegeneration, and neuroinflammation to levels comparable to a tauopathy model with human APOE4 knocked-in globally. Single-nucleus RNA sequencing further revealed similar transcriptomic changes in neurons and glia of both models. Together, these findings demonstrate that neuronal APOE4 alone can initiate and propagate AD pathologies, underscoring its pivotal role in disease pathogenesis and its potential as a therapeutic target.},
}

@article {pmid41394599,
year = {2025},
author = {Deshpande, A and Bei, Z and Ma, J and Krieger, S},
title = {MIMYR: Generative modeling of missing tissue in spatial transcriptomics.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.24.690239},
pmid = {41394599},
issn = {2692-8205},
abstract = {Spatial transcriptomics enables the study of how gene expression is organized across tissues, revealing how cells interact within their native microenvironments in health and disease. However, tissue damage during sectioning and the allocation of intermediate slices to other assays often result in regions or entire planes missing from the data, limiting downstream analysis. Here, we introduce MIMYR, a generative framework for reconstructing realistic spatial transcriptomics data in unmeasured tissue regions. MIMYR addresses this challenge through three coupled components: predicting cell locations via guided diffusion, assigning cell types through supervised classification, and generating gene expression profiles with a transformer conditioned on spatial and cellular context. MIMYR accurately reconstructs held-out regions in mouse brain data and generalizes across experimental conditions, including variations in gene panels and slicing orientations. After finetuning on limited Alzheimer's disease data, MIMYR captures disease-associated transcriptional changes in unmeasured brain regions. By enabling high-fidelity spatial imputation from limited training data, MIMYR extends the utility of spatial transcriptomics, allowing researchers to recover unmeasured tissue states and deepen investigations into tissue spatial organization and dynamics.},
}

@article {pmid41394596,
year = {2025},
author = {Liu, A and De Jager, PL and Bennett, D and , and Wang, G and Denault, WRP},
title = {mfSuSiE enables multi-cell-type fine-mapping and multi-omic integration of chromatin accessibility QTLs in aging brain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.25.690439},
pmid = {41394596},
issn = {2692-8205},
abstract = {Molecular quantitative trait locus (QTL) studies increasingly profile chromatin accessibility, histone modifications, DNA methylation, RNA modifications such as N6-methyladenosine (m6A), and transcription across multiple cell types using high-throughput sequencing, generating dense base-pairresolved measurements. The conventional approach of testing each variant against each molecular feature independently suffers from severe multiple testing burden and ignores linkage disequilibrium and spatial correlation. Existing fine-mapping methods only partially address these challenges and are suboptimal for analyzing such datasets: multivariate approaches such as mvSuSiE jointly analyze multiple molecular contexts but are designed for a single trait value per context and cannot accommodate thousands of base-resolution measurements per context, while functional approaches such as fSuSiE model spatial structure across thousands of measurements but analyze each context separately. Here, we introduce mfSuSiE , which integrates multivariate analysis with wavelet-based functional regression to jointly fine-map thousands of base-resolution traits across multiple cell types. In simulations, mfSuSiE identified causal variants and affected molecular features more accurately than fSuSiE , while mvSuSiE cannot be applied to this type of data. Applied to single-nucleus chromatin accessibility data from six brain cell types from postmortem aging human brains, mfSuSiE substantially increased discovery and resolution, with substantial power gains for cell types with limited samples. Multi-cell-type analysis revealed extensive sharing of regulatory effects on chromatin accessibility (caQTL). Importantly, mfSuSiE produces Bayesian inference compatible with the SuSiE framework, enabling systematic multi-omic integration. Applied to Alzheimer's disease loci, we integrated caQTL with expression QTLs, epigenomic QTLs, and GWAS, observing regulatory patterns suggesting complex mechanisms at loci including EARS2, CHRNE, SCIMP , and RABEP1 .},
}

@article {pmid41394565,
year = {2025},
author = {Cardona-Gómez, GP and Salomón-Cruz, ID and Lozano-Trujillo, LA and Galvis-Garrido, ND and Agudelo-Castrillon, SC and Barbosa-Carvajal, JP and Ríos, MH and Trujillo-Chacón, LM and Henao, E and Fernandez, GJ and Osorio, E and Quiroz, YT and Schon, E and Lopera, F and Villegas, A and Aguirre-Acevedo, DC and Arias-Londoño, JD and Aguillón, D and Area-Gómez, E},
title = {Serum Lipidome as an Early Peripheral Indicator in Familial Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.25.690392},
pmid = {41394565},
issn = {2692-8205},
abstract = {Protein biomarkers in biofluids are highly sensitive indicators of prodromal cognitive impairment yet remain limited for primary prevention. Lipids, essential to brain structure and function, offer untapped prognostic value. Here, we identify a lipidomic signature in serum from asymptomatic PSEN1-E280A mutation carriers aged 6-40 years, that differentiate carriers from non-carriers with an AUC 80-90%. Similarly, to symptomatic carriers (≥41 years; 93%) and sporadic AD cases (85%), using high-resolution mass spectrometry. Latent profile analysis revealed lipid-based signatures of dementia risk and resilience, shaped by genotype, sex, and APOE isoform, and supported by SIMOA protein biomarkers. Age-dependent dysregulation in sphingolipid and glycolipid metabolism was validated by enzymatic activity (TLC), glial phenotyping (flow cytometry), and gene expression (snRNAseq) in postmortem brain. Ganglioside clearance deficits emerged by age 6-12, followed by proinflammatory shifts from age 13 and p-tau217 elevation by age 20, with greater burden in females and APOE4 carriers. APOE3Ch individuals showed differential salvage pathways of ceramides and gangliosides. These findings position early lipid pathway dysregulation as a biological contributor to Alzheimer's pathogenesis and a potential therapeutic target for primary prevention.},
}

@article {pmid41394556,
year = {2025},
author = {Seto, M and Klinger, HM and Clifton, M and Janve, VA and Brown, JA and Birkenbihl, C and Coughlan, G and Townsend, DL and Wang, TC and Properzi, M and Hanseeuw, B and Chhatwal, J and Yang, HS and Rissman, RA and Aisen, P and Cuppels, M and Donohue, MC and Raman, R and Johnson, KA and Sperling, RA and Dumitrescu, L and Hohman, TJ and Buckley, RF},
title = {Blood-based Transcriptomics Reveal Sex- and Amyloid-Modulated Biology of Plasma pTau217 in Preclinical Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.21.689770},
pmid = {41394556},
issn = {2692-8205},
abstract = {Plasma pTau217, an emerging Alzheimer's disease (AD) biomarker, may reflect a synaptic response to β-amyloid (Aβ) plaques before cortical tangle formation, but the broader biological processes at play remain unclear. Using whole blood RNAseq, we sought to identify gene expression associated with plasma pTau217 and to determine whether APOE ε4, sex, and neocortical Aβ-PET burden further amplify these associations in 724 participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Studies. 1,540 genes were moderated by Aβ-PET, and 772 genes were moderated by both Aβ-PET and sex. Our findings include genes previously associated with AD (e.g., TREML2) and implicate biological functions such as chromatin remodeling, lipid signaling, and RNA processing that interact with Aβ-PET and sex to impact plasma pTau217. Our results underscore the complexity of molecular mechanisms that can be linked to plasma pTau217, particularly in the context of elevated Aβ-PET.},
}

@article {pmid41394343,
year = {2025},
author = {Schweitzer, N and Cover, C and Aizenstein, H and Wu, M and Vazquez, A and Iordanova, B},
title = {Near-lifespan mesoscopic optical imaging of cerebrovascular function reveals age and sex differences in preclinical Alzheimer's disease model.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf472},
pmid = {41394343},
issn = {2632-1297},
abstract = {Growing evidence suggests vascular dysfunction plays a critical role in the early stages of Alzheimer's disease, commonly associated with amyloid-β deposition. This vascular dysfunction is particularly relevant in the context of cerebral amyloid angiopathy, where amyloid-β accumulates within cerebral vessel walls. Notably, sex differences impact progression of both Alzheimer's disease and cerebrovascular dysfunction, with post-menopausal females displaying increased small vessel disease burden and diminished carbon dioxide reactivity compared to older males and pre-menopausal females. Moreover, the cerebrovasculature is a target of sex hormones where they exert influence in numerous vascular functions and pathologies across lifespan. Combined, cerebrovascular dysfunction along with amyloid-β deposition may have differential effects on sex. Despite observational studies in humans, preclinical mechanistic and functional research on sex-specific vascular differences in Alzheimer's disease has been limited. In this near-lifespan longitudinal study, we investigated age and sex-specific neurovascular coupling and carbon dioxide reactivity in a transgenic mouse model expressing chimeric mouse/human amyloid precursor and mutant human presenilin 1 (APP/PS1) and control mice using widefield optical imaging. Neurovascular coupling was probed via whisker stimulation and then vascular reactivity was measured using hypercapnic challenge. During whisker stimulation, neuronal activity was measured through GCaMP6f fluorescence change, while vascular response was quantified via haemoglobin-based optical intrinsic signal. Carbon dioxide reactivity was evaluated by measuring dilatory changes of vessel diameters across the cerebrovascular tree. In vivo two-photon microscopy was used to longitudinally measure cerebral amyloid angiopathy vessel coverage and amyloid-β tissue plaque volume. We observed that APP/PS1 mice exhibited attenuated neurovascular coupling during whisker stimulation and this response worsened through lifespan compared to controls. Compared to controls, APP/PS1 mice exhibited decreased carbon dioxide reactivity with age. No sex differences between control mice were observed in the neurovascular response to whisker, whereas during hypercapnia, control females had higher carbon dioxide reactivity than control males. While both APP/PS1 males and females showed reduced dilatory responses with age, APP/PS1 females exhibited this decrease in small arteries, whereas APP/PS1 males experienced decreased dilation in larger arteries. Diminished vascular reactivity in APP/PS1 mice was associated with increased cerebral amyloid angiopathy and amyloid-plaque burden. This study highlights sex-specific pathophysiology's of vascular dysfunction across the lifespan. Our findings underscore needs to incorporate sex differences in preclinical Alzheimer's disease research, given the rising importance of vascular contributions to cognitive impairment and dementia. Our findings have important implications for developing targeted, age and sex-specific biomarkers and therapeutics for cerebrovascular health in Alzheimer's disease.},
}

@article {pmid41394158,
year = {2025},
author = {Li, Y and Zhang, Y and Liu, M and Dawuti, T and Chen, X and Xiao, H},
title = {Polyphenol-rich Morus nigra L. extract mitigates neuroinflammation and cognitive impairment through gut-brain axis modulation in an Alzheimer's disease rat model.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1695768},
pmid = {41394158},
issn = {1663-9812},
abstract = {BACKGROUND: The gut-brain axis (GBA) has emerged as a critical pathway in the pathogenesis of Alzheimer's disease (AD), offering a potential target for dietary interventions. This study aimed to explore the neuroprotective effects of a polyphenol-enriched extract from Morus nigra L. fruits (MMF) in an AD rat model, focusing on gut-brain communication.

METHODS: AD-like pathology was induced in rats using a combination of D-galactose and aluminum chloride, followed by a 10-week MMF treatment. Cognitive performance was evaluated using the Morris water maze, and brain Aβ1-42 accumulation and neuroinflammation (Iba1, GFAP) were assessed. Multi-omics approaches, including 16S rDNA sequencing and untargeted colonic metabolomics, were applied.

RESULTS: MMF treatment significantly enhanced spatial memory, reduced hippocampal Aβ burden, and attenuated glial activation. Furthermore, MMF restored gut microbial diversity and increased the abundance of short-chain fatty acid-producing Firmicutes taxa, which were inversely correlated with inflammation. Metabolomics analysis revealed that MMF modulated bile acid and lipid metabolic pathways, with β-muricholic acid, DHA, and ergosterol identified as key effectors.

CONCLUSION: MMF alleviates AD pathology through modulation of the gut microbiota and metabolic reprogramming, suggesting a promising microbiota-targeted strategy for AD prevention.},
}

@article {pmid41394066,
year = {2025},
author = {Rubiño-Díaz, JÁ and Zapata-Moreno, M},
title = {Highly sensitive early-onset Alzheimer's disease: a case report.},
journal = {Frontiers in psychology},
volume = {16},
number = {},
pages = {1688924},
pmid = {41394066},
issn = {1664-1078},
abstract = {BACKGROUND: Early-onset Alzheimer's disease (EOAD) is an atypical syndrome that can be confused with other neurodegenerative diseases. This disease presents before the age of 65, with symptoms that generally affect executive functions, praxis, and visuoperceptual abilities, as opposed to episodic memory. Highly sensitive individuals present the temperament trait of sensory processing sensitivity, which is characterized by a differential susceptibility compared to other individuals. Neuropsychological evaluation should involve a holistic and integrative person-centered care approach for optimal treatment and disease progression.

CASE SUMMARY: A highly sensitive 54-year-old individual was diagnosed with EOAD at age 47 in 2017. Neuropsychological follow-up was conducted for 6 years. Initial neuropsychological testing revealed a cognitive pattern with impairments in executive functions, attention, and visual perception, the advancement of which led to a progressive deterioration in daily, occupational, and social functioning. During this period, he received psychotherapy from a psychologist specializing in neuropsychology and high sensitivity, using a holistic and integrative approach. Initially, sessions were held twice a week throughout the first year of consultation and, subsequently, continued at the patient's home and in his usual context, using a completely ecological perspective and consisting of person-centered care. In 2022, the patient, aged 59, was admitted to a nursing home. This situation, outside his usual environment, without autobiographical references and his own life story, led to accelerated deterioration, with the patient ultimately dying at age 60, in 2023.

CONCLUSION: The patient with highly sensitive EOAD was followed for 6 years by a psychologist specializing in neuropsychology and high sensitivity. Neuropsychological intervention was maintained with a holistic and integrative person-centered approach using the unmet needs model to address cognitive, psychological, and functional levels. Follow-up with this approach could be key to slowing the disease and ensuring patient satisfaction throughout the entire progression of the illness. Greater visibility into unusual cases like this will enable psychology professionals to be vigilant for timely differential and diagnostic testing, which will significantly impact the treatment and progression of the illness, ultimately influencing quality of life and well-being through an optimal neuropsychological approach.},
}

@article {pmid41393998,
year = {2025},
author = {Wang, Y and Zhou, J and Zhou, Q and Wang, H},
title = {New progress on the role and mechanism of tau protein in Alzheimer's disease and depression.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1551273},
pmid = {41393998},
issn = {1664-2295},
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by two major pathological hallmarks: (1) the formation of extracellular β-amyloid (Aβ) plaques; (2) the accumulation of intracellular neurofibrillary tangles (NFTs) composed of phosphorylated tau. The number of NFTs is positively correlated with the severity of AD. However, there are still no effective strategies to treat or slow AD progression. Despite recent approvals of anti-Aβ therapies, their limited clinical benefit has shifted increasing attention toward tau pathology as a parallel driver of AD progression. In recent years, the importance of tau in the pathogenesis of Alzheimer's disease increasingly recognized. The transmission of pathogenic tau proteins in the brain, known as prion-like seeding, is considered a key driving factor for AD. Post-translational modifications of tau-such as hyperphosphorylation, acetylation, glycosylation, ubiquitination, and truncation-promote the onset and progression of Alzheimer's disease. Consequently, tau-targeting therapies have become a major focus in anti-AD research, though most remain at the pre-clinical stage. Furthermore, depression is highly prevalent in AD patients, representing both a potential risk factor and a consequence of the disease. Depression is a risk factor of AD, it is also a consequence of AD. Researchers have found that tau is closely related to depression, not Aβ. This review will focus on tau, tau and AD, post-translational modification of tau, tau targeting strategies, and the role of tau in depression. Since tau pathology not only disrupts synaptic and neuronal networks but also affects limbic and cortical circuits involved in emotion regulation, its dysfunction may underlie depressive symptoms frequently observed in AD. Therefore, understanding tau's neural impact provides a mechanistic bridge between AD pathology and depression.},
}

@article {pmid41393958,
year = {2025},
author = {Nacer, M and Kalla, A and Tamfu, AN and Boudiba, S and Hanini, K and Hioun, S and Messaoudi, M and Atoki, AV and Kucukaydin, S and Latifa, K and Ceylan, O and Boudiba, L},
title = {Phenolic profile of different solvent extracts of Reseda alba L. and evaluation of anti-quorum sensing, antioxidant, and enzyme inhibition activities.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1699534},
pmid = {41393958},
issn = {2296-861X},
abstract = {BACKGROUND: Reseda alba (white mignonette) is a wild, edible, and medicinal plant native to the Mediterranean region, with limited studies on its chemical composition and bioactivities.

METHODS: The phenolic profile and bioassays of antioxidant, anti-swarming, quorum sensing (QS), and enzyme inhibitory activities of different solvent extracts of R. alba are investigated using high-performance liquid chromatography with diode-array detection (HPLC-DAD).

RESULTS: Rosmarinic acid was identified as the predominant phenolic compound in the ethyl acetate extract (197.5 ± 0.25 μg/g) and n-butanol extract (205.4 ± 0.47 μg/g). Minimal inhibitory concentrations (MICs) ranged from 0.3125 to 2.5 mg/mL against Chromobacterium violaceum and Pseudomonas aeruginosa PA01. These extracts demonstrated significant inhibition of quorum sensing and swarming motility against C. violaceum and P. aeruginosa PA01 at MIC and sub-MIC. Extracts exhibited inhibition of enzymes, especially cholinesterases implicated in neurodegenerative diseases. The extracts demonstrated antioxidant activity, as determined through six assays, with the dichloromethane extract (DCME) exhibiting higher antioxidant activity compared to the standards α-tocopherol and ascorbic acid in the ferric-reducing antioxidant power (FRAP) assay.

CONCLUSION: The results demonstrate that R. alba extracts (RAEs) possess significant inhibitory effects on enzymes implicated in neurodegenerative disorders, such as Alzheimer's disease, particularly through butyrylcholinesterase inhibition. Additionally, the extracts show promising anti-quorum sensing and anti-swarming activities, which could reduce microbial virulence and biofilm formation, suggesting potential as alternative antimicrobial agents. The moderate antioxidant activity further supports its therapeutic potential. Overall, R. alba could be developed as a natural source for managing enzyme-related diseases and controlling bacterial infections by targeting microbial communication mechanisms.},
}

@article {pmid41393957,
year = {2025},
author = {Wei, L and Li, Z and Shi, M and Song, W and Teng, Z and Zhang, C},
title = {Neuroprotective properties of extra virgin olive oil polyphenols in Alzheimer's disease: a multi-target mechanistic review.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1736633},
pmid = {41393957},
issn = {2296-861X},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, hyperphosphorylated tau protein, neuroinflammation, and mitochondrial dysfunction. The limited efficacy of single-target pharmacological strategies has spurred interest in multi-target therapeutic approaches. Extra virgin olive oil (EVOO), rich in diverse polyphenolic compounds, has emerged as a promising source of such multi-target neuroprotective agents. This review systematically elucidates the mechanisms of key EVOO polyphenols-hydroxytyrosol, oleuropein, tyrosol, verbascoside, oleocanthal, and ligustroside-in combating AD pathology. We highlight the growing body of evidence demonstrating that these polyphenols can synergistically inhibit the aggregation of Aβ and tau, mitigate neuroinflammation, restore mitochondrial function, reduce oxidative stress, and promote neurogenesis. Preclinical studies in cellular and animal models of AD consistently show that EVOO polyphenols can ameliorate cognitive deficits and pathological hallmarks. Future research should focus on validating these benefits in animals and clinical trials and developing optimized formulations for clinical application. In conclusion, the bioactive polyphenols in EVOO present a compelling multi-targeted therapeutic strategy with significant potential to delay the progression of AD by concurrently modulating multiple key pathological pathways.},
}

@article {pmid41393939,
year = {2025},
author = {Li, L and Wang, K},
title = {Integrative effects of saffron and physical activity on endurance performance, quality of life, cognitive, emotional, and metabolic outcomes in age-related and neurodegenerative diseases.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1698135},
pmid = {41393939},
issn = {2296-861X},
abstract = {Age-related diseases, including cardiovascular disorders, type 2 diabetes, neurodegenerative conditions such as Alzheimer's and Parkinson's disease, and age-related eye diseases, represent leading causes of disability and mortality worldwide. Growing evidence highlights the therapeutic promise of non-pharmacological interventions, notably saffron (Crocus sativus L.) and structured exercise, both of which exert pleiotropic effects through antioxidant, anti-inflammatory, and neuroprotective pathways. In this review, we summarize current experimental and clinical data on saffron's bioactive compounds, crocin, crocetin, and safranal, and their capacity to modulate lipid metabolism, insulin sensitivity, mitochondrial function, and protein aggregation. Parallel findings from exercise research demonstrate improvements in cardiovascular function, glycemic control, neuroplasticity, and ocular health. Importantly, emerging studies reveal synergistic benefits when saffron supplementation is combined with physical activity, resulting in amplified improvements in vascular remodeling, glycemic regulation, neurotrophic signaling, and behavioral outcomes. These complementary interventions target shared molecular pathways, including PI3K/Akt/mTOR signaling, SIRT1-PGC-1α activation, Nrf2-mediated antioxidant defense, and modulation of inflammatory cytokines. Taken together, saffron and exercise represent safe, accessible, and multi-target strategies that may delay or attenuate the progression of aging-related diseases. Future large-scale, long-term clinical trials are warranted to establish optimal protocols and to integrate these interventions into preventive and therapeutic frameworks for healthy aging.},
}

@article {pmid41393862,
year = {2025},
author = {Stein, RG and Falck, RS and Tai, D and Crockett, RA and Davis, JC and Hsiung, GYR and Eng, JJ and Middleton, LE and Hall, PA and Liu-Ambrose, T},
title = {The interaction effect of physical activity and sleep on cognitive function in stroke.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70185},
pmid = {41393862},
issn = {2352-8737},
abstract = {INTRODUCTION: Having a stroke increases risk for dementia two-fold. Poor sleep quality and quantity are common after a stroke and are associated with cognitive impairment. Physical activity benefits cognitive function. Whether there is an interaction effect of physical activity and sleep on cognitive function among persons living with chronic stroke is unknown.

METHODS: A cross-sectional study used baseline data acquired from 97 community-dwelling adults aged ≥55 years, living with chronic stroke (71±9 years; n = 38, female), and enrolled in a 6-month randomized controlled trial. We measured physical activity (i.e., moderate to vigorous physical activity [MVPA] and light physical activity [PA]) and sleep quality and quantity (i.e., efficiency, latency, duration) using wrist-worn accelerometry. Global cognitive function was measured with the 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-13). We assessed whether the interaction of physical activity (MVPA and light PA) with sleep quality and quantity (interaction term: physical activity * sleep) was associated with ADAS-Cog-13 score: (1) in the full sample and (2) among males and females separately (i.e., sex-stratified). Significant moderations were plotted as continuous simple slopes.

RESULTS: In the full sample, there was a significant interaction effect between MVPA and sleep duration on the ADAS-COG-13 score (ß = 1.636 ± 0.787; p = 0.041). Specifically, among individuals with shorter sleep duration (i.e., one standard deviation below mean sleep duration), those with greater MVPA had better ADAS-Cog-13 performance. In the sex-stratified analysis, the interaction effect of MVPA and sleep duration on cognitive function was significant in males (ß = 3.417 ± 1.374; p = 0.016) but not females.

DISCUSSION: Moderate to vigerous physical activity may mitigate the negative impact of shorter sleep on cognitive function among persons living with stroke, particularly males.

HIGHLIGHTS: Physical activity and sleep are associated with cognitive function following stroke.Physical activity may ameliorate the negative effects of poor sleep on cognitive function.Females suffer greater health consequences of sleep dysregulation than males.Physical activity moderates the association of sleep duration and cognitive function.Physical activity may promote cognitive function in males with short sleep duration.},
}

@article {pmid41393810,
year = {2025},
author = {Terao, CM and Erani, F and Weigand, AJ and Gross, AL and Edmonds, EC and Bangen, KJ and An, Y and Walker, KA and Resnick, SM and Thomas, KR},
title = {Data-driven neuropsychological phenotypes in the Baltimore Longitudinal Study of Aging.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70220},
pmid = {41393810},
issn = {2352-8729},
abstract = {INTRODUCTION: This study aimed to identify phenotypes of subtle variation in multidomain cognitive performance and examine their longitudinal associations with Alzheimer's disease and related dementias (AD/ADRD) biomarkers and cognitive outcomes.

METHODS: Among 1192 cognitively unimpaired (CU) older adults from the Baltimore Longitudinal Study of Aging, latent profile analysis (LPA) identified phenotypes based on baseline patterns of neuropsychological test performance. Mixed-effects and Cox models examined longitudinal differences in cognitive status and AD/ADRD biomarkers (phosphorylated tau-181 [pTau181], amyloid-beta 42/40 ratio [Aβ42/Aβ40], neurofilament light [NfL], and glial fibrillary acidic protein [GFAP]) across phenotypes.

RESULTS: LPA identified the following cognitive phenotypes: Overall Low Average, Dysexecutive (n = 112); Overall Average, Low Memory (n = 284); Overall Average, High Memory (n = 449); High Executive, Relatively Low Memory (n = 214); and Overall High Performing (n = 133). Phenotypes differed in longitudinal rates of cognitive decline and increases in NfL.

DISCUSSION: Subtle variations in neuropsychological performance among CU older adults have implications for long-term cognitive health and may help inform Alzheimer's disease and related dementias diagnosis and disease monitoring.

HIGHLIGHTS: Significant cognitive heterogeneity exists in CU older adults.LPA identified phenotypes based on cognitive performance.Personality and psychosocial characteristics differed by cognitive phenotype.Cognition over time and risk of cognitive impairment differed by cognitive phenotypes.The phenotype with greatest executive dysfunction had the fastest increase in NfL.},
}

@article {pmid41393654,
year = {2025},
author = {Arai, H},
title = {MRI-Based Medial Temporal Atrophy May Reflect Amyloid PET Positivity in Cognitively Normal Individuals: A Preliminary Study.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e96751},
pmid = {41393654},
issn = {2168-8184},
abstract = {This study investigated whether magnetic resonance imaging (MRI)-based medial temporal morphometry can predict amyloid positron emission tomography (PET) positivity in cognitively normal individuals. Sixteen consecutive participants (eight amyloid PET-positive and eight PET-negative) were retrospectively identified, all within the normal cognitive range (Mini-Mental State Examination 28-30). Amyloid PET was performed using florbetapir, with visual interpretation as the primary diagnostic criterion and Centiloid values as supportive measures. MRI-derived volumetric analysis was conducted using the voxel-based specific regional analysis system for Alzheimer's disease (AD) to quantify medial temporal atrophy. Although between-group differences in hippocampal indices did not reach statistical significance, the PET-positive group showed a trend toward greater atrophy, and centiloid values correlated positively with medial temporal indices. Receiver operating characteristic analysis indicated fair discrimination, highest for the volume-of-interest-to-gray-matter ratio (area under the curve = 0.83). These preliminary findings suggest that subtle hippocampal alterations on routine structural MRI may mirror early amyloid pathology even before cognitive impairment, supporting the potential of MRI-based morphometric assessment as an adjunctive biomarker for early AD detection.},
}

@article {pmid41393341,
year = {2025},
author = {Mekulu, K and Aqlan, F and Yang, H},
title = {Agentic artificial intelligence in cognitive screening: A translational roadmap for dementia care.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251407989},
pmid = {41393341},
issn = {2542-4823},
abstract = {Conventional dementia screening tools, whether paper tests or static artificial intelligence (AI) models, capture only a snapshot of cognition and need to be adminstered periodically. Yet decline is dynamic, shaped by environment, comorbidities, and life history. Current approaches rarely adapt, integrate feedback, or provide transparent reasoning that clinicians can trust. We propose agentic AI systems: modular agents built on large language models (LLMs) that collaborate, adapt, and mirror interdisciplinary care. The Cognitive Agent Lab exemplifies this framework, emphasizing functional aspects (inputs, outputs, workflows) and non-functional aspects (transparency, adaptivity, robustness, clinical alignment). Embedding reasoning and collaboration, agentic AI offers a roadmap toward more personalized and explainable cognitive health tools.},
}

@article {pmid41393340,
year = {2025},
author = {Porsteinsson, AP and Sabbagh, M and Tariot, PN and Church, KJ and San Martin, J and Ooi, KC and Daggett, S and Hale, MD and Holub, R and Moebius, HJ},
title = {Fosgonimeton in mild-to-moderate Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251405817},
pmid = {41393340},
issn = {2542-4823},
abstract = {BACKGROUND: Fosgonimeton, a small-molecule positive modulator of the neurotrophic hepatocyte growth factor (HGF) system, was studied in participants with Alzheimer's disease (AD).

OBJECTIVE: To assess the efficacy and safety of fosgonimeton in AD.

METHODS: LIFT-AD was a randomized, placebo-controlled, Phase 2/3 trial (NCT04488419; 23Jun2020), the primary analysis (N = 287) included participants with mild-to-moderate AD not receiving concomitant acetylcholinesterase inhibitors (AChEIs) randomized 1:1 to daily subcutaneous fosgonimeton 40 mg or placebo. The primary endpoint, the Global Statistical Test (GST) score, combined ADAS-Cog11 and ADCS-ADL23. Secondary endpoints included ADAS-Cog11, ADCS-ADL23, and NfL. Exploratory endpoints included plasma biomarkers of AD. Safety included all dosed participants, including those receiving and not receiving AChEIs or randomized to fosgonimeton 70 mg (N = 549).

RESULTS: The trial did not achieve its primary or secondary endpoints; between-group difference in the least-square mean change (SE) from baseline to Week 26 in the GST score was -0.08 (0.10) (p = 0.70), -0.70 (0.77) (p = 0.35) in ADAS-Cog11, and +0.67 (0.92) (p = 0.61) in ADCS-ADL23. This showed small differences favoring fosgonimeton versus placebo. Nominally significant changes in plasma biomarkers were observed in p-τ217 only. Fosgonimeton had an acceptable safety profile. Serious AEs were balanced between groups (4.2% fosgonimeton, 6.9% placebo). More participants in the fosgonimeton group (14.2%) discontinued due to AEs versus placebo (4.6%), mostly from injection site reactions.

CONCLUSIONS: Fosgonimeton did not significantly improve ADAS-Cog11 or ADCS-ADL23 versus placebo. However, the consistently observed non-significant improvements favoring fosgonimeton suggests potentially relevant biological activity with fosgonimeton and that positive modulation of HGF signaling may impact components of the pathophysiologic processes of neurodegenerative diseases.},
}

@article {pmid41393339,
year = {2025},
author = {Parhizi, B and Kolady, R and Vogel, MT and Singh, RK and Bekena, S and Chokkalingam, R and Zhu, Y and Babulal, GM},
title = {Driving into diagnosis: Leveraging high-resolution telematics and sensorimotor profiling to identify preclinical Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251407543},
pmid = {41393339},
issn = {2542-4823},
abstract = {BACKGROUND: Early detection of preclinical Alzheimer's disease (AD) could expand preventative care. Current biomarkers are costly, invasive, or lack generalizability. Driving and sensorimotor performance may reveal prodromal changes.

OBJECTIVE: We tested whether features from high-frequency driving trips detect preclinical AD and whether demographic, genetic, or sensorimotor data improve accuracy.

METHODS: Drivers aged ≥ 65 (n = 254) from Driving Real-World In-Vehicle Evaluation System (DRIVES) completed cerebrospinal fluid Aβ42/Aβ40 and amyloid Positron emission tomography (PET) to label amyloid positive (preclinical AD) or negative. A GPS datalogger recorded location (1 Hz) and accelerometer/gyroscope (20 Hz) data between June 2022 and January 2024. Eleven driving features (e.g., average speed, jerk, idle time, turns) were extracted per trip. Vision, hearing, olfaction, gait, and grip strength were assessed. TabNet models classified amyloid status using (1) driving only, (2) driving plus age and APOE ε4, and (3) driving plus age, APOE ε4, sex, and education. LightGBM models evaluated sensorimotor features. Performance was measured on a 20% held-out test set (AUC, accuracy, precision, recall, F1).

RESULTS: The top-performing model (driving, age, APOE ε4, sex, education) achieved an AUC of 0.84, accuracy of 0.85, and F1 score of 0.85. Key predictors were idle time, turns, and average jerk. Sensorimotor models performed modestly (AUCs of 0.66 [sensory alone] and 0.67 [sensory and sociodemographic]), with grip strength and word-in-noise scores as the top contributors.

CONCLUSIONS: A high-frequency trip's driving telemetry, combined with age and APOE ε4 status, discriminates preclinical AD, outperforming multisensory measures. Driving offers a scalable, digital biomarker to complement conventional testing. Monitoring may enable population-level screening for older adults at risk.},
}

@article {pmid41393338,
year = {2025},
author = {Georgescu, MF and Fischer, IC and Beydoun, MA and Vaccarino, V and Pietrzak, RH},
title = {Subjective cognitive decline among older U.S. military veterans: A 3-year, nationally representative, longitudinal study.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251407258},
pmid = {41393338},
issn = {2542-4823},
abstract = {Subjective cognitive decline (SCD) is an early risk marker for dementia. This study examined the 3-year incidence and predictors of SCD using the Medical Outcomes Study Cognitive Functioning Scale-Revised in a national sample of 1858 U.S. military veterans aged ≥60. Clinically significant SCD occurred in 5.4% of veterans, with an average decline of 1.73 standard deviations. Lower perceived resilience-specifically lower endorsement of "I bounce back after hardship" (35.1% relative variance explained) and "Coping with stress can make me stronger" (33.8%)-chronic pain (18.7%) and sleep difficulties (12.4%) emerged as the strongest predictors of SCD. Interventions targeting these risk factors may help mitigate SCD in veterans.},
}

@article {pmid41393111,
year = {2025},
author = {Costa, T and Liloia, D},
title = {Are current etiological theories of Alzheimer's disease falsifiable? An epistemological assessment.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1708234},
pmid = {41393111},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) research is plagued by a proliferation of competing etiological theories, often coexisting without undergoing systematic critical comparison. This article examines the epistemological limitations of the traditional falsifiability criterion, formulated by Karl Popper, and demonstrates how this principle fails to function effectively in the context of AD research. Biological complexity, the absence of unequivocal biomarkers, institutional resistance to paradigm shifts, and academic incentives to preserve dominant hypotheses all contribute to the erosion of falsifiability as an operational standard. In response, we propose an alternative framework based on Bayesian inference, understood as eliminative induction-a process in which scientific theories are modeled as probabilistic hypotheses with gradable plausibility, continuously updated considering new evidence. Within this framework, models are not regarded as literally "true," but as pragmatic tools whose predictive performance determines their scientific value. We advocate for a more comparative, predictive, and transparent scientific practice, wherein progress does not hinge on identifying a unique cause or on proving (or disproving) a hypothesis, but rather on enhancing our ability to rationally distinguish among competing models using quantitative criteria.},
}

@article {pmid41393110,
year = {2025},
author = {Kim, EH and Lee, YJ and Moon, YS and Kwon, OD and Kwon, DR},
title = {Evaluation of microcurrent as an adjunct to donepezil therapy in an Alzheimer's disease mouse model: a pilot study.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1689593},
pmid = {41393110},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder due to Aβ plaque accumulation, followed by loss of synapses and decline in cognitive abilities. Donepezil is currently one of the standard pharmacological treatments for Alzheimer's disease. Recently, microcurrent (MC) therapy has emerged as a non-pharmacological adjunct for AD management. Recently, microcurrent therapy emerged as a non-pharmacological alternative to treat AD.

OBJECTIVE: The study investigates the therapeutic outcomes of the MC as an adjuvant to donepezil in mitigating cognitive dysfunction in the transgenic mouse model (5XFAD).

METHODS: Transgenic 5xFAD mice were assigned to the control, donepezil, MC, or MC + donepezil (combination) groups. Behavioral performance was assessed using the novel object recognition (NOR) and radial arm maze (RAM) tests. Amyloid burden, glial activation, cytokine expression, apoptotic signaling, and intracellular pathways (PI3K-AKT, AMPK, and JAK2/3) were analyzed by immunohistochemistry and Western blotting.

RESULTS: Combined treatment with donepezil and microcurrent showed a trend toward improved cognitive performance and reduced pathology compared to donepezil alone, although these differences were not statistically significant. Aβ plaque burden in the cortex and the hippocampus was reduced by approximately 68%, thereby exceeding reductions observed with either treatment alone. Microglial and astroglial activation (Iba1, GFAP, and CD68) and pro-inflammatory cytokines (TNF-α and IL-1β) were reduced in both the donepezil and combination groups compared with untreated 5xFAD mice, with no significant difference between 5xD and 5xD + MC. Apoptotic markers (cleaved caspase-3 and cleaved PARP) were significantly reduced in both treatment groups compared with untreated controls but not significantly different between donepezil and combination therapy. At the molecular level, both donepezil and combination therapy activated PI3K-AKT and AMPK signaling and increased inhibitory phosphorylation of GSK-3β compared with untreated 5xFAD mice; no significant difference was observed between the two treatment groups.

CONCLUSION: Donepezil combined with microcurrent therapy showed comparable efficacy to donepezil alone, with numerical trends toward further improvement in cognitive function and pathology, but without statistically significant differences. Both treatments reduced Aβ burden, attenuated glial activation, and modulated survival-related pathways to a similar extent. These findings support a multi-target therapeutic strategy and highlight the translational potential of integrating microcurrent therapy with standard pharmacological treatment for AD.},
}

@article {pmid41393109,
year = {2025},
author = {Sacchi, L and Arcaro, M and Bocca, G and Schmid, L and Carandini, T and Ghezzi, L and Pintus, M and Pietroboni, AM and Fenoglio, C and Serpente, M and Conte, G and Triulzi, F and Lanzarotti, R and Dolci, C and Galimberti, D and Arighi, A},
title = {Association between Klotho levels in cerebrospinal fluid and choroid plexus enlargement in neurodegeneration.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1688996},
pmid = {41393109},
issn = {1663-4365},
abstract = {BACKGROUND: Klotho is a longevity-associated protein found in membrane-bound and secreted forms, with the latter detectable in blood and cerebrospinal fluid (CSF). Circulating Klotho mainly originates from the kidney, while the choroid plexus (CP) secretes it into the CSF. CP dysfunction is associated with reduced Klotho expression and neurodegeneration and may result in CP enlargement on magnetic resonance imaging (MRI). In this preliminary study, we investigated Klotho levels in neurodegenerative patients and their association with CP enlargement.

MATERIALS AND METHODS: We retrospectively analyzed 40 patients from the IRCCS Ca' Granda Ospedale Policlinico, Milan, including 32 neurodegenerative patients (Deg) and 8 cognitively normal controls (NonDeg). CSF and serum Klotho levels were measured using an ELISA kit. KL-VS and apolipoprotein E (APOE) genotyping were performed. CP volumes were segmented using ITK-SNAP and normalized to total intracranial volume (TIV), resulting in a measure known as the CP volume fraction (CPVF). A multivariate linear regression analysis was conducted, adjusting for diagnostic group, age, sex, APOEε4, CPVF, and gray matter volume fraction (GMVF).

RESULTS: CSF Klotho levels were significantly lower in Deg patients (mean = 729 pg./mL, SD = 364) compared to NonDeg individuals (mean = 1,077 pg./mL, SD = 220) (t = 3.44, p = 0.003). Higher CPVF (β = -0.34, 95% CI [-0.64, -0.05], p = 0.023) was independently associated with lower CSF Klotho levels.

CONCLUSION: In this preliminary study, we observed a strong association between CSF Klotho levels and CP enlargement. Reduced CSF Klotho levels, due to CP dysfunction, may contribute to neurodegeneration. If confirmed in larger cohorts, this association suggests that CSF Klotho may serve as a biomarker for CP enlargement, possibly reflecting its underlying dysfunction.},
}

@article {pmid41392985,
year = {2025},
author = {Herz, J},
title = {From synaptic guardian to neurodegenerative culprit: rewiring the amyloid-β feedback loop in Alzheimer's disease.},
journal = {The Journal of clinical investigation},
volume = {135},
number = {24},
pages = {},
doi = {10.1172/JCI200393},
pmid = {41392985},
issn = {1558-8238},
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Amyloid beta-Peptides/metabolism ; *Synapses/metabolism/pathology ; Animals ; Feedback, Physiological ; },
abstract = {Studies of amyloid-β (Aβ) in Alzheimer's disease pathology have revealed the peptide's complex roles in synaptic function. The study by Siddu et al. in this issue clarifies the contexts in which Aβ peptides may be synaptogenic or synaptotoxic. This commentary integrates the study's major findings with the salient findings of others that, over recent years, have redefined Aβ from a troublesome waste product into a physiological agent of the innate immune response and a modulator of synaptic homeostasis. Convergent evidence demonstrates how free, nonaggregated Aβ supports synaptic structure and activity, whereas oligomeric assemblies enact an adaptive brake on excitatory drive that can become maladaptive with age and inflammation. This redefined perspective on Aβ function emphasizes an evolutionarily conserved feedback loop linking neuronal activity, amyloid generation, and synaptic tuning that protects energy balance under stress but, when dysregulated, promotes proteostatic failure, persistent neuroinflammation, and network dysfunction characteristic of Alzheimer's disease.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Amyloid beta-Peptides/metabolism
*Synapses/metabolism/pathology
Animals
Feedback, Physiological

@article {pmid41392969,
year = {2025},
author = {Zaheer, S and Baindoor, S and Connolly, NMC and Siebenbrodt, K and Bauer, S and Rosenow, F and Andersen, JS and Venø, MT and Kjems, J and Henshall, DC and Prehn, JHM},
title = {Temporal Dynamics of tsRNA Regulation Mark an Abrupt Transition After Epileptogenesis.},
journal = {Journal of neurochemistry},
volume = {169},
number = {12},
pages = {e70317},
doi = {10.1111/jnc.70317},
pmid = {41392969},
issn = {1471-4159},
support = {18/CRT/6214//Taighde Éireann - Research Ireland Centre for Research Training in Genomics Data Science/ ; H2020 FET - GA 964712//Horizon 2020 'PRIME - A Personalised Living Cell Synthetic Computing Circuit for Sensing and Treating Neurodegenerative Disorders'/ ; H2020 MSCA RISE GA 873127//Horizon 2020 'InterTau - Integrative structural biology of pathological tau protein, an appealing therapeutic target for Alzheimer´s disease modifying drugs/ ; 21/RC/10294_P2//Taighde Éireann - Research Ireland/ ; 602130//European Union's "Seventh Framework" Programme (FP7)/ ; },
mesh = {Animals ; Rats ; Male ; Argonaute Proteins/metabolism/genetics ; *Epilepsy/genetics/metabolism ; Rats, Sprague-Dawley ; *RNA, Transfer/genetics/metabolism ; Gene Expression Regulation ; },
abstract = {Epileptogenesis involves widespread molecular remodeling, including transcriptional and post-transcriptional changes that reshape neuronal networks. While microRNAs have been extensively studied in this context, the contribution of transfer RNA-derived small RNAs (tsRNAs) remains largely unexplored. Understanding how tsRNAs engage in Argonaute 2 (Ago2)-mediated regulation during epileptogenesis could uncover new layers of post-transcriptional control relevant to seizure development and progression. Recent studies increasingly recognize transfer RNA-derived small RNAs or tsRNAs, especially those bound to Argonaute 2 (Ago2), as functional regulators of gene expression. Here, we analyzed Ago2-immunoprecipitated small RNA-Seq data along with matching transcriptomic and proteomic data across seven defined timepoints in a rat model of epilepsy that was induced using perforant pathway stimulation (PPS). The analysis showed dynamic shifts in Ago-2 bound tsRNA expression, with early and intermediate stages showing upregulation of shorter tsRNA fragments, whereas Day of First Seizure (DOFS) and chronic timepoints showed a shift toward 5' tiRNAs, including highly upregulated GlyGCC-derived fragments. Cluster analysis using Weighted Gene Co-Expression Network Analysis (WGCNA) identified modules specific to the DOFS timepoint where tsRNAs clustered together with genes enriched in pathways including neuronal metabolism, mitochondrial function, and synaptic stability. Target prediction analysis using RNAhybrid at DOFS predicted targets in 3' UTR, 5' UTR, and CDS regions showing an association with glycolysis, protein localization, and vesicle trafficking. Subsequent gene-disease association analysis further associated the predicted targets with neurodegenerative conditions including but not limited to Alzheimer's disease, intellectual disability, and epilepsy. This study highlights that tsRNAs potentially play a temporal dynamic regulatory role in epileptogenesis with an evident shift in tsRNA accumulation at DOFS suggesting a potential rewiring of post-transcriptional control at the completion of epileptogenesis. This work also highlights a first integrative approach of tsRNA downstream effects on the transcriptome and proteome in epilepsy and suggests innovative tsRNA-driven mechanisms relevant to disease progression.},
}

Animals
Rats
Male
Argonaute Proteins/metabolism/genetics
*Epilepsy/genetics/metabolism
Rats, Sprague-Dawley
*RNA, Transfer/genetics/metabolism
Gene Expression Regulation

@article {pmid41392765,
year = {2025},
author = {Clelland, JD and Cure, HW and Canizares, AM and Anderson, JH and Rawal, B and Wong, SA and Kerner, N and Huey, ED and Honig, LS and Devanand, DP and Clelland, CL},
title = {A proof-of-concept study: investigating the impact of COMT genotype and proline on negative symptoms in Alzheimer's disease.},
journal = {BJPsych open},
volume = {12},
number = {1},
pages = {e15},
doi = {10.1192/bjo.2025.10926},
pmid = {41392765},
issn = {2056-4724},
abstract = {BACKGROUND: Negative neuropsychiatric symptoms, such as apathy, are a core feature of Alzheimer's disease. Previous studies have shown that levels of fasting plasma proline and differential activity of the catechol-O-methyltransferase (COMT) enzyme, which metabolises dopamine, influence negative symptoms in patients with severe psychiatric illness and those at risk for psychosis. For patients with the COMT high activity enzyme (as assessed via the COMT Val[158]Met polymorphism), high plasma proline was associated with less severe negative symptoms. Conversely, high proline was associated with more severe negative symptoms in patients with the low activity COMT enzyme.

AIMS: In this proof-of-concept cross-sectional study, we tested the hypothesis that proline and COMT Val[158]Met interact to modify negative symptom severity across neuropsychiatric disease, specifically now investigating patients with Alzheimer's disease dementia.

METHOD: Least Absolute Shrinkage and Selection Operator regression was employed to model the interaction between proline and COMT on negative symptoms in n = 50 patients with probable Alzheimer's disease or mild cognitive impairment with underlying Alzheimer's disease biomarkers.

RESULTS: The proline × COMT interaction significantly predicted symptoms as assessed via the negative items of the Positive and Negative Symptom Scale, interaction coefficient 0.025, p = 0.031, with a trend toward significance when assessed via the Scale for Assessment of Negative Symptoms in Alzheimer's disease, interaction coefficient 0.075, p = 0.055. Higher proline was beneficial for both Val/Val and Val/Met dementia patients, but detrimental to patients with the low activity Met/Met COMT enzyme.

CONCLUSIONS: Higher proline also has opposing effects on negative symptoms by COMT genotype in patients with dementia and further supports the development of therapeutics aimed at modulating this interaction pathway across neuropsychiatric disorders.},
}

@article {pmid41392395,
year = {2025},
author = {Giangiulio, O and Maccarone, R},
title = {The Blood-Brain Barrier as an Integration Hub in Alzheimer's Disease: How Microbiota Metabolites Modulate Central Signal Processing.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {12},
pages = {e70703},
doi = {10.1002/cns.70703},
pmid = {41392395},
issn = {1755-5949},
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology/physiopathology ; *Blood-Brain Barrier/metabolism ; *Gastrointestinal Microbiome/physiology ; Animals ; Signal Transduction/physiology ; },
abstract = {BACKGROUND: While both gut-brain axis dysfunction and blood-brain barrier (BBB) breakdown are documented in Alzheimer's disease (AD), current research treats these as separate phenomena. However, emerging evidence suggests that the BBB may function as an active integration interface that processes microbiota-derived metabolites and thereby potentially modulates how peripheral signals influence cognitive health.

OBJECTIVE: This review synthesizes current evidence on microbiota metabolites as modulators of BBB integration capacity, discussing how such mechanisms may contribute to variability in cognitive outcomes despite similar gut microbiome profiles by demonstrating how BBB signal-integration mechanisms determine gut-brain communication effectiveness in AD.

METHODS: We analyzed peer-reviewed literature from 2010 to 2025, focusing on BBB dynamic properties, microbiota metabolite effects on BBB function, and their integration patterns, emphasizing functional evidence supporting the BBB's active signal processing capabilities.

RESULTS: Current evidence suggests that the BBB exhibits integration properties, including dynamic permeability regulation, context-dependent metabolite processing, and coordinated responses to complex signal streams. Short-chain fatty acids enhance integration capacity through HDAC inhibition and coordinated receptor activation, while lipopolysaccharides and trimethylamine N-oxide may overwhelm integration processes through TLR4-mediated disruption. BBB dysfunction precedes classical AD pathology and correlates with altered metabolite processing capacity. Individual variations in BBB integration capacity may help account for why individuals with similar gut microbiome profiles show different cognitive outcomes.

CONCLUSION: Viewing the BBB as an active integration interface offers a useful perspective for organizing current evidence on gut-brain interactions in AD. This conceptual perspective suggests that therapeutic strategies might benefit from supporting BBB integration capacity and optimizing metabolite-processing mechanisms alongside improving gut health.},
}

Humans
*Alzheimer Disease/metabolism/microbiology/physiopathology
*Blood-Brain Barrier/metabolism
*Gastrointestinal Microbiome/physiology
Animals
Signal Transduction/physiology

@article {pmid41392302,
year = {2025},
author = {Akhbari, MH and Movahedi, F and Zameni, M and Shahavi, MH},
title = {Developing a QSPR model for Alzheimer's drugs using topological indices and M-polynomial: A computational study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-31486-0},
pmid = {41392302},
issn = {2045-2322},
abstract = {Topological indices, which are numerical descriptors that encode molecular structure, are widely used in computational drug discovery due to their efficiency and interpretability. In this study, we developed a robust quantitative structure-property relationship (QSPR) framework to predict the core physicochemical properties of nine clinically relevant Alzheimer's disease drugs, including Donepezil, Galantamine, and Memantine. We employed a streamlined computational approach, using MATLAB and the M-polynomial method, to efficiently calculate a series of degree-based topological indices. Through comprehensive regression analyses, we identified strong correlations between degree-based topological indices and key physicochemical properties, including boiling point and molar refractivity. While linear models provided a reasonable baseline, nonlinear models, particularly cubic and power equations, delivered significantly improved predictive accuracy. The analysis highlighted the critical interplay between the choice of the index and the regression model. For instance, the cubic model was frequently the most effective for predicting properties such as boiling point and flash point, while the power model performed best for molar refractivity and polarizability. Notably, the redefined first Zagreb index and the modified first Zagreb index exhibited exceptional predictive capacity, reflecting their sensitivity to structural features that govern physicochemical behavior. The strong performance of these QSPR models underscores their potential to accelerate the rational design of Alzheimer's therapeutics. By enabling rapid, cost-effective, and reliable property prediction prior to synthesis, this framework offers a valuable tool for future drug development efforts.},
}

@article {pmid41392219,
year = {2025},
author = {Shen, Y and Wang, X and Liu, X and Wang, G and Hou, X and Zhou, X},
title = {Research Progress of Lipid Metabolism-Mediated Neuroinflammation in Alzheimer's Disease.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-025-01648-9},
pmid = {41392219},
issn = {1573-6830},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease closely associated with age. The main clinical manifestations include cognitive impairment, including visuospatial ability, memory, language, and behavioral disorders. These manifestations considerably impair the patients' ability to perform daily activities. Although the pathogenesis of AD remains unclear, many studies have confirmed the essential role of abnormal lipid metabolism and inflammatory response in AD occurrence and progression. In this review, based on the relationship between lipid metabolism disorders and neuroinflammation, the regulatory mechanism of lipid mediators, and the role of microglia, we systematically discuss how lipid metabolism affects the pathological process of AD by regulating the inflammatory response.},
}

@article {pmid41392105,
year = {2025},
author = {Barani, M and Zargari, F and Mirinejad, S and Madani, F and Hajinezhad, MR and Sargazi, S},
title = {Ginsenoside Rg3-encapsulated pegylated niosomes exhibit multimodal therapeutic potential in Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-32528-3},
pmid = {41392105},
issn = {2045-2322},
support = {4021411//National Institute for Medical Research Development/ ; },
abstract = {Ginsenoside Rg3 (GRg3), a bioactive compound extracted from ginseng, has demonstrated the ability to inhibit Aβ production and deposition. In this study, PEGylated GRg3-loaded niosomes were developed and characterized for potential AD treatment. Their efficacy was assessed using in vitro and in vivo models, as well as molecular dynamics simulations of self-assembly. Our formulation achieved a relatively high encapsulation efficiency of 83.02% and a controlled release profile, with 75.73% of the drug released over 48 h. In vitro, co-administration of Aβ with free or PEGylated GRg3-loaded niosomes markedly reduced the levels of Total Antioxidant Capacity, Malondialdehyde (MDA), and caspase-3 gene expression compared to the Aβ-only group. In vivo evaluations revealed that treatment with the niosomal formulation did not significantly alter behavioral parameters, MDA levels, or Superoxide Dismutase activity. However, catalase activity was significantly higher than in the control group. Histopathological and immunohistochemical analyses showed reduced neurovascular damage and preservation of blood-brain barrier (BBB) and hippocampal integrity in the treated group. MD simulations confirmed the spontaneous self-assembly of surfactant molecules into a bilayer structure with successful incorporation of GRg3. Our findings underscore the potential of PEGylated niosomes as efficient nanocarriers for GRg3 delivery in the AD treatment.},
}

@article {pmid41392092,
year = {2025},
author = {Leffa, DT and Povala, G and Ferreira, PCL and Ferrari-Souza, JP and Bauer-Negrini, G and Rodrigues, MS and Amaral, L and Lussier, FZ and Medeiros, MS and Soares, C and Aguzzoli, CS and Macedo, AC and Therriault, J and Rosa-Neto, P and Tudorascu, DL and Zimmer, ER and Bellaver, B and Pascoal, TA},
title = {In vivo-measured Lewy body pathology is associated with neuropsychiatric symptoms across the Alzheimer's disease continuum.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41392092},
issn = {1476-5578},
support = {24AARFD-1243899//Alzheimer's Association/ ; AARFD-22-923814//Alzheimer's Association/ ; AARFD-23-1150249//Alzheimer's Association/ ; AARFD-24-1313939//Alzheimer's Association/ ; 24AACSF-1200375//Alzheimer's Association/ ; AARFD-22-974627//Alzheimer's Association/ ; 88887.951210/2024-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazilian Federal Agency for the Support and Evaluation of Graduate Education)/ ; 5R01AG073267//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 5R01AG075336//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Intracellular alpha-synuclein aggregates, known as Lewy bodies (LB), are commonly observed in Alzheimer's disease (AD) dementia. Post-mortem studies have shown a higher frequency of neuropsychiatric symptoms among individuals with AD and LB co-pathology. However, the effects of in vivo-measured LB pathology on neuropsychiatric symptoms in AD remain underexplored. This study aimed to evaluate cross-sectional and longitudinal effects of in vivo-measured LB pathology on neuropsychiatric symptoms across the AD continuum. We analyzed data from 1169 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants had in vivo measures of LB pathology (assessed using an alpha-synuclein seed amplification assay), amyloid-beta (Aβ) and phosphorylated tau (p-tau) levels in cerebrospinal fluid, and neuropsychiatric symptoms evaluated using the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Logistic and Cox proportional hazards regression models were used to assess cross-sectional and longitudinal effects, respectively, adjusting for age, sex, and cognitive status. Participants had a mean baseline age of 73.05 (SD 7.22) years, 47.13% were women, 426 (36.44%) cognitively unimpaired, and 743 (63.56%) cognitively impaired. In cross-sectional analyses, LB pathology was associated with higher rates of anxiety, apathy, motor disturbances, and appetite disturbances. In longitudinal analyses, LB pathology increased the risk of developing psychosis and anxiety. These effects were independent of Aβ and p-tau. Our results suggest that in vivo-measured LB pathology is closely associated with neuropsychiatric symptoms across the AD continuum. These findings underscore the potential of in vivo LB detection as a marker for identifying individuals at increased risk of neuropsychiatric symptoms, both in clinical trials and in clinical practice.},
}

@article {pmid41392001,
year = {2025},
author = {Saha, S and Spalzang, S and Padhy, SK and Parmar, A},
title = {Reflections on a Study of Low-Dose Agomelatine as Add-on for Agitation in Alzheimer's Disease.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.11.011},
pmid = {41392001},
issn = {1545-7214},
}

@article {pmid41391736,
year = {2025},
author = {Chen, H and Zhang, Z and Yi, W and Wang, N and Dong, X and Xing, Y and Liu, Q and Wu, Y and Ma, X},
title = {Bone-brain crosstalk: emerging roles of osteocalcin in central nervous system disorders.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.12.028},
pmid = {41391736},
issn = {1873-7544},
abstract = {Despite significant advancements in understanding the pathogenesis of various central nervous system (CNS) disorders, challenges remain in the early intervention and targeted therapies for common neurodegenerative and psychiatric conditions such as Parkinson's disease (PD), Alzheimer's disease (AD), anxiety, depression, and strokes. Recent studies have increasingly focused on the interaction between the peripheral and central nervous systems, emphasizing the regulatory influence of peripheral mechanisms on CNS disorders. This evolving perspective paves the way for innovative treatment strategies for CNS diseases, with the bone-brain axis emerging as a key regulatory pathway. This axis was first systematically proposed to highlight the role of bone-derived hormones in brain function. Importantly, bone tissue extends its functions beyond mere structural support and movement; it secretes molecules like osteocalcin (OCN) that influence neuronal and glial cell activities. This interaction is vital for regulating multiple CNS processes, including mood, cognition, inflammation, and the formation and differentiation of myelin. Upon release from bone tissue, OCN enters the bloodstream and affects peripheral organs via the Gprc6a receptor, while also crossing the blood-brain barrier to interact with receptors such as Gpr158 and Gpr37 in specific brain areas. This intra-brain interaction significantly impacts the progression and prognosis of various CNS disorders. This article undertakes a comprehensive analysis of OCN modulation in CNS disorders and its underlying mechanisms, laying the groundwork for further exploration of its clinical applications and suggesting new research avenues and therapeutic strategies for CNS diseases.},
}

@article {pmid41391685,
year = {2025},
author = {Wang, H and Qiao, Y and Lu, H and Bo, X and Chen, F and Pu, N and Zhou, Y and Cheng, Q},
title = {Central integration mechanisms of neurovascular unit dysfunction and novel synergistic therapeutic strategies.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107224},
doi = {10.1016/j.nbd.2025.107224},
pmid = {41391685},
issn = {1095-953X},
abstract = {The neurovascular unit (NVU) is a highly integrated multicellular complex composed of neurons, astrocytes, microglia, brain microvascular endothelial cells (BMECs), pericytes, and the extracellular matrix (ECM). It forms the structural and functional basis of the blood-brain barrier (BBB) and is pivotal for maintaining the homeostasis of the brain. Traditional neuroprotective strategies targeting individual cell types have shown limited efficacy in central nervous system (CNS) diseases, mainly due to the neglect of intricate intercellular crosstalk within the NVU. In this review, we first systematically summarize the core mechanisms by which the NVU functional unit causes NVU dysfunction in representative acute CNS injuries (ischemic/hemorrhagic stroke, traumatic brain injury), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis), and systemic diseases (diabetic encephalopathy, depression). Based on this, we innovatively summarize and clarify six major cross-disease pathological mechanisms of NVU dysfunction, including intercellular communication disorders, abnormal epigenetic modifications, microbiome-NVU interaction dysregulation, metabolic reprogramming dysfunction, neuroimmune-vascular coupling imbalance, and mechanical microenvironment imbalance. Additionally, we integrate emerging NVU models (co-culture systems, organoids, microfluidic chips, 3D bioprinting) with multi-omics technologies to establish a cross-scale dynamic research paradigm, and propose multicomponent coordinated regulatory strategies for NVU-targeted therapies. This framework aims to expand the understanding of NVU-centered pathological processes across diverse CNS diseases and provides a novel theoretical basis for precise therapeutic interventions, thereby bridging the gap between basic research and clinical translation.},
}

@article {pmid41391557,
year = {2025},
author = {Liu, C and Zhao, Y and Dao, JJ and Ma, YK and Liu, J and Qiao, CM and Cui, C and Shen, YQ and Chen, SX and Yu, L and Zhao, WJ},
title = {Food-borne polystyrene microplastic exposure exacerbates cognitive deficiency via enhanced neuronal synaptic damage and neuroinflammation in Alzheimer's disease.},
journal = {Toxicology},
volume = {},
number = {},
pages = {154371},
doi = {10.1016/j.tox.2025.154371},
pmid = {41391557},
issn = {1879-3185},
abstract = {The impact of polystyrene microplastics (PS-MPs) on the nervous system has been documented, yet the potential role of PS-MPs exposure in exacerbating neuronal damage and neuroinflammation in Alzheimer's disease (AD) remains unclear. Our research demonstrated that exposure to PS-MPs (50mg/kg) caused hippocampal mitochondrial damage in APP/PS1 mice, reduced expression of hippocampal mitochondrial and synapse-associated proteins, inhibited ErbB4 signaling pathway, and damaged hippocampal neurons. Additionally, PS-MPs exposure induced overactivation of astrocytes and microglia with NLRP3 pathway activation, increased β-amyloid (Aβ) deposition, and ultimately worsened cognitive dysfunction in APP/PS1 mice. Subsequent in vitro findings showed that PS-MPs (100μg/mL) exacerbated hippocampal neuronal damage under Aβ pathology, suppressed ErbB4 pathway, and disrupted mitochondrial and synaptic function. The compromised hippocampal neurons enhanced microglial NLRP3 pathway activation. These findings suggest that exposure to PS-MPs induces hippocampal neuronal damage, impairs mitochondrial and synaptic function, and exacerbates neuroinflammation and cognitive deficits, ultimately contributing to AD progression. These findings enhance our understanding of the mechanisms by which MPs expedite the progression and influence management of AD.},
}

@article {pmid41391511,
year = {2025},
author = {Gawai, M and Nistane, N and Tatode, AA and Qutub, M and Umekar, MJ and Premchandani, T and Taksande, JB},
title = {Transforming Anti-Alzheimer's therapy by targeting endogenous receptorrial system through ligand-conjugated Nanoformulations.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102994},
doi = {10.1016/j.arr.2025.102994},
pmid = {41391511},
issn = {1872-9649},
abstract = {Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder, contributing to the majority of dementia cases in the elderly globally. Characterized by progressive cognitive decline, AD is associated with complex neuropathological changes, including the accumulation of amyloid-beta (Aβ) plaques and tau tangles, synaptic loss, and neuroinflammation. One of the significant challenges in treating AD is the blood-brain barrier (BBB), which prevents many therapeutic agents from reaching the brain. Despite advancements in understanding AD's pathology, limited treatment options are available, largely due to the inability of conventional drugs to effectively target the brain. Ligand-conjugated nanoparticles (NPs) are promising for targeted drug delivery to the brain. These NPs, engineered with ligands that can bind to specific receptors or transporters on the BBB, facilitate the crossing of the barrier via receptor-mediated endocytosis or adsorptive-mediated transcytosis. This strategy enhances therapeutic agents' bioavailability and cellular uptake, offering a potential solution to overcome current limitations in AD treatment. Using nanotechnology to design ligand-conjugated NPs for targeted and sustained drug delivery could significantly improve therapeutic outcomes for AD patients by addressing key pathological processes in the brain.},
}

@article {pmid41391505,
year = {2025},
author = {Liu, Y and Zhang, J and Li, W and Qu, Q and Shan, Z and Liu, C and Jiao, K and Hou, X},
title = {Osthole Ameliorates Cognitive Impairment in Ovariectomized Rats via Estrogen-Mediated Enhancement of Cholinergic Function and Regulation of Neurotransmitter Homeostasis.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110806},
doi = {10.1016/j.neuropharm.2025.110806},
pmid = {41391505},
issn = {1873-7064},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen-cholinergic-NGF axis: E2, ERα, and ERβ expression were upregulated; Ach, ChAT, NGF, and TrkA levels were increased, whereas AChE activity was decreased. Moreover, OST inhibited neuronal apoptosis by elevating Bcl-2 and reducing Bax expression, enhanced the expression of markers of synaptic plasticity (PSD95, SYN, and BDNF), and modulated neurotransmitter release (GABA and E). Collectively, these multi-target effects identify OST as a promising candidate for treating AD in women.},
}

@article {pmid41391342,
year = {2025},
author = {Guévremont, D and Roy, J and Garvey, A and McLean, C and Cutfield, N and Williams, J},
title = {Plasma microRNA predict cognitive decline in Parkinson's disease.},
journal = {Parkinsonism & related disorders},
volume = {143},
number = {},
pages = {108149},
doi = {10.1016/j.parkreldis.2025.108149},
pmid = {41391342},
issn = {1873-5126},
abstract = {BACKGROUND: Parkinson's disease (PD), the second most common neurodegenerative disease, is currently diagnosed clinically by impairments in motor control. PD, however, includes a diversity of non-motor symptoms, such as cognitive decline. Thus, it is imperative to establish a diagnostic framework for PD which reflects this heterogeneous phenotype. While misfolded α-synuclein is a cellular hallmark of PD and candidate biofluid marker, microRNA are an important class of biomarkers that are stable and easily detectable in blood, and are dysregulated at post-mortem in PD patients. This study aimed to establish PD plasma microRNA biomarkers that reflect cognitive abilities, as determined by the Montreal Cognitive Assessment (MoCA).

METHODS: Using custom-designed low-density TaqMan arrays we assessed plasma levels of 187 neurodegeneration-related microRNA, in cross-sectional (n = 102), and longitudinal cohorts (n = 26) as well as in post-mortem brain tissue (n = 16).

RESULTS: We found numerous microRNA were altered with increasing cognitive decline in PD and that the overall direction of change moved towards downregulation. A notable exception was miR-192-5p which was consistently upregulated in plasma and was found to be downregulated at postmortem in the superior frontal gyrus. Overall, microRNA identified were largely distinct from those known to be regulated in Alzheimer's disease. Focusing on a longitudinal cohort, controlled for disease progression and age we showed that miR-151-3p and miR-192-5p provided the best predictive model for separating cognitively normal PD patients from those who decline cognitively.

CONCLUSION: Plasma microRNA are altered in PD patients, can predict cognitive decline and therefore may be clinically useful biomarkers.},
}

@article {pmid41391236,
year = {2025},
author = {Padrela, BE and Tecelão, S and Kirsebom, BE and Geier, O and Tranfa, M and Masserini, F and Sneve, MH and Slivka, M and Falch, ES and Pålhaugen, L and Mahroo, A and Eickel, K and Thomas, DL and Günther, M and Selnes, P and Bjørnerud, A and Walhovd, KB and Fjell, AM and Barkhof, F and Petr, J and Fladby, T and Mutsaerts, HJMM},
title = {Blood-brain barrier water exchange in relation to amyloid, cognition and cerebrovascular burden.},
journal = {NeuroImage. Clinical},
volume = {49},
number = {},
pages = {103926},
doi = {10.1016/j.nicl.2025.103926},
pmid = {41391236},
issn = {2213-1582},
abstract = {Blood-brain barrier (BBB) water exchange may serve as a sensitive early biomarker for Alzheimer's disease and age-related cognitive decline. This study applied a non-invasive multi-echo arterial spin labeling (ASL) technique to measure BBB water exchange time (Tex), cerebral blood flow (CBF), and arterial transit time (ATT) in 160 adults aged 50 years and older. Participants were classified as cognitively normal (CN), having subjective cognitive decline (SCD), or mild cognitive impairment (MCI). They were assessed for amyloid status and cerebrovascular burden. Compared to CN participants, Tex was significantly lower in both SCD (-9.5 %) and MCI (-14.5 %) groups, suggesting that reductions in BBB water exchange emerge early in the course of cognitive decline. In contrast, CBF was reduced only in MCI participants (-20.8 % compared to CN), and ATT was significantly increased only in individuals with severe cerebrovascular burden (Fazekas score 3). Notably, Tex showed a stepwise decrease with increasing Fazekas scores (1-2), supporting its sensitivity to moderate small vessel disease. No associations were found between Tex and amyloid positivity after adjusting for age and sex. These findings indicate that Tex alterations may precede changes in traditional perfusion markers and are more closely related to vascular and early cognitive changes than to amyloid pathology. BBB water exchange mapping may therefore provide a promising, non-invasive tool to detect early neurovascular dysfunction that contributes to cognitive decline in aging populations, potentially offering a useful biomarker for early intervention trials targeting vascular contributions to dementia.},
}

@article {pmid41390894,
year = {2025},
author = {Sasanian, N and Halipi, V and Sjögren, M and Bengtsson, J and Bernson, D and Esbjörner, EK},
title = {Ganglioside GM1 slows down Aβ(1-42) aggregation by a primary nucleation inhibitory mechanism that is modulated by sphingomyelin and cholesterol.},
journal = {Communications chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42004-025-01846-y},
pmid = {41390894},
issn = {2399-3669},
support = {2019.0238//Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)/ ; },
abstract = {The conversion of soluble amyloid-β peptides into fibrils is central in Alzheimer's disease. Lipids modulate amyloid-β aggregation, but whilst the mechanistic effect of individual lipid species is increasingly addressed, principles explaining their combinatorial contributions in biologically heterogenous membranes remain to be established. We used kinetic analyses to establish an inhibitory mechanism of GM1 gangliosides on the aggregation of amyloid-β variant Aβ(1-42) by which membrane-associated GM1 sequesters soluble Aβ(1-42) and retards primary nucleation. The kinetic inhibition increased in presence of the raft-enabling lipids cholesterol and sphingomyelin, although these lipids, intrinsically, catalysed primary and secondary nucleation respectively. These results decipher important trade-offs between the specific chemical properties of lipids and their general contributions to the physical state of membranes, show principles of competition, and identify low fluidity domains as key regulators of membrane-mediated Aβ(1-42) aggregation. The study thereby highlights a versatile, regulatory role of membranes in the molecular pathology of Alzheimer's disease.},
}

@article {pmid41390810,
year = {2025},
author = {Gallo, C and Verrillo, L and Manzo, E and Cauzzi, E and La Barbera, L and Sabatino, G and De Paolis, ML and Sciacca, MFM and Barra, G and Peroni, E and Monasson, O and Dell'Isola, M and Carbone, D and Nobili, A and Ziaco, M and Fioretto, L and Pirozzi, M and D'Ippolito, G and Castiglia, D and Soluri, A and Nuzzo, G and Milardi, D and Miano, MG and D'Amelio, M and Fontana, A},
title = {Microglial clearance, neuroprotection and cognitive recovery via a novel synthetic sulfolipid in Alzheimer's disease.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-025-03634-w},
pmid = {41390810},
issn = {1742-2094},
support = {PG/2018/0494374//Regione Campania/ ; PG/2018/0494374//Regione Campania/ ; AIRALTZH-AGYR2021//Italian Association for Alzheimer's Disease/ ; PRIN 2022PAAYZE//Ministero dell'Università e della Ricerca/ ; AARG-18-566270//American Alzheimer's Association/ ; RF-2018-12365527//Ministero della Salute/ ; PNRR-MAD-2022-12376849//Ministero della Salute/ ; PO FESR LAZIO 2014/2020//Regione Lazio/ ; 2022BNZLMN//Italian Ministry of University and Research/ ; },
}

@article {pmid41390778,
year = {2025},
author = {Fu, M and Tran, T and Pasaniuc, B and Vossel, K and Chang, TS},
title = {Multi-task learning identifies shared genetic risk for late-onset epilepsy and alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-32329-8},
pmid = {41390778},
issn = {2045-2322},
abstract = {Aging populations face increasing incidence of neurological disorders, including Alzheimer's disease (AD) and late-onset epilepsy (LOE), which demonstrate a bidirectional relationship where AD is a risk factor for LOE and LOE is a risk factor for AD. While the APOE gene is a known shared risk factor, comprehensive genetic studies for LOE remain limited. This study employed a multi-task learning framework using Elastic Net modeling to systematically identify shared genetic risk factors between AD and LOE. We analyzed electronic health records from UCLA Health System (N = 416,212; genetic subset N = 16,500) and validated findings in the All of Us dataset (N = 52,493). Longitudinal analyses confirmed strong bidirectional associations between AD and LOE. The multi-task learning approach identified eight shared-risk single nucleotide polymorphisms mapping to key genes including the APOE-TOMM40-APOC1 cluster, BIN1, CLU, PVRL2, and TRAPPC6A. These shared-risk genes were enriched in pathways related to lipid metabolism, amyloid catabolic processes, and tau protein binding. A shared genetic risk score effectively stratified patients into distinct AD-LOE risk groups. This study represents an initial systematic identification of potential shared genetic factors between AD and LOE using multi-task learning. While our findings suggest possible shared genetic contributions, particularly in the APOE region, and highlight tau-mediated mechanisms as potential therapeutic targets, further validation is needed to establish the extent of genetic overlap between these conditions.},
}

@article {pmid41390776,
year = {2025},
author = {AlOkda, A and Yadav, S and Pacis, A and Jacob-Tomas, S and Parkhitko, AA and Van Raamsdonk, JM},
title = {Cyrene: a novel geroprotective compound that extends lifespan and healthspan in C. elegans and Drosophila.},
journal = {npj aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41514-025-00309-x},
pmid = {41390776},
issn = {2731-6068},
support = {AG082801/AG/NIA NIH HHS/United States ; GM146869/GM/NIGMS NIH HHS/United States ; },
abstract = {As aging is the primary risk factor for many chronic diseases, geroscience aims to target aging to delay age-related decline. Here, we identify Cyrene (dihydrolevoglucosenone), a sustainable, biocompatible solvent, as a novel geroprotective compound. Cyrene extends lifespan and healthspan in C. elegans, improving locomotor function and resistance to oxidative, thermal, osmotic, genotoxic, and proteotoxic stress. It also confers protection in neurodegenerative models of Alzheimer's, Parkinson's, and Huntington's disease. Cyrene is effective when delivered during development or early adulthood and requires administration before day 8 to extend longevity. Its benefits are independent of bacterial metabolism and at least partially independent of the FOXO transcription factor DAF-16. Importantly, Cyrene also extends lifespan and enhances oxidative stress resistance in Drosophila melanogaster, demonstrating cross-species efficacy. These findings identify Cyrene as a novel geroprotective compound that promotes longevity, resilience, and neuroprotection. Conservation across species supports future work to dissect molecular mechanisms and test its potential in mammals.},
}

@article {pmid41390681,
year = {2025},
author = {Saeed, R and Tariq, HZ and Althobaiti, A and Sadeghian, N and Taslimi, P and Al-Rashida, M and Islam, T and Thabet, HK and Aftab, H and Şenol, H and Ameen, M and Li, J and Shafiq, Z},
title = {Design, synthesis, and multi-target evaluation of 4-phenyl quinoline-8-sulfonate thiosemicarbazones as potential anti-Alzheimer agents.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-32012-y},
pmid = {41390681},
issn = {2045-2322},
}

@article {pmid41390476,
year = {2025},
author = {Jia, L and Chen, Y and Li, H and Zhao, K and Ge, S and Wang, C and Zhao, J and Li, F and Zhang, L and Yao, A},
title = {The glymphatic system in neurodegenerative diseases and brain tumors: mechanistic insights, biomarker advances, and therapeutic opportunities.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-025-02203-9},
pmid = {41390476},
issn = {2051-5960},
support = {26A310011//The Plan for Key Scientific Research Projects of Higher Education Institutions in Henan Province for 2026/ ; YNZX2024005//The research project of 988th Hospital of Joint Logistic Support Force of PLA/ ; LHGJ20230703//The joint construction project of Henan Province/ ; KFJJ23-09M//The opening project of State Key Laboratory of Explosion Science and Technology (Beijing Institute of Technology)/ ; },
abstract = {Dysfunction of the glymphatic system (GS), a brain-wide waste clearance pathway dependent on polarized aquaporin-4 (AQP4) water channels on astrocytic endfeet, is increasingly recognized as a critical mechanism in both neurodegenerative diseases and brain tumors. In Alzheimer's (AD) and Parkinson's (PD) diseases, impaired glymphatic function leads to the accumulation of neurotoxic proteins, including amyloid-β (Aβ), tau, and α-synuclein (α-syn). Contributing factors include loss of AQP4 polarization, reduced arterial pulsatility, genetic risks (e.g., APOE4, FAM171A2 mutations), and sleep disturbances. These functional impairments can be quantified using neuroimaging biomarkers such as the diffusion tensor imaging along the perivascular space (DTI-ALPS) index and choroid plexus volume (CPV), which correlate with pathological burden and clinical decline, though the direct physiological interpretation of these metrics requires further validation. Conversely, in glioblastoma and other brain tumors, mechanical compression and lactate-driven acidosis obstruct perivascular fluid transport, promoting an immunosuppressive tumor microenvironment that limits T-cell infiltration and confers therapeutic resistance. Here, too, glymphatic dysfunction is reflected by a reduced ALPS index, which correlates with tumor grade, peritumoral edema, and survival. Emerging therapeutic strategies aimed at restoring GS function include pharmacological interventions (e.g., circadian regulators, AQP4 modulators), non-invasive techniques (e.g., cervical lymphatic stimulation, gamma stimulation, exercise), and surgical approaches (e.g., lymphatic-venous anastomosis). Advances in multimodal MRI and artificial intelligence (AI)-enhanced analytics further support novel diagnostic capabilities. This review highlights the dual role of the GS across neurological disorders and underscores its potential as a therapeutic target for enhancing waste clearance and immune modulation. However, significant challenges remain, including the validation of human biomarkers, elucidating bidirectional tumor-glymphatic crosstalk, and translating preclinical discoveries into clinical practice.},
}

@article {pmid41390473,
year = {2025},
author = {Yang, C and Chu, F and Chen, X and Meng, F and Li, Y and Chen, J and Sun, C and Shang, Y and Guo, R and Wang, J and Wu, C and Duan, H and Shao, M and Yuan, W},
title = {Glutamine: fructose-6-phosphate amidotransferase (GFAT) in the pathology of diseases: a review.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-025-02898-8},
pmid = {41390473},
issn = {2058-7716},
support = {202403021221004, 2024030212211348, 202203021221300//Natural Science Foundation of Shanxi Province (Shanxi Province Natural Science Foundation)/ ; },
abstract = {Glutamine: fructose-6-phosphate amidotransferase (GFAT), a conserved enzyme across prokaryotic and eukaryotic species, is the first and rate-limiting step in the hexosamine biosynthetic pathway (HBP), diverting 2-5% of fructose-6-phosphate derived from glucose toward the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a key substrate for the glycosylation of proteins and lipids. While substantial progress has been made in elucidating the basic biochemical properties and regulatory mechanisms of GFAT, its functional impact on pathological processes remains incompletely understood. Emerging evidence implicates GFAT in a spectrum of human diseases, including cancer, diabetes, cardiovascular disorders, and neurodegenerative conditions such as Alzheimer's disease. This review aims to provide a comprehensive synthesis of current insights into GFAT's role in disease etiology, with the goal of informing future research and therapeutic strategies targeting this essential metabolic regulator.},
}

@article {pmid41390238,
year = {2025},
author = {Mummery, CJ and Rasmussen, J and Blackburn, D and Coulthard, E and Davies, RR and Dorsey, R and Fox, NC and Hosseini, AA and Ivenso, C and Jones, M and Kennelly, SP and Kipps, C and Lashley, D and Mackay, G and Negi, R and Nilforooshan, R and Passmore, PA and Perry, R and Raymont, V and Rowe, JB and Russ, TC and Taylor, JP and Burns, A},
title = {Lecanemab appropriate use recommendations for clinical practice in the UK.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-336597},
pmid = {41390238},
issn = {1468-330X},
abstract = {Lecanemab is an anti-amyloid monoclonal antibody, recently approved in the UK as a treatment for mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD) in adults who are apolipoprotein E ε4 gene (APOE4) heterozygotes or non-carriers.A group of UK neurologists, old age psychiatrists and geriatricians with expertise in AD convened to agree appropriate use recommendations for lecanemab in UK clinical practice. The primary focus of these recommendations is safety.Eligibility criteria for lecanemab in the UK include (a) a clinical diagnosis of MCI or mild dementia due to AD, (b) the presence of amyloid-β pathology, confirmed using approved methods (ie, an amyloid positron emission tomography scan or cerebrospinal fluid assay) and (c) APOE4 heterozygous or non-carrier status. Eligibility screening should be conducted in secondary care and those identified as being potentially eligible for lecanemab should be referred to a specialist centre for confirmation of the likely pathological diagnosis, APOE4 counselling and testing and a multidisciplinary consensus decision regarding treatment eligibility. Lecanemab is administered as an intravenous infusion every 2 weeks, and those eligible for treatment should have brain magnetic resonance imaging (MRI) scans prior to the 1st, 5th, 7th and 14th infusions. Specific guidance is provided for safety monitoring and management of potential adverse reactions, including amyloid-related imaging abnormalities and infusion-related reactions.The introduction of lecanemab into UK clinical practice provides an important opportunity to improve services for all people living with dementia, not just those eligible for lecanemab treatment.},
}

@article {pmid41390237,
year = {2025},
author = {Ancidoni, A},
title = {Appropriate use recommendations in search of reimbursement: lecanemab and the UK dilemma.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-337659},
pmid = {41390237},
issn = {1468-330X},
}

@article {pmid41390197,
year = {2026},
author = {Yabuki, Y and Shioda, N},
title = {RNA-mediated aggregation mechanism of prion-like proteins and its application to drug discovery.},
journal = {Journal of pharmacological sciences},
volume = {160},
number = {1},
pages = {64-68},
doi = {10.1016/j.jphs.2025.11.006},
pmid = {41390197},
issn = {1347-8648},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy/etiology ; *RNA/metabolism/chemistry ; *Drug Discovery/methods ; G-Quadruplexes ; *Prion Proteins/metabolism/chemistry ; *Prions/metabolism/chemistry ; RNA-Binding Proteins/metabolism ; tau Proteins/metabolism ; *Protein Aggregates ; Animals ; alpha-Synuclein/metabolism ; Phase Transition ; *Protein Aggregation, Pathological ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease are on the rise in super-aging societies. However, the mechanisms underlying the aggregation and propagation of prion-like proteins such as α-synuclein and Tau that contribute to the pathogenesis of neurodegeneration remain poorly understood. Although prion-like proteins are known to undergo liquid-liquid phase separation (LLPS) followed by a sol-gel transition in vitro, the key factors governing their phase transition remain to be elucidated in vivo. Most prion-like proteins are classified as RNA-binding proteins, and recent studies suggest that RNA plays a critical role in mediating both LLPS and the subsequent sol-gel transition of these proteins. In the review, we summarized our findings on RNA G-quadruplexes (rG4s) as a pathological key molecule in neurodegenerative disorders and introduce recent advances in RNA-induced phase transition of prion-like proteins.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy/etiology
*RNA/metabolism/chemistry
*Drug Discovery/methods
G-Quadruplexes
*Prion Proteins/metabolism/chemistry
*Prions/metabolism/chemistry
RNA-Binding Proteins/metabolism
tau Proteins/metabolism
*Protein Aggregates
Animals
alpha-Synuclein/metabolism
Phase Transition
*Protein Aggregation, Pathological

@article {pmid41390193,
year = {2026},
author = {Ohi, Y and Hada, K and Murata, Y and Kodama, D and Wakiya, Y},
title = {Bidirectional effects of orexin receptor antagonists on long-term potentiation in the hippocampus of wild type and Alzheimer's disease model mice.},
journal = {Journal of pharmacological sciences},
volume = {160},
number = {1},
pages = {37-40},
doi = {10.1016/j.jphs.2025.11.003},
pmid = {41390193},
issn = {1347-8648},
mesh = {Animals ; *Alzheimer Disease/physiopathology/drug therapy ; *Orexin Receptor Antagonists/pharmacology/administration & dosage ; *Long-Term Potentiation/drug effects ; Disease Models, Animal ; *Azepines/pharmacology/administration & dosage ; *Triazoles/pharmacology/administration & dosage ; *Hippocampus/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; *Pyridines/pharmacology ; *CA1 Region, Hippocampal/drug effects ; },
abstract = {The orexinergic system is dysregulated in patients with Alzheimer's disease (AD). In the present study, we evaluated the effects of chronic administration of dual orexin receptor antagonists, suvorexant (Suv) and lemborexant (Lem), on long-term potentiation (LTP) in the hippocampal CA1 region of wild-type (WT) and APP[NL-G-F] knock-in (APP-KI) mice. LTP was enhanced in APP-KI mice compared with WT mice. Chronic administration of Suv and Lem further potentiated LTP in WT mice. In contrast, in APP-KI mice, Suv moderately and Lem markedly reduced LTP. These findings suggest that orexin receptor antagonists bidirectionally modulate LTP in WT and AD model mice.},
}

Animals
*Alzheimer Disease/physiopathology/drug therapy
*Orexin Receptor Antagonists/pharmacology/administration & dosage
*Long-Term Potentiation/drug effects
Disease Models, Animal
*Azepines/pharmacology/administration & dosage
*Triazoles/pharmacology/administration & dosage
*Hippocampus/drug effects
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
*Pyridines/pharmacology
*CA1 Region, Hippocampal/drug effects

@article {pmid41390157,
year = {2025},
author = {Light, SW and Tomasino, F and Del Salto, M and Vela, A and Wolf, MS and Sideman, AB},
title = {'It keeps your body strong, your muscles strong, your brain strong:' perceptions about the role of physical activity and nutrition in brain health among middle-aged Latinos.},
journal = {Ethnicity & health},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/13557858.2025.2600276},
pmid = {41390157},
issn = {1465-3419},
abstract = {OBJECTIVES: Latinos are disproportionately impacted by Alzheimer's disease and related dementias (ADRD). It is estimated that interventions targeting lifestyle and health behaviors could prevent or delay up to 50% of ADRD cases worldwide. This study aimed to explore middle-aged Latinos' perceptions of the link between physical activity and nutrition with the maintenance of brain health.

DESIGN: Individual, semi-structured interviews were conducted with 30 English- or Spanish-speaking Latinos 35 to 64 years old. Participants were recruited via social media, flyers, direct contact of participants from prior studies, and snowball sampling. Questions addressed knowledge about the brain, perceptions of aging, and ideas of how to care for the brain. Responses that emerged pertaining to physical activity and nutrition were analyzed using conceptual content analysis to quantify the frequency of themes and identify trends.

RESULTS: Most participants were female (n = 18) and college educated (n = 17), with an average age of 47 years; two thirds reported being foreign born, and half reported lower acculturation levels. Physical activity and nutrition were spontaneously described as strategies to promote brain health by 22 and 24 participants, respectively. With regards to physical activity, walking was most often mentioned (n = 8), followed by yoga (n = 4). Few participants clarified frequency (n = 3), duration (n = 1), or intensity (n = 2). With regards to nutrition, common strategies mentioned were increasing fruit and vegetable consumption (n = 19), limiting processed foods (n = 9), and taking vitamins or supplements (n = 9).

CONCLUSION: Most participants demonstrated foundational knowledge of the link between nutrition, physical activity, and brain health. Some misconceptions were identified, such as participants overestimating the benefits of vitamins/supplements, which have weak correlations with preventing cognitive decline. Messaging may benefit from emphasizing recommendations regarding the role of frequency, duration, and intensity in physical activity, and specific nutrient, portioning, and preparation recommendations for dietary practices. Incorporating these messages into intergenerational programming may be particularly beneficial.},
}

@article {pmid41390089,
year = {2025},
author = {Sheng, J and Wang, L and Zhang, Q and Chien Chou, JT and Zhang, R and Li, T and Lu, Y},
title = {Integrating multimodal data to identify single nucleotide polymorphism-related biomarkers and regulatory mechanisms in Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.12.022},
pmid = {41390089},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease with unclear regulatory mechanisms at the cell-type level. A multi-omics model called single nucleotide polymorphisms (SNPs)-transcriptomic-single-nucleus ribonucleic acid sequencing (snRNA-seq) integration (STSNI) is proposed to identify SNPs-related biomarkers and regulatory mechanisms in AD. Differential expression analysis identified differentially expressed genes (DEGs) between AD patients and healthy controls (HCs) in the GSE118553 dataset. Cell-type annotation in the GSE138852 dataset revealed several cell subclusters, and DEGs were identified within these subclusters. Intersection analysis among DEGs from the GSE118553 dataset, cell-subcluster-specific DEGs from the GSE138852 dataset, and SNP-associated genes from the ADNI2 dataset yielded 14 overlapping genes. Using the least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) algorithms, six biomarkers were identified. Functional enrichment and gene set enrichment analysis (GSEA) linked these biomarkers to pathways such as carboxylic acid catabolic process, exocytic vesicle membrane, and carbon metabolism. Meanwhile, six cell types were identified, including astrocytes, endothelial cells, oligodendrocytes, oligodendrocyte progenitor cells (OPCs), microglia, and neurons. The biomarker-transcription factor (TF) network indicated that Cispb M4676 regulates IQGAP2, NRXN1, GRIA3 and FGF14. Overall, our study identified six SNP-related biomarkers (IQGAP2, HHAT, FGF14, CTNNA3, GRIA3, and NRXN1) associated with AD. The STSNI framework provided novel insights into the cellular and molecular mechanisms underlying AD. Significance Statement: As the global population continues to age, Alzheimer's disease (AD) has emerged as a major public health concern. The pathological changes associated with AD include the formation of extracellular amyloid plaques, intracellular neurofibrillary tangles, and neuronal loss with gliosis proliferation. Bioinformatics methods are used to explore the immune infiltration characteristics, biological pathways and regulatory mechanisms of single nucleotide polymorphisms (SNPs) related key genes in AD. The pathogenesis of AD from the overall level and single-cell level is explored based on SNPs-related genes, combined with snRNA-seq data and transcriptome data. This study provides an opportunity for the discovery of novel diagnostic molecular markers and potential treatment targets to serve as the foundation for the development of more effective management techniques for AD.},
}