@article {pmid40956407,
year = {2025},
author = {Guo, S and Wei, F and Chang, Y and Wu, S and Lou, Z and Ma, Y and Huang, Q and He, K and Fu, C and Cao, X and Liang, S and Cheng, W and Yin, Y},
title = {Early astrocyte-targeted intervention guided by [18]F-SMBT-1 imaging attenuates disease progression in 3xTg-AD mice.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {40956407},
issn = {1619-7089},
support = {82472014//National Natural Science Foundation of China/ ; 81974270//National Natural Science Foundation of China/ ; 24ZR1450000//Natural Science Foundation of Shanghai Municipality/ ; 23ZR1441200//Natural Science Foundation of Shanghai Municipality/ ; },
abstract = {PURPOSE: Astrocyte reactivity is a key pathological feature and potential therapeutic target of Alzheimer's disease (AD), however, the optimal timing of its modulation remains unexplored. This study aims to combine [18]F-SMBT-1 based molecular imaging with astrocyte-targeted intervention in 3xTg-AD mice to address this challenge.

METHODS: PET imaging with [18]F-SMBT-1 was conducted in 3xTg-AD mice at 4, 6, 10, and 12 months of age, with age-matched wild-type (WT) mice as controls. The standardized uptake value ratio was calculated using cerebellum as the reference region by PMOD software. Immunofluorescence (IF) analysis was used to assess astrocyte reactivity ex vivo. Astrocyte-targeted intervention via Nrf2 overexpression was performed in 4-month-old 3xTg-AD mice using adeno-associated virus vectors. Following intervention, PET imaging with [18]F-SMBT-1 was performed to assess astrocyte reactivity, open field test and Morris water maze test were performed to evaluate cognitive function, and IF analysis was used to assess pathological feature of AD.

RESULTS: In 3xTg-AD mice of different ages, higher uptake of [18]F-SMBT-1 was observed in the cortex and hippocampus compared to age-matched WT controls. IF analysis further confirmed the presence of reactive astrocytes activation in 3xTg-AD mice. Both in vivo [18]F-SMBT-1 imaging and ex vivo IF analysis identified early-onset astrocyte activation in 3xTg-AD mice. Based on these observations, we implemented early astrocyte-targeted intervention via Nrf2 overexpression at 4 months of age in 3xTg-AD mice. Subsequent in vivo [18]F-SMBT-1 PET imaging demonstrated a significant reduction in astrocyte reactivity following this intervention. Our findings also demonstrated that early astrocyte-targeted intervention might delay AD pathological progression in 3xTg-AD mice, as supported by attenuated anxiety-like behavior and ameliorated neuropathological features.

CONCLUSION: [18]F-SMBT-1 PET imaging served as a diagnostic biomarker for monitoring astrocyte reactivity to guide therapeutic timing decisions, and as a therapeutic response indicator for evaluating treatment efficacy. Early astrocyte-targeted intervention demonstrated significant therapeutic potential. These findings highlighted the translational potential of molecular imaging-guided strategies and astrocyte-targeted therapies in AD.},
}

@article {pmid40956223,
year = {2025},
author = {Madhusoodanan, J},
title = {Prevention Intervention: The evidence is clear that racial discrimination, physical health and the environment contribute to Alzheimer's and other dementias. Now researchers are looking for ways to intervene.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {102},
doi = {10.1038/scientificamerican102025-6qOZmIz2H1y5DlHqxZtdYy},
pmid = {40956223},
issn = {0036-8733},
}

@article {pmid40956221,
year = {2025},
author = {Willyard, C},
title = {Decoding Blood: New biomarkers promise easier and earlier detection of Alzheimer's, but the results aren't always clear.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {96},
doi = {10.1038/scientificamerican102025-40sXDAeTyBigx9YFSG0eGe},
pmid = {40956221},
issn = {0036-8733},
}

@article {pmid40956220,
year = {2025},
author = {Seegert, L},
title = {A Dangerous Silver Bullet: Drugs that hit an Alzheimer's target are gaining traction. Some neurologists remain dubious.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {93},
doi = {10.1038/scientificamerican102025-4pkqWZs4A0HrkVXMH94mN1},
pmid = {40956220},
issn = {0036-8733},
}

@article {pmid40956219,
year = {2025},
author = {Landhuis, E and Christiansen, J and Studios, NM},
title = {A Multipronged Assault: A new understanding of Alzheimer's is leading to a variety of new treatment approaches.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {89},
doi = {10.1038/scientificamerican102025-5T8bP0cW0x69LnvyUGc4td},
pmid = {40956219},
issn = {0036-8733},
}

@article {pmid40956218,
year = {2025},
author = {Harrison, S},
title = {Cultivating Resilience: Early research suggests that Alzheimer's risk can be mitigated through diet, exercise and social stimulation. But definitive studies remain elusive.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {86},
doi = {10.1038/scientificamerican102025-2g8oOmVVXgGO5qSV8D6mRJ},
pmid = {40956218},
issn = {0036-8733},
}

@article {pmid40956217,
year = {2025},
author = {Gravitz, L},
title = {Hope Swells in Alzheimer's Research: Breakthrough therapies, new diagnostics and preventive measures for fighting a devastating disease.},
journal = {Scientific American},
volume = {333},
number = {3},
pages = {85},
doi = {10.1038/scientificamerican102025-6WQaHREGezLtKv4MzX4EQr},
pmid = {40956217},
issn = {0036-8733},
}

@article {pmid40956166,
year = {2025},
author = {Li, S and Chen, R and Cao, Z and Zhu, Q and Ma, Y and Zhu, K and Lin, Z and Wu, D and , },
title = {Microstructural Bias in the Assessment of Periventricular Flow as Revealed in Postmortem Brains.},
journal = {Radiology},
volume = {316},
number = {3},
pages = {e250753},
doi = {10.1148/radiol.250753},
pmid = {40956166},
issn = {1527-1315},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/diagnostic imaging/pathology ; *Diffusion Tensor Imaging/methods ; Aged, 80 and over ; Autopsy ; Middle Aged ; *Brain/diagnostic imaging/pathology ; *Glymphatic System/diagnostic imaging/pathology ; },
abstract = {Background Diffusion tensor imaging (DTI) analysis along the perivascular space (ALPS) has been proposed to assess global glymphatic activity in several neurologic diseases. However, it is unclear whether this measurement is biased by fiber microstructure. Purpose To determine the impact of fiber microstructure on DTI-ALPS in postmortem brains with or without Alzheimer disease (AD) and to evaluate the corrected ALPS in living participants. Materials and Methods From June 2021 to August 2023, amyloid β (Aβ)-positive and Aβ-negative postmortem human brains underwent DTI-ALPS. DTI-ALPS and microstructural asymmetries in the postmortem samples were compared between pathologic groups with use of two-way analysis of variance and correlated with age with use of Pearson correlation. The corrected ALPS index, where the age-dependent and pathologic abnormality-related microstructural effect was removed, was applied to in vivo data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and was compared among diagnostic groups with use of analysis of covariance controlling for clinical covariates, with a family-wise error-corrected P < .05 considered indicative of a statistically significant difference. Results Eighteen donors with or without AD (mean age, 69 years ± 13 [SD]; 15 men) and 110 ADNI participants (mean age, 76 years ± 6.8; 65 women) were evaluated. Microstructural asymmetry of the projection fibers was higher in Aβ-negative postmortem specimens than Aβ-positive (Aβ-negative mean, 0.98; Aβ-positive mean, 0.95; P = .045), while asymmetry of the association fibers correlated negatively with age (r = -0.48; P = .044). In the ADNI data, the uncorrected ALPS correlated positively with the Preclinical Alzheimer's Cognitive Composite (PACC) score (r = 0.30; P = .001) and negatively with florbetapir (AV45) PET (r = -0.27; P = .005). For the corrected ALPS, the correlation with AV45 PET was not statistically significant (r = -0.18; P = .059), and the correlation with the PACC score (r = 0.26; P = .006) decreased (Steiger test z = 2.99; P = .003). Conclusion Microstructural asymmetry observed in postmortem DTI-ALPS varied with Aβ pathologic characteristics and age, and after the minimization of microstructural bias, the corrected ALPS correlated less with AD markers in vivo. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Rovira and Pareto in this issue.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/diagnostic imaging/pathology
*Diffusion Tensor Imaging/methods
Aged, 80 and over
Autopsy
Middle Aged
*Brain/diagnostic imaging/pathology
*Glymphatic System/diagnostic imaging/pathology

@article {pmid40956013,
year = {2025},
author = {Sáez, JC and Ocaranza, FJ and Prieto-Villalobos, J and Orellana, JA},
title = {Connexin and Pannexin Hemichannels: Broad-Spectrum Players in Neuroinflammatory Signaling.},
journal = {Journal of neurochemistry},
volume = {169},
number = {9},
pages = {e70237},
doi = {10.1111/jnc.70237},
pmid = {40956013},
issn = {1471-4159},
support = {1231523//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; 1250847//Fondo Nacional de Desarrollo Científico y Tecnológico/ ; },
mesh = {*Connexins/metabolism ; Humans ; Animals ; *Neuroinflammatory Diseases/metabolism ; *Signal Transduction/physiology ; *Nerve Tissue Proteins/metabolism ; },
abstract = {Connexin- and pannexin-formed hemichannels have emerged as pivotal, upstream amplifiers of neuroinflammation. Under physiological stressors-depolarization, Ca[2+] overload, redox shift, or cytokine exposure-these large pores release adenosine triphosphate, glutamate, and other danger signals that activate P2X/P2Y and N-methyl-D-aspartate receptors, ignite NLR family pyrin domain containing (NLRP) 3 inflammasome, and propagate Ca[2+]/reactive oxygen species waves between mast cells, microglia, astrocytes, oligodendrocytes, neurons, and brain endothelium. Evidence across acute (e.g., stroke, trauma, seizure, and sepsis) and chronic (e.g., Alzheimer's, and multiple sclerosis) models shows that genetic ablation or pharmacological blockade of hemichannels shrinks lesions, preserves synaptic plasticity, restores blood-brain barrier integrity, and rescues cognition, often without altering the primary pathogenic trigger. Translational leads include mimetic peptides (e.g., Gap19, [10]panx1), the nanomolar, gap junction-sparing small-molecule D4, and the pleiotropic alkaloid boldine, all of which curb epileptiform activity, neurodegeneration, and depressive-like behavior. Yet key gaps persist, such as the long-term safety of chronic inhibition, which remains poorly defined and will be critical to translate these "gatekeeper" channels into next-generation neuro-anti-inflammatory therapeutics.},
}

*Connexins/metabolism
Humans
Animals
*Neuroinflammatory Diseases/metabolism
*Signal Transduction/physiology
*Nerve Tissue Proteins/metabolism

@article {pmid40955908,
year = {2025},
author = {Atewogboye, O and Taylor, JP and Harrison, JR},
title = {Pharmacological strategies for managing dementia with Lewy Bodies: an expert review of symptom-targeted care.},
journal = {Expert review of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17512433.2025.2562151},
pmid = {40955908},
issn = {1751-2441},
abstract = {INTRODUCTION: Dementia with Lewy Bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease, characterized by a complex combination of cognitive, neuropsychiatric, motor, autonomic, and sleep-related symptoms. Symptom fluctuation, polypharmacy risks, and high sensitivity to commonly used drugs present unique challenges in its management.

AREAS COVERED: This review provides a comprehensive overview of the symptomatic management of DLB, organized by clinical domains. It critically evaluates current pharmacological and non-pharmacological treatment strategies for cognitive impairment, hallucinations, parkinsonism, autonomic dysfunction, and sleep disturbances. Evidence is drawn from clinical trials, meta-analyses, and extrapolated findings from related disorders such as Alzheimer's disease and Parkinson's disease.

EXPERT OPINION: Effective DLB management requires an individualized, symptom-prioritized approach that carefully balances therapeutic benefit with potential adverse effects, particularly given the high risk of antipsychotic sensitivity and treatment-induced worsening of symptoms. Despite recent progress, evidence remains sparse for many symptom domains. Greater investment in DLB-specific clinical trials and development of targeted therapies is urgently needed to improve patient outcomes.},
}

@article {pmid40955892,
year = {2025},
author = {Mehndiratta, MM and Singla, M and Dixit, A},
title = {Unlocking the Future of Alzheimer's Disease: Innovations in Diagnosis and Therapy.},
journal = {The Journal of the Association of Physicians of India},
volume = {73},
number = {8},
pages = {92-97},
doi = {10.59556/japi.73.1075},
pmid = {40955892},
issn = {0004-5772},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; Biomarkers/metabolism ; Disease Progression ; Cognitive Dysfunction/diagnosis ; Amyloid beta-Peptides/metabolism ; Neurofibrillary Tangles/pathology/metabolism ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is one of the most common forms of dementia, making up around two thirds of all dementia cases globally. Despite its high prevalence, it is estimated to remain undiagnosed in 41 million people with dementia, and with only about 25% of dementia individuals being clinically identified. AD is the major neurodegenerative disorder leading to dementia, characterized by neuronal atrophy and loss. The accumulation of toxic amyloid-beta (Aβ) oligomers, protein aggregates, along with the formation of neurofibrillary tangles (NFTs) within neurons, is the key pathological feature of AD. NFTs are composed of hyperphosphorylated tau protein. These abnormalities contribute to a decline in cerebral glucose metabolism in the brain, synaptic dysfunction, and mitochondrial impairment. The progression of AD occurs in three stages: (1) the presymptomatic stage, (2) mild cognitive impairment (MCI), and (3) the clinical stage of AD. Many biomarkers have been identified for diagnosing AD and differentiating it from atypical AD. It has emerged as a key area of research, offering significant potential for early detection of AD, prognostication, as well as planning drug therapy and monitoring.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
Biomarkers/metabolism
Disease Progression
Cognitive Dysfunction/diagnosis
Amyloid beta-Peptides/metabolism
Neurofibrillary Tangles/pathology/metabolism
tau Proteins/metabolism

@article {pmid40955736,
year = {2025},
author = {Xia, K and Tian, W and Xu, H and Wang, L and Li, X},
title = {Unraveling the structural dynamics of Aβ42 monomer: insights from K16A and K16A + K28A mutations through molecular dynamics simulations.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/07391102.2025.2554351},
pmid = {40955736},
issn = {1538-0254},
abstract = {Alzheimer's disease is a degenerative disease of the central nervous system that pre-dominantly affects the elderly population. The main reason is that amyloid beta 42 has a strong tendency to aggregate, which easily induces the damage to the central nervous system. It was shown that residues 16 and 28 play a key role in the self-assembly process. Moreover, these studies have revealed that substituting alanine for these residues can weaken the toxicity of Aβ. While numerous studies,including molecular dynamics simulations, have emphasized the significance of K16 and K28 in Aβ aggregation and toxicity, the specific impact of their combined mutation(K16A + K28A) on the structural dynamics and toxicity of Aβ remain unclear. Therefore, in this paper, molecular dynamics simulations were used to investigate the structural changes and kinetic properties of Aβ42 protein by the two mutant systems. The results show that both mutant systems inhibit the high flexibility of wild-type Aβ protein during the simulation. By observing the changes in protein structure in different systems, it is found that the K16A system was able to maintain the natural helical conformation of Aβ42 and also inhibit the generation of β-sheet structures. However, for the K16A + K28A system, it not only destroys the helical structure, but also produces more β-sheet structures. The analysis of residue contacts revealed that this phenomenon. The K16A system was able to decrease the interaction between the hp1fragment and the C-terminus in the Aβ42 monomer, whereas the two-point mutation increased this interaction.},
}

@article {pmid40955720,
year = {2025},
author = {Yaari, R and Holdridge, KC and Williamson, M and Wessels, AM and Shcherbinin, S and Kotari, V and Reiman, EM and Tariot, PN and Alexander, R and Langbaum, JB and Sims, JR},
title = {Donanemab in preclinical Alzheimer's disease: Screening and baseline data from TRAILBLAZER-ALZ 3.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70662},
doi = {10.1002/alz.70662},
pmid = {40955720},
issn = {1552-5279},
support = {//Eli Lilly and Company/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/diagnostic imaging ; Aged ; *tau Proteins/blood ; Double-Blind Method ; Male ; Female ; Aged, 80 and over ; Positron-Emission Tomography ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Amyloid beta-Peptides ; },
abstract = {INTRODUCTION: TRAILBLAZER-ALZ 3 is investigating donanemab in preclinical Alzheimer's disease (AD).

METHODS: This double-blind, placebo-controlled trial used a plasma phosphorylated tau-217 (p-tau217) assay to detect AD pathology for eligibility and a decentralized design to enhance screening and enrollment. After nine monthly infusions, clinical assessments continue every 6 months with a time-to-event primary outcome. A sub-study will evaluate longitudinal changes in amyloid and tau positron emission tomography (PET).

RESULTS: Participants 55-80 years of age were screened (N = 63,124). Plasma p-tau217-eligible participants were enrolled (N = 2196), with Clinical Dementia Rating (CDR) scale-Global score (CDR-GS) of 0 (n = 1202) and 0.5 (n = 664). Plasma p-tau217 eligibility increased with age, differing across races and ethnicities. Mean baseline amyloid levels were 63.2 (CDR-GS: 0) and 70.7 Centiloids (CDR-GS: 0.5). Elevated global tau signal (standardized uptake value ratio ≥1.10) was observed in 15.1% and 26.3% of CDR-GS 0 and 0.5 subgroups, respectively.

DISCUSSION: Utilizing a unique decentralized design, the trial showed baseline data consistent with preclinical AD.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05026866, TRAILBLAZER-ALZ 3 HIGHLIGHTS: TRAILBLAZER-ALZ 3 screened 63,124 participants in the United States and Japan Plasma phosphorylated tau-217 (p-tau217) was used to determine Alzheimer's disease pathology for eligibility A decentralized model was used, including remote raters for clinical testing Randomized participants had Clinical Dementia Rating scale-Global scores of 0 and 0.5.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis/diagnostic imaging
Aged
*tau Proteins/blood
Double-Blind Method
Male
Female
Aged, 80 and over
Positron-Emission Tomography
Middle Aged
*Antibodies, Monoclonal, Humanized/therapeutic use
Amyloid beta-Peptides

@article {pmid40955711,
year = {2025},
author = {Tan, A and Wang, Z and Aumont, E and Li, A and Qin, X and Yang, X and Feng, W and Yang, J and Li, X and Xiao, J and Zhou, B and Xing, Y and Yi, Y and Li, J},
title = {Determinants of Treatment Willingness and Willingness-to-Pay for Lecanemab in China: A Network Analysis.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000689},
pmid = {40955711},
issn = {1546-4156},
abstract = {BACKGROUND: Lecanemab is the first disease-modifying therapy for Alzheimer's disease (AD) approved in China. However, the factors affecting patient and caregiver willingness to adopt this novel treatment have not been assessed yet.

OBJECTIVE: To investigate the factors influencing both treatment willingness and willingness-to-pay for lecanemab among Chinese AD patients and their caregivers.

METHODS: We surveyed 195 AD patients and their caregivers using structured questionnaires assessing key factors influencing treatment willingness, including efficacy (Wefficacy), adverse effects (Wadverse), inconvenience (Winconvenience), cost (Wcost), overall willingness to treat (Wtreat), and amount willing to pay (Wamount). Additional variables included income, cognitive and functional assessments, caregiver burden (ZBI), health status (HS), education levels (patient/caregiver: edu, edu.c), psychiatric symptoms (PSY), and satisfaction with conventional treatments (effect). Network analysis mapped variable inter-relationships.

RESULTS: Wtreat showed a strong direct association with Wcost (0.99). Wefficacy and Winconvenience indirectly influenced Wtreat through Wcost (Wefficacy-Winconvenience: 1.5, Winconvenience-Wcost: 1.12, Wcost-Wtreat: 0.99). Income (0.48) and effect (0.51) directly impacted Wtreat. Edu, edu.c, CDR, PSY, ZBI, and HS were indirectly correlated with Wtreat. Wamount was directly associated with Wtreat (0.31), Wcost (0.68), and Wadverse (0.16). Wefficacy and Winconvenience indirectly influenced Wamount through Wcost (Wefficacy- Winconvenience: 1.5, Winconvenience-Wcost: 1.12, Wcost-Wamount: 0.68). Network stability tests (CS >0.50) confirmed robustness.

CONCLUSION: This study demonstrates that reducing payment barriers has a greater impact on real-world adoption of innovative therapies than clinical efficacy alone. Addressing financial constraints also enhances patients' willingness to pay. These findings provide evidence-based insights for developing patient-centered clinical decision pathways.},
}

@article {pmid40955699,
year = {2025},
author = {Guo, J and Zhang, H and Geng, Z and Dai, N and Fu, B and Kong, QX and Fu, X},
title = {Application of Mendelian Randomization Analysis on the Exploration of the Association Between Immune Cell Phenotypes and Alzheimer's disease.},
journal = {The Journal of nervous and mental disease},
volume = {},
number = {},
pages = {},
pmid = {40955699},
issn = {1539-736X},
support = {2023YXNS061//the Key Research and Development Plan of Jining City/ ; },
abstract = {INTRODUCTION: This study explores the correlation between immune inflammation and Alzheimer's disease (AD), focusing on immune-brain interactions impacting neurodevelopment and function.

METHODS: Public genetic data were used to analyze 731 immune cell signals, employing two-sample Mendelian randomization, with multiple testing corrected by the Bonferroni-adjusted false discovery rate (FDR).

RESULTS: Six immune phenotypes were identified as significantly increasing AD risk (effect sizes ranging from OR=1.038 to 1.123), including HLA DR on CD33+ HLA DR+ CD14-, HLA DR on CD14+ monocyte, CD4+ CD8dim T cells (% lymphocytes), CD33 on HLA DR on CD14+ CD16- monocyte, CD33 on CD33+ HLA-DR+ CD14dim cells and CD11c on CD62L+ myeloid dendritic cell.

CONCLUSION: This study confirms the genetic association between specific immune cells and AD, highlighting potential immune-related biomarkers for AD risk.},
}

@article {pmid40955614,
year = {2025},
author = {Baek, MJ and Park, YH and Kim, S},
title = {Comparison Between the Mini-Mental State Examination and the Mini-Mental State Examination-2 in Patients With Mild Cognitive Impairment and Alzheimer's Disease.},
journal = {Journal of Korean medical science},
volume = {40},
number = {36},
pages = {e235},
doi = {10.3346/jkms.2025.40.e235},
pmid = {40955614},
issn = {1598-6357},
support = {//Ministry of Knowledge/Saudi Arabia ; 10035434/KEIT/Korea Evaluation Institute of Industrial Technology/Korea ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; *Alzheimer Disease/diagnosis/psychology ; Male ; Aged ; Female ; ROC Curve ; *Mental Status and Dementia Tests ; Area Under Curve ; Aged, 80 and over ; Neuropsychological Tests ; Middle Aged ; Sensitivity and Specificity ; Discriminant Analysis ; Republic of Korea ; },
abstract = {BACKGROUND: This study aimed to compare the diagnostic utility of the Mini-Mental State Examination-2 (MMSE-2) and the Korean version of the Mini-Mental State Examination (K-MMSE) in differentiating normal cognitive aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD) within a Korean population.

METHODS: A total of 226 individuals with MCI, 97 with AD, and 91 cognitively healthy older adults were recruited. Participants underwent the MMSE-2, K-MMSE, and a comprehensive neuropsychological assessment battery. Discriminant analysis was employed to compare the classification accuracy of each tool, while sensitivity and specificity were evaluated using receiver operating characteristic (ROC) curve analysis.

RESULTS: Discriminant analysis revealed that the MMSE-2 accurately classified 71.1% of participants, including 68.6% of MCI patients, 78.4% of AD patients, and 72.5% of healthy controls. In contrast, the K-MMSE achieved an overall classification accuracy of 67.9%, with 83.6% accuracy for MCI, 68.0% for AD, and 28.6% for healthy controls. ROC analysis indicated that the area under the curve (AUC) values for the MMSE-2: Brief Version (BV) (0.708), Standard Version (SV) (0.720), and Expanded Version (EV) (0.728) surpassed that of the K-MMSE (0.703) in distinguishing healthy controls from MCI patients. However, the K-MMSE (AUC = 0.936) demonstrated superior performance compared to the MMSE-2:BV (0.930), MMSE-2:SV (0.925), and MMSE-2:EV (0.921) in differentiating MCI from AD.

CONCLUSION: The MMSE-2:SV and MMSE-2:EV exhibit greater sensitivity in detecting cognitive impairment between normal aging and MCI. Conversely, the MMSE-2:BV and K-MMSE demonstrate superior sensitivity in distinguishing between MCI and AD. These findings underscore the importance of selecting an appropriate cognitive assessment tool based on specific diagnostic objectives and clinical contexts.},
}

Humans
*Cognitive Dysfunction/diagnosis
*Alzheimer Disease/diagnosis/psychology
Male
Aged
Female
ROC Curve
*Mental Status and Dementia Tests
Area Under Curve
Aged, 80 and over
Neuropsychological Tests
Middle Aged
Sensitivity and Specificity
Discriminant Analysis
Republic of Korea

@article {pmid40955474,
year = {2025},
author = {Edler, MC and Faber, K and Lacy, K and Jackson, J and Foroud, T},
title = {NCRAD: Advancing Alzheimer's research through high-quality biospecimens and data.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70682},
doi = {10.1002/alz.70682},
pmid = {40955474},
issn = {1552-5279},
support = {U24 AG021886/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; *Biological Specimen Banks ; Biomarkers ; *Biomedical Research ; Specimen Handling ; },
abstract = {The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) was established in 2002 to support research on the genetics of Alzheimer's disease. NCRAD quickly became a central resource, banking samples from numerous studies and distributing them to researchers worldwide. As genetic risk variants were identified, NCRAD prepared for functional studies by expanding its collections to include peripheral blood mononuclear cells (PBMCs), RNA, and biofluids. Over the past decade, NCRAD's extensive repository of plasma, serum, and cerebrospinal fluid was essential to the development of fluid biomarkers. NCRAD's rigorous best practices for sample collection, processing, and distribution ensure biospecimens are of the highest quality for a broad range of experimental approaches. Currently, NCRAD banks samples from 91 studies representing over 135,000 unique, well-characterized participants, and has distributed over 440,000 aliquots to more than 300 researchers. Data from NCRAD-supported studies have contributed to over 1100 publications and numerous key discoveries in Alzheimer's disease and related dementias (ADRD) genetics and biomarkers. HIGHLIGHTS: Centralized Biobanking for ADRD Research: National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) supports over 90 National Institute on Aging (NIA) -funded studies by providing standardized, high-quality biospecimens and longitudinal sample collections, enabling reproducible and scalable research into Alzheimer's disease and related dementias (ADRD). Enabling Genetic Discovery and Functional Genomics: NCRAD partnerships with numerous research initiatives has facilitated major advances in gene discovery, while also supporting downstream functional studies using induced pluripotent stem cells (iPSCs), transcriptomics, and post mortem brain tissue. Rigorous QA/QC and Automation Infrastructure: NCRAD employs comprehensive quality assurance/quality control (QA/QC) systems and cutting-edge automation-including robotic liquid handling, automated nucleic acid extraction, and ultra-low temperature storage-to ensure biospecimen integrity and reduce preanalytical variability. Unique Sample Distribution and Data Sharing Model: NCRAD's blinded sample distribution system and emphasis on returning data to public repositories ensure broad research access, maximize scientific output, and promote transparency and reproducibility. Collaborative, Scalable Repository Ecosystem: As part of Indiana University's integrated biobanking infrastructure, NCRAD supports efficient cross-study and cross-repository research, enabling large-scale multi-omic and biomarker analyses across diverse neurodegenerative diseases.},
}

Humans
*Alzheimer Disease/genetics
*Biological Specimen Banks
Biomarkers
*Biomedical Research
Specimen Handling

@article {pmid40955309,
year = {2025},
author = {Wang, L and Feng, L and Ning, B and Wang, Z and Dai, C and Li, M},
title = {Natural Products from Chinese Medicine Targeting NF-κB Signaling: Emerging Therapeutic Avenues for Neurodegenerative Diseases.},
journal = {Drug design, development and therapy},
volume = {19},
number = {},
pages = {8135-8159},
pmid = {40955309},
issn = {1177-8881},
mesh = {Humans ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Biological Products/pharmacology/chemistry ; *Medicine, Chinese Traditional ; Signal Transduction/drug effects ; Animals ; *Drugs, Chinese Herbal/pharmacology/chemistry ; },
abstract = {This review summarizes recent advances in leveraging natural products from Chinese medicine to modulate the nuclear factor kappa B (NF-κB) signaling pathway for the prevention and treatment of neurodegenerative diseases (NDDs), focusing specifically on Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). NF-κB proteins regulate cellular biological activity by binding to promoter regions in the nucleus and transcribing various protein-coding genes. Emerging evidence indicates that NF-κB plays a pivotal role in driving key hallmarks of NDD progression, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and dysregulation of the cell cycle. Natural products from Chinese medicine exert modulatory effects on NF-κB signaling through diverse pharmacological mechanisms, ultimately improving cognitive and motor impairments in preclinical NDDs models. The pleiotropic nature of natural products derived from traditional Chinese medicine (TCM)-which operate through subunit-specific modulation of NF-κB-underscores their potential as next-generation therapeutics. Investigating the intricate regulation of NF-κB by natural products from Chinese medicine will not only enrich our understanding of the pathogenesis of NDDs but also establish a theoretical foundation for the development of new therapeutic drugs for NDDs, providing innovative strategies for prevention and treatment.},
}

Humans
*NF-kappa B/metabolism/antagonists & inhibitors
*Neurodegenerative Diseases/drug therapy/metabolism
*Biological Products/pharmacology/chemistry
*Medicine, Chinese Traditional
Signal Transduction/drug effects
Animals
*Drugs, Chinese Herbal/pharmacology/chemistry

@article {pmid40955230,
year = {2025},
author = {Qasim, H and Khattab, K and Abu Shugaer, M and Varrassi, G},
title = {Epigenetic Dysregulation in Neurodegenerative Disease: Implications for Neuropathology and Therapy.},
journal = {Cureus},
volume = {17},
number = {8},
pages = {e90188},
pmid = {40955230},
issn = {2168-8184},
abstract = {Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by progressive neuronal dysfunction, yet their underlying mechanisms remain incompletely understood. Emerging evidence implicates epigenetic dysregulation as a central contributor to the pathogenesis of these disorders. A thematic literature review was conducted across major databases using targeted search terms related to epigenetics and neurodegeneration. Studies were selected based on relevance, methodological quality, and contribution to mechanistic understanding, in accordance with Scale for the Assessment of Narrative Review Articles (SANRA) guidelines. Across AD, PD, and HD, distinct yet overlapping patterns of epigenetic alterations were identified. In AD, dysregulated DNA methylation and histone acetylation affect genes linked to amyloid and tau pathology. In PD, hypomethylation of SNCA and altered histone acetylation contribute to α-synuclein overexpression and neuronal loss. In HD, mutant huntingtin protein disrupts chromatin remodeling by sequestering histone acetyltransferases and altering microRNA expression. These changes disrupt neuronal identity, synaptic function, and inflammatory responses, often forming feedback loops that exacerbate disease progression. Epigenetic mechanisms play a pivotal role in neurodegeneration by mediating gene-environment interactions and perpetuating neuropathological changes. Their reversible nature presents opportunities for therapeutic intervention, though challenges related to specificity, delivery, and timing remain. Continued research into epigenetic biomarkers and precision-targeted epigenetic therapies holds promise for advancing early diagnosis and disease modification in NDDs.},
}

@article {pmid40954504,
year = {2025},
author = {Yang, X and Geng, X and Xu, Z and Xu, Y and Han, H and Zhang, Q and Jin, H and Wang, Y and Sun, B and Zhang, M and Zhang, S and Chen, L},
title = {Ap1s1 reduction in the aging brain heightens neuronal vulnerability to amyloid-β and oxidative stress in Alzheimer's pathogenesis.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {203},
pmid = {40954504},
issn = {1758-9193},
support = {21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 21ZY18//Changchun Science and Technology Bureau/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; 20230399//Liaoning Huayang Grain Co., Ltd/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; *Oxidative Stress/physiology ; *Aging/metabolism/pathology/genetics ; *Brain/metabolism/pathology ; Humans ; Mice ; *Amyloid beta-Peptides/metabolism/toxicity ; *Neurons/metabolism/pathology/drug effects ; Mice, Transgenic ; Disease Models, Animal ; Male ; Aged ; Female ; },
abstract = {Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is characterized by cognitive decline and memory impairment. Brain aging is indisputably the most significant risk factor for AD. Given that aging is a fundamental driving force behind the onset of AD, identifying the aging - regulated genes that contribute to AD development is of utmost importance. Such genes might hold the key to preventing AD or delaying the transition from normal aging to the disease state. In the present study, a comprehensive bioinformatic analysis was conducted on brain transcriptomic datasets obtained from both aging individuals and those with Alzheimer's disease. Among the shared differentially expressed genes, eight genes were found to be downregulated in both aging and AD datasets. Notably, reduced expression of adaptor protein complex 1 sigma 1 subunit (Ap1s1) was validated across multiple mouse models with varying degree of dementia, including aged mice, senescence-accelerated SAMP8 mice, 5xFAD amyloidosis mice, as well as cellular models, including senescent Neuro-2a (N2a) cells, and Aβ-treated or expressing N2a neurons. Functional studies revealed that Ap1s1 knockdown induced cellular senescence without directly impairing viability. However, Ap1s1 silencing exacerbated neuronal vulnerability to oxidative stress (H2O2) and Aβ toxicity, manifesting as Golgi-dispersion and reduced survival. Proteomic profiling following Ap1s1 depletion implicated dysregulation of rRNA modifications in the nucleus and cytosol, Golgi-associated vesicle biogenesis. These findings position Ap1s1 as a critical aging-related gene at the nexus of brain aging and AD pathogenesis, whose decline may predispose neurons to Alzheimer's-related insults. As such, Ap1s1 may represent a potential therapeutic target for mitigating aging-related cognitive decline and delaying the onset of AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
*Oxidative Stress/physiology
*Aging/metabolism/pathology/genetics
*Brain/metabolism/pathology
Humans
Mice
*Amyloid beta-Peptides/metabolism/toxicity
*Neurons/metabolism/pathology/drug effects
Mice, Transgenic
Disease Models, Animal
Male
Aged
Female

@article {pmid40954500,
year = {2025},
author = {Wang, C and Bu, X and Cao, M and Lian, Y and Ling, H and You, M and Yi, J and Gao, X and Wu, D and Li, Y},
title = {Publisher Correction: Mir-199a-3p aggravates neuroinflammation in an Alzheimer's disease transgenic mouse model by promoting M1-polarization microglia.},
journal = {BMC neuroscience},
volume = {26},
number = {1},
pages = {58},
doi = {10.1186/s12868-025-00974-4},
pmid = {40954500},
issn = {1471-2202},
}

@article {pmid40954413,
year = {2025},
author = {Yi, C and Su, Y and Verkhratsky, A},
title = {Targeting Microglial Connexin43 Hemichannels: A Novel Therapeutic Avenue for Alzheimer's Disease.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {40954413},
issn = {1995-8218},
}

@article {pmid40954412,
year = {2025},
author = {Di Stadio, A and Hamiter, MJ and Roccamatisi, D and Lalwani, AK},
title = {Correction to: Hearing Loss and Alzheimer Disease.},
journal = {Current topics in behavioral neurosciences},
volume = {69},
number = {},
pages = {C3},
doi = {10.1007/978-3-031-84920-6_577},
pmid = {40954412},
issn = {1866-3370},
}

@article {pmid40954312,
year = {2025},
author = {Tideman, P and Karlsson, L and Strandberg, O and Calling, S and Smith, R and Midlöv, P and Verghese, PB and Braunstein, JB and Mattsson-Carlgren, N and Stomrud, E and Palmqvist, S and Hansson, O},
title = {Primary care detection of Alzheimer's disease using a self-administered digital cognitive test and blood biomarkers.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {40954312},
issn = {1546-170X},
abstract = {After the clinical implementation of amyloid-β-targeting therapies for people with cognitive impairment due to Alzheimer's disease (AD), there is an urgent need to efficiently identify this patient population in primary care. Therefore, we created a brief and self-administered digital cognitive test battery (BioCog). Based on its sub-scores, a logistic regression model was developed in a secondary care cohort (n = 223) and then evaluated in an independent primary care cohort comprising 19 primary care centers (n = 403). In primary care, BioCog had an accuracy of 85% when using a single cutoff to define cognitive impairment, which was significantly better than the assessment of primary care physicians (accuracy 73%). The accuracy increased to 90% when using a two-cutoff approach. BioCog had significantly higher accuracy than standard paper-and-pencil tests (that is, Mini-Mental State Examination, Montreal Cognitive Assessment, Mini-Cog) and another digital cognitive test. Furthermore, BioCog combined with a blood test could detect clinical, biomarker-verified AD with an accuracy of 90% (one cutoff), significantly better than standard-of-care (accuracy 70%) or when using the blood test alone (accuracy 80%). In conclusion, this proof-of-concept study shows that a brief, self-administered digital cognitive test battery can detect cognitive impairment and, when combined with a blood test, accurately identify clinical AD in primary care.},
}

@article {pmid40954136,
year = {2025},
author = {Martínez-García, J and Fernández, B and Artime, E and Álvarez, L and González-Iglesias, H and Clases, D and Pereiro, R},
title = {ICP-MS for Multiplexed Protein Determination in Extracellular Vesicles from APP/PS1 Mice Blood Serum-Application to a Zn Supplementation Pilot Study.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c03630},
pmid = {40954136},
issn = {1520-6882},
abstract = {Neurodegenerative diseases represent a significant challenge due to their complex etiology, late diagnosis, and lack of effective treatments. Extracellular vesicles (EVs) have emerged as promising carriers of disease biomarkers, especially proteins, but their low abundance in biological fluids complicates their detection. Here, we present a novel strategy for the multiplexed quantitative determination of EV-associated proteins in blood serum from APP/PS1 transgenic mice, a model of Alzheimer's disease. The method combines inductively coupled plasma-time-of-flight mass spectrometry (ICP-ToFMS) with competitive immunoassays using metal nanocluster-labeled (AuNCs, PtNCs, IrNCs) antibodies targeting Alpha-Actinin 1 (ACTN), Galectin-3-binding protein (LG3BP), and Moesin (MSN). EVs were isolated using an optimized ultracentrifugation protocol to reduce the level of serum protein contamination. Proteomic screening identified target proteins with a known relevance to neurodegeneration, and the developed assay achieved detection limits in the low femtomolar range. The approach was applied to a pilot study on Zn supplementation in 16-month-old APP/PS1 mice, revealing sex-dependent and genotype-specific differences in protein expression but sex-independent patterns in regulatory mechanisms (especially for MSN and LG3BP). Among the studied markers, MSN levels showed statistically significant differences with Zn treatment in male homozygous mice. This work demonstrates the potential of ICP-MS for sensitive and multiplexed biomarker quantification in EVs, supporting its use in neurodegenerative research and supplementation studies.},
}

@article {pmid40953827,
year = {2025},
author = {Norevik, CS and Huuha, AM and Røsbjørgen, RN and Bergersen, LH and Jacobsen, K and Miguel-Dos-Santos, R and Ryan, L and Skender, B and Moreira, JBN and Kobro-Flatmoen, A and Witter, MP and Scrimgeour, N and Tari, AR},
title = {Corrigendum to "Exercised blood plasma promotes hippocampal neurogenesis in the Alzheimer's disease rat brain" [J Sport Health Sci 13 (2024) 245-255].},
journal = {Journal of sport and health science},
volume = {},
number = {},
pages = {101084},
doi = {10.1016/j.jshs.2025.101084},
pmid = {40953827},
issn = {2213-2961},
}

@article {pmid40953636,
year = {2025},
author = {Crouse, B and Rossom, RC and Crain, AL and O'Connor, PJ and Jaka, MM and Maciosek, MV and Appana, D and Sharma, R and Gustafson, SK and Werner, AM and Svitak, AL and Ekstrom, HL and Borson, S and Rosenbloom, MH and Sperl-Hillen, JM and O'Keefe, LR and Hanson, LR},
title = {Design and protocol of a pragmatic clinical trial to improve cognitive impairment detection in primary care.},
journal = {Contemporary clinical trials},
volume = {},
number = {},
pages = {108080},
doi = {10.1016/j.cct.2025.108080},
pmid = {40953636},
issn = {1559-2030},
abstract = {BACKGROUND: The prevalence of cognitive impairment (CI) including Alzheimer's disease (AD) and related dementias (ADRD) continues to rise worldwide, but often goes undiagnosed leading to increased burden on patients and families. A clinical decision support system (CDSS) could improve care quality by assisting primary care clinicians (PCCs) to recognize, evaluate, diagnose, and manage patients with CI.

METHODS: 38 primary care clinics are randomized to receive the study intervention or usual care (UC). The study intervention consists of a cognitive impairment clinical decision support system (CI-CDSS) and a brief CI-focused training. The CI-CDSS utilizes electronic health record (EHR) data to alert PCCs of patients who may be at high risk for CI, determined by either an abnormal cognitive assessment or identification as high risk using a prototype prediction model developed for this study that estimates likelihood of developing CI in the next 3 years. It also provides tools and resources to evaluate and diagnose CI and gives recommendations for managing care of patients with CI.

ENDPOINTS: The primary outcome is EHR documentation of CI diagnosis up to 18 months after accrual. Secondary outcomes include healthcare costs and PCC confidence in diagnosis and management of patients with CI.

CONCLUSION: This pragmatic, cluster-randomized, Phase III clinical trial aims to assess the effectiveness of a CDSS in increasing detection of CI in primary care. If successful, this system could provide up-to-date personalized recommendations for CI diagnosis and management to improve patient care.},
}

@article {pmid40953390,
year = {2025},
author = {Creapeau, LJ and Airth-Kindree, NM and Goodman, JA},
title = {Brain and Body Fitness Group for Those With Dementia and Their Caregivers Through Community Partnership: A Program Evaluation.},
journal = {WMJ : official publication of the State Medical Society of Wisconsin},
volume = {124},
number = {3},
pages = {265-269},
pmid = {40953390},
issn = {2379-3961},
mesh = {Humans ; *Caregivers/psychology ; Male ; Female ; *Dementia/psychology/therapy ; Quality of Life ; Aged ; Program Evaluation ; Middle Aged ; Aged, 80 and over ; Wisconsin ; },
abstract = {INTRODUCTION: The growing prevalence of dementia calls for nonpharmacological interventions to reduce negative quality of life effects for those living with dementia and their caregivers. Brain and Body Fitness, a community-based collaborative group program, engages people living with dementia and their caregivers through a combination of physical, cognitive, and socialization strategies, to maximize health benefits for sustained functioning.

METHODS: Using an adapted form of the Patient-Reported Outcomes Measurement Information System (PROMIS) Applied Cognition tool, ex post facto data were collected from both participants affected with Alzheimer's disease and related dementias and their caregivers during 12 biweekly sessions of the Brain and Body Fitness program conducted from 2017 through 2021.

RESULTS: Brain and Body Fitness program participants were affected by 4 quality of life indicators: anxiety, sleep, fatigue, and depression. Data reveal significant reductions in anxiety symptoms and significant improvements in fatigue for affected participants. Anecdotally, the program demonstrates nonsignificant trends of overall mood improvement.

CONCLUSIONS: Given the positive outcomes, communities may consider adopting a similar program to provide additional support for participants.},
}

Humans
*Caregivers/psychology
Male
Female
*Dementia/psychology/therapy
Quality of Life
Aged
Program Evaluation
Middle Aged
Aged, 80 and over
Wisconsin

@article {pmid40953372,
year = {2025},
author = {Parkman, S and Larouche, J and Condon, A and Aboueissa, AE},
title = {Enhancing Empathy: A Mixed Methods Exploration of Dementia Simulation in Occupational Therapy and Nursing Education.},
journal = {Journal of gerontological nursing},
volume = {},
number = {},
pages = {1-7},
doi = {10.3928/00989134-20250908-03},
pmid = {40953372},
issn = {0098-9134},
abstract = {PURPOSE: Dementia, including Alzheimer's disease, poses complex challenges requiring health care providers to respond with empathy and skill. The current study examined whether a simulation-based dementia education intervention could enhance empathy in health care students.

METHODS: Using embedded mixed methods, one-group quasi-experimental design, empathy levels in 125 prelicensure nursing and graduate occupational therapy students were measured via the Kiersma-Chen Empathy Scale-Revised (KCES-R) before, immediately after, and 6 weeks post-simulation. In addition, 36 post-debriefing focus groups explored student experiences qualitatively.

RESULTS: Findings showed significant empathy score increases across all time points (F[2,124] = 17.02, p < 0.001). Thematic analysis revealed five themes: The Illusion of Empathy, Developing Empathetic Skills, Confronting Uncomfortable Truths, The Eureka Moment: Transformative Realizations, and Empathy and Power Dynamics.

CONCLUSION: Findings suggest that simulation-based dementia experience improves empathy and motivates students to provide better care. Experiential learning is critical to preparing future health care professionals to meet the growing demands of dementia care.},
}

@article {pmid40953349,
year = {2025},
author = {Pinheiro, A and Ekenze, O and Aparicio, HJ and Beiser, AS and Decarli, CS and Demissie, S and Seshadri, S and Romero, JR},
title = {Multimarker Cerebral Small Vessel Disease Score and Risk of Incident Dementia in the Framingham Heart Study.},
journal = {Neurology},
volume = {105},
number = {7},
pages = {e214113},
doi = {10.1212/WNL.0000000000214113},
pmid = {40953349},
issn = {1526-632X},
mesh = {Humans ; Male ; Female ; *Cerebral Small Vessel Diseases/diagnostic imaging/epidemiology/complications ; Aged ; Magnetic Resonance Imaging ; *Dementia/epidemiology/diagnostic imaging ; Middle Aged ; Biomarkers ; Cohort Studies ; Risk Factors ; Incidence ; Aged, 80 and over ; Risk Assessment ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND AND OBJECTIVES: Individual MRI markers of cerebral small vessel disease (CSVD) are associated with impaired cognition and dementia but may not reflect the overall burden of CSVD. In addition, it is unclear whether these markers provide additional value in dementia risk assessment beyond vascular risk factors alone. Thus, we studied the association between the additive burden of multiple CSVD markers and incident dementia and determined whether this relationship remains independent of the Framingham Stroke Risk Profile (FSRP), a tool used commonly used for stroke risk prediction.

METHODS: A total of 1,152 MRI scans from participants in the Original and Offspring cohorts of the Framingham Heart Study, a large observational cohort study, were included. Participants were older than 55 years and free of prevalent dementia, stroke, or other neurologic conditions at the time of MRI. A multimarker score capturing CSVD burden was defined as the sum of CSVD features detected in the MRI: cerebral microbleeds, covert brain infarcts, extensive white matter hyperintensities, high-burden perivascular spaces, and cortical superficial siderosis. Multivariate Cox regression models examined the association between the multimarker CSVD score and incident all-cause dementia, Alzheimer dementia (AD), and vascular dementia.

RESULTS: The mean age was 70.9 years (SD 8.7) (527 [46%] were male), and 211 (18%) had a CSVD score of ≥2. Over a median follow-up time of 7.4 years (interquartile range 4.6-11.3), participants with a score ≥2 had significantly elevated risk of all-cause dementia compared with those with no CSVD markers after adjustment for the FSRP (hazard ratio [HR] 1.67; 95% CI 1.05-2.66) and vascular risk factors (HR 1.76; 95% CI 1.10-2.81). The multimarker CSVD score demonstrated similar model performance metrics to the FSRP (Harrell c-statistics 0.82-0.83).

DISCUSSION: We found a significant association between all-cause dementia and multimarker CSVD scores, which was independent of the FSRP as well as its individual components. Our results support the use of a multimarker CSVD score as an indicator for incident all-cause dementia risk and suggest that it may be as robust as the FSRP. Further studies are necessary to validate the use of a multimarker CSVD score in dementia risk prediction.},
}

Humans
Male
Female
*Cerebral Small Vessel Diseases/diagnostic imaging/epidemiology/complications
Aged
Magnetic Resonance Imaging
*Dementia/epidemiology/diagnostic imaging
Middle Aged
Biomarkers
Cohort Studies
Risk Factors
Incidence
Aged, 80 and over
Risk Assessment
Brain/diagnostic imaging

@article {pmid40953123,
year = {2025},
author = {Haaland, B and Dickson, SP and Santana, AF and Tanzi, RE and Dubois, B and Peters, O and Grimmer, T and Christensen, J and Mallinckrodt, C and Schneeberger, A and Hendrix, SB},
title = {Efficacy of AD04, an aluminum-based vaccine adjuvant, in patients with early Alzheimer's disease: Post hoc analysis of AFF006 (NCT01117818), a proof-of-concept, phase 2 randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375985},
doi = {10.1177/13872877251375985},
pmid = {40953123},
issn = {1875-8908},
abstract = {BackgroundThe AFF006 trial (NCT01117818) provided unexpected evidence of benefits of the vaccine adjuvant AD04 (aluminum oxyhydroxide) in patients with early Alzheimer's disease (AD), compared with AD02, a vaccine consisting of a peptide that mimics the N-terminal region of human amyloid-β (Aβ) conjugated with keyhole limpet hemocyanin.ObjectiveThe objective of this post hoc analysis was to assess whether this unexpected benefit of AD04 was an artifact of multiple testing (i.e., type I error inflation) or a robust result.MethodsIn this post hoc assessment, we used permutation testing to estimate type I error inflation due to the evaluation of multiple outcomes in AFF006. Efficacy was assessed using a patient-level global statistical test combining composite endpoints of cognition, function, and global AD. In addition, we examined the observed treatment benefits of AD04 in the context of effects observed in trials of aducanumab, donanemab, and lecanemab, monoclonal anti-Aβ antibodies that received regulatory approval for AD.ResultsThe global statistical test suggested a treatment benefit of AD04 versus ineffective AD02 arms, even after accounting for multiplicity (primary methodology p-value, 0.03; permutation test p-value, 0.02). The observed effect estimates for AD04 compared favorably with approved monoclonal antibodies.ConclusionsPost-hoc analyses are hypothesis generating rather than confirmatory. Adjusting for multiplicity using permutation testing can determine whether post-hoc effects are worth pursuing, or unlikely to be confirmed. These analyses have motivated a follow-up prospective randomized controlled trial, ADVANCE (EudraCT 2022-003532-73), in which optimized AD04 dosing will be compared to placebo in early AD.},
}

@article {pmid40953121,
year = {2025},
author = {Gao, M and Chen, J and Zhang, B and Li, J and Lang, J and Zhao, X and Zhang, Q},
title = {Melatonin alleviates cognitive impairment via modulating NLRP3/Caspase 1 pathway in db/db mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375479},
doi = {10.1177/13872877251375479},
pmid = {40953121},
issn = {1875-8908},
abstract = {BackgroundActivation of NLRP3 inflammasome has been implicated in cognitive impairment. Melatonin, known for its anti-inflammatory properties and traditional use in regulating circadian rhythms, is the focus of this study. This study intended to investigate the role of melatonin in diabetic cognitive impairment model.ObjectiveThe present study aimed to investigate the underlying mechanism of melatonin in alleviating diabetic cognitive impairment by suppressing NLRP3/Caspase 1 signaling pathway.MethodsCognitive function was assessed using Morris water maze test and Novel Object Recognition test. Apoptosis rate of hippocampal neurons was evaluated by TUNEL staining. Western blot was used to evaluate NLRP3/Caspase 1 pathway expression. Double immunofluorescence labelling of GFAP, Iba-1 or NeuN with NLRP3 respectively showed the localization of NLRP3 in hippocampus of db/db mice. In vitro, HT-22 cells treated with high glucose as cellular model were transfected with pc-DNA3.1-mNLRP3 or co-cultured with NLRP3 inhibitor MCC950 to elucidate NLRP3/Caspase 1 pathway in neuronal apoptosis regulation.ResultsMelatonin treatment improved cognitive function and morphologic abnormalities of hippocampal neurons. The double immunofluorescence labelling revealed melatonin inhibited NLRP3 inflammasome activation in hippocampal neurons rather than microglia or astrocytes. TUNEL staining and western blot showed melatonin markedly reversed the upregulation of NLRP3/Caspase 1 signaling pathway against neuronal apoptosis.ConclusionsMelatonin attenuates diabetic cognitive impairment in db/db mice with down-regulation of NLRP3/Caspase 1 signaling pathway. In vivo and vitro studies supported that NLRP3 activation in hippocampal neurons was associated with diabetic cognitive impairment progression.},
}

@article {pmid40953110,
year = {2025},
author = {Lohman, T and Sible, I and Kapoor, A and Engstrom, AC and Shenasa, F and Alitin, JPM and Gaubert, A and Rodgers, KE and Bradford, D and Mather, M and Han, SD and Head, E and Sordo, L and Thayer, JF and Nation, DA},
title = {Impaired parasympathetic network function confers susceptibility to neurodegeneration and memory impairment in older adults with elevated beat-to-beat blood pressure variability.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251376715},
doi = {10.1177/13872877251376715},
pmid = {40953110},
issn = {1875-8908},
abstract = {BackgroundBlood pressure variability (BPV) is associated with neurodegeneration and cognitive decline independent of average pressure. The effect of parasympathetic central autonomic network (CAN) impairment on this relationship has not been assessed.ObjectiveDetermine whether parasympathetic CAN network function affects the relationship between BPV and neurodegenerative markers.Methods100 independently living older adults (55-89 years) underwent continuous blood pressure monitoring, neuropsychological testing, venipuncture, and brain MRI. Hippocampal volumes and entorhinal cortex thicknesses were assessed. Functional connectivity within a parasympathetic cardiovascular control network was used as a measure of parasympathetic CAN function. Plasma glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) were used as measures of glial and neuronal injury, respectively.ResultsElevated BPV was associated with left hippocampal atrophy (p = 0.03) and elevated plasma GFAP (p = 0.005) independent of age, sex, vascular risk factor burden, total intracranial volume (when applicable) and average blood pressure. These relationships were not mediated by parasympathetic central autonomic network impairment. Instead, parasympathetic CAN impairment conferred a vulnerability to elevated BPV. In participants with decreased parasympathetic CAN connectivity elevated BPV was associated with left entorhinal cortex atrophy (p = 0.0001), elevated plasma GFAP (p = 0.0001), elevated plasma NfL (p = 0.001), and memory impairment (p = 0.007).ConclusionsFindings suggest elevated beat-to-beat BPV is directly related to brain injury, and this effect is not mediated by CAN dysfunction. Instead, CAN impairment may confer a susceptibility to glial and neuronal injury in older adults with elevated beat-to-beat blood pressure variability. Mechanisms underlying increased susceptibility to BPV elevation in those with CAN dysfunction warrants further study.},
}

@article {pmid40953107,
year = {2025},
author = {Li, H and Wu, Y and Huang, T and Sun, Y and Lu, Z and Li, M and Wo, H and Shao, F and Tang, S and Zhao, Y and Dai, J and Yi, H},
title = {Development of a risk prediction model for Alzheimer's disease based on the UK Biobank prospective study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375473},
doi = {10.1177/13872877251375473},
pmid = {40953107},
issn = {1875-8908},
abstract = {BackgroundEarly prevention and intervention for Alzheimer's disease (AD) are critical due to the absence of effective therapeutic treatment. However, a widely accepted risk prediction model for AD has yet to be established.ObjectiveTo develop a novel risk prediction model for AD by leveraging recent advances in identifying risk factors, focusing on multi-omics data.MethodsGenetic data from the UK Biobank were employed to calculate the polygenic risk score (PRS) using the clumping and thresholding (C + T) method. Univariate Cox regression and Elastic Net Cox models were utilized to identify significant predictors in the training cohort. Subsequently, a multivariate Cox regression model was developed to construct the prediction model, which was visualized using a nomogram. The performance of the model was evaluated through calibration curves, receiver operating characteristic (ROC) curves, and the Hosmer-Lemeshow test.ResultsTen risk factors, including age, education, family history of dementia, diabetes, depression, hypertension, anemia, coronary heart disease (CAD), falls and PRS, were identified as significant predictors through Cox regression and Elastic Net Cox model. The model demonstrated strong predictive performance, with area under the curves (AUCs) of 0.864 [95% CI: (0.814, 0.911)], 0.860 [95% CI: (0.842, 0.876)], and 0.842 [95% CI: (0.819, 0.863)] at 5, 10, and 14 years, respectively, in the validation cohort.ConclusionsIncorporating colocalized single nucleotide polymorphisms (SNPs) into the PRS derived using the C + T method significantly enhances predictive accuracy. This study highlights the importance of integrating multimodal patient data, including colocalized genetic information, to refine AD risk prediction.},
}

@article {pmid40953029,
year = {2025},
author = {Park, R and Chevalier, C and Kieser, S and Marizzoni, M and Paquis, A and Armand, S and Scheffler, M and Allali, G and Assal, F and Momjian, S and Frisoni, GB},
title = {Gut microbiome signatures in iNPH: Insights from a shotgun metagenomics study.},
journal = {PloS one},
volume = {20},
number = {9},
pages = {e0330251},
doi = {10.1371/journal.pone.0330251},
pmid = {40953029},
issn = {1932-6203},
abstract = {Idiopathic normal pressure hydrocephalus (iNPH), a leading cause of reversible dementia in older adults, is marked by ventriculomegaly, gait disturbances, cognitive decline, and urinary incontinence. Emerging evidence suggests that gut dysbiosis (microbial imbalance) may influence neuroinflammation and cerebrospinal fluid dynamics, potentially contributing to glymphatic system dysfunction and ventricular enlargement. This study used shotgun metagenomics to analyze the gut microbiome in iNPH patients (n = 18) compared to healthy controls (n = 50), individuals with ventriculomegaly but no iNPH symptoms (n = 50), and Alzheimer's disease patients (n = 50). Microbiome analysis showed an enrichment of species previously linked to various disease states, such as Enterocloster bolteae and Ruminococcus gnavus, indicating general dysbiosis. In contrast, enrichment of specific taxa, including Evtepia gabavorous and Cuneatibacter sp., were specifically associated with iNPH clinical traits, pointing to possible disease-specific microbial markers. Functional analysis showed enrichment of pathways related to carbohydrate and amino acid metabolism, including the S-adenosyl-L-methionine superpathway, implicating inflammatory and immune processes. These findings suggest distinct gut microbiome signatures in iNPH, offering insights into potential gut-brain interactions that may contribute to the disorder's pathophysiology and highlighting possible targets for future therapeutic strategies.},
}

@article {pmid40953027,
year = {2025},
author = {Casanova, F and Tian, Q and Williamson, DS and Lucas, MR and Zweibaum, D and Ding, J and Atkins, JL and Melzer, D and Ferrucci, L and Pilling, LC},
title = {Predictors of MRI-estimated brain iron deposition in dementia and Parkinson's disease-associated subcortical regions: Genetic and observational analysis in UK Biobank.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375432},
doi = {10.1177/13872877251375432},
pmid = {40953027},
issn = {1875-8908},
abstract = {BackgroundBrain iron in specific subcortical regions increases risk of dementia and Parkinson's disease (PD). Genetic and environmental factors affect iron deposition, but underlying mechanisms are unclear.ObjectiveIdentify risk factors and diseases associated with brain iron; assess causality using genetics.Methods41,581 UK Biobank participants had MRI-estimated brain iron (QSM method) in five dementia or PD-associated subcortical regions (caudate, hippocampus, putamen, substantia nigra, thalamus). We investigated common risk factors (including adiposity, blood pressure, health behaviors, inflammation) and diseases observationally, using covariate-adjusted regression models, and genetically, with Mendelian randomization.ResultsParticipants diagnosed with Alzheimer's disease, PD, or other diseases had higher MRI-estimated brain iron. Anemia, osteoporosis, and hyperparathyroidism were associated with lower brain iron. Higher body mass index and blood pressure, smoking history, and self-reported meat consumption, increased brain iron. Hematological parameters, inflammatory and kidney biomarkers, and calcium, were also associated. Genetics support causal effects of depression, type-2 diabetes, and 7 other diseases with increased iron, but not Alzheimer's disease. Evidence supports a causal effect of osteoporosis on lower iron in the substantia nigra. We found causal associations between adiposity and proteins (including IL-6 receptor and transferrin receptor) on subcortical brain iron.ConclusionsWe identified causal effects for liability to type-2 diabetes, depression, and other conditions, on subcortical MRI-estimated brain iron, but not to Alzheimer's disease, supportive of dementia as a consequence of brain iron deposition, not a cause. The role of adiposity reducing interventions on brain iron should be investigated. Relationships between brain iron, osteoporosis, calcium, and hyperparathyroidism warrant further investigation.},
}

@article {pmid40952998,
year = {2025},
author = {Jeon, S and Alia, AO and Popovic, J and Vassar, R and Cuddy, LK},
title = {ACE1 does not influence cerebral Aβ degradation or amyloid plaque accumulation in 5XFAD mice.},
journal = {PloS one},
volume = {20},
number = {9},
pages = {e0330193},
doi = {10.1371/journal.pone.0330193},
pmid = {40952998},
issn = {1932-6203},
abstract = {Alzheimer's disease is the most common form of dementia, and multiple lines of evidence support the relevance of Aβ deposition and amyloid plaque accumulation in the neurotoxicity and cognitive decline in AD. Rare mutations in angiotensin-converting-enzyme-1 have been highly associated with late onset AD patients; however, the mechanism for ACE1 mutation in AD pathogenesis is unknown. While numerous studies have shown that ACE1 indeed catabolizes Aβ, majority of these studies were performed in vitro, and conflicting results have been reported in clinical and in vivo systems. Therefore, we further investigated this in vivo by generating and examining a novel mouse model. Specifically, we analyzed 6-month-old 5XFAD mice with ACE1 knockdown restricted to excitatory neurons, achieved by driving Cre recombinase expression under the CamKIIα promoter. These mice were generated by crossing 5XFAD mice to ACE1 conditional knockout mice expressing Cre specifically in excitatory neurons. Our analyses revealed that neuronal ACE1 knockdown does not significantly affect amyloid plaque load and neuroinflammation in the hippocampus and cortex of 5XFAD mice at 6-months of age.},
}

@article {pmid40952927,
year = {2025},
author = {Cardoso, S and Montalvo, A and Maroco, J and Silva, D and Alves, L and Guerreiro, M and de Mendonça, A},
title = {Long-term predictive accuracy of the 'mild cognitive impairment due to Alzheimer's disease' criteria.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251375927},
doi = {10.1177/13872877251375927},
pmid = {40952927},
issn = {1875-8908},
abstract = {BackgroundThe development and clinical use of biomarkers has dramatically changed the framework of Alzheimer's disease (AD) management, allowing the diagnosis at the mild cognitive impairment (MCI) stage. In 2015 we compared the prevalence and prognosis of AD at the MCI stage according to different criteria available at that time, and we found that the National Institute of Aging-Alzheimer Association (NIA-AA) criteria provided higher predictive accuracy for AD dementia after 3 years. Since then, we adopted these criteria in clinical practice.ObjectiveTo evaluate the long-term predictive accuracy of the 'MCI due to AD - high likelihood' criteria by taking advantage from an extended follow-up in a memory clinic setting.MethodsPatients were diagnosed according to the 'MCI due to AD - high likelihood' criteria and followed up until conversion to dementia.ResultsOne hundred and fourteen patients with 'MCI due to AD - high likelihood' were enrolled in the study and followed-up for 3.0 ± 1.8 [0.4-8.3] years. During the follow-up 106 (93.0%) patients progressed to dementia, 2 (1.8%) had stroke, 6 (5.3%) died, and none remained in MCI or reverted to normal cognitive status. The average survival time remaining in MCI, analyzed with Kaplan-Meier curve, was 3.2 (95% CI 2.9-3.6) years. Using a multivariate Cox proportional hazards regression model, patients with higher Mini-Mental State Examination kept the MCI status longer.ConclusionsThe diagnostic criteria of NIA-AA 'MCI due to AD - high likelihood' have an excellent long-term predictive accuracy in a memory clinic setting.},
}

@article {pmid40952824,
year = {2025},
author = {Çelik, F and Ünver, Y and Güler, Hİ and Oğuz, E and Türkan, F},
title = {New methyl/benzyl-1,2,4-triazole-3-one Derivatives: Synthesis, Characterization (IR, NMR), Antidiabetic, Anti-Alzheimer, and Molecular Docking Study.},
journal = {Journal of biochemical and molecular toxicology},
volume = {39},
number = {9},
pages = {e70510},
doi = {10.1002/jbt.70510},
pmid = {40952824},
issn = {1099-0461},
abstract = {New 1,2,4-triazole compounds were synthesized in this study. These compounds (2,3,5,6 (a-f)) were characterized by IR, [1]H-NMR, and [13]C-NMR studies. Acarbose was used as a standard for alpha glycosidase and alpha amylase enzymes, while tacrine molecule was used as a standard for acetylcholinesterase enzyme. While the IC50 result of acarbose was found to be 6.430 ± 0.736, the IC50 values for α-gly and α-amly enzymes were 1.454 ± 0.087 µM-3.7973 ± 0.3352 µM and 1.509 ± 0.161 µM-3.797 ± 0.335 µM, respectively. In addition, the IC50 values for AChE enzyme were found to be in the range of 1.330 ± 0.118 µM-11.104 ± 3.463 µM. Except for molecules 5a, 5b and 5 f, all other molecules were found to be more active than the standard. Molecular docking simulations were conducted to explore the interactions of 3e and 3 f compounds with Human Acetylcholinesterase, using tacrine as a reference molecule, to evaluate binding affinities and key ligand-protein interactions.},
}

@article {pmid40952756,
year = {2025},
author = {Salvadó, G and Janelidze, S and Bali, D and Dolado, AO and Therriault, J and Brum, WS and Pichet Binette, A and Stomrud, E and Mattsson-Carlgren, N and Palmqvist, S and Coomans, EM and Teunissen, CE and van der Flier, WM and Rahmouni, N and Benzinger, TLS and Gispert, JD and Blennow, K and Doré, V and Feizpour, A and Rowe, CC and Alcolea, D and Fortea, J and Villeneuve, S and Johnson, SC and Rosa-Neto, P and Petersen, RC and Jack, CR and Schindler, SE and Suárez-Calvet, M and Ossenkoppele, R and Hansson, O and , },
title = {Plasma Phosphorylated Tau 217 to Identify Preclinical Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.3217},
pmid = {40952756},
issn = {2168-6157},
abstract = {IMPORTANCE: Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology.

OBJECTIVE: To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]).

This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964).

EXPOSURES: Plasma p-tau217 levels measured by immunoassay.

MAIN OUTCOME AND MEASURES: Aβ status, determined by CSF or Aβ PET biomarkers.

RESULTS: Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001).

CONCLUSIONS AND RELEVANCE: The findings highlight the potential of plasma p-tau217 as a stand-alone test-or when used in a sequential 2-step approach alongside PET or CSF testing-as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.},
}

@article {pmid40952625,
year = {2025},
author = {Kocanci, FG and Sarban, HE and Yildiz, F},
title = {Evaluating the Neuroprotective and Acetylcholinesterase Inhibitory Properties of Four Calcineurin Inhibitor Drugs: Tacrolimus, Pimecrolimus, Cyclosporin A, and Voclosporin.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40952625},
issn = {1559-1182},
support = {32126//President of the Turkish Health Institutes (TUSEB)/ ; 32126//President of the Turkish Health Institutes (TUSEB)/ ; 32126//President of the Turkish Health Institutes (TUSEB)/ ; },
abstract = {Neurodegenerative diseases (ND), marked by progressive neuronal degeneration, often involve dysregulation of acetylcholinesterase (AChE), a key enzyme in cholinergic neurotransmission. AChE inhibition is a well-established therapeutic strategy for Alzheimer's disease (AD), the most prevalent ND, as it aims to restore impaired cholinergic function. However, the effects of calcineurin inhibitors (CNIs), primarily used as immunosuppressants, on AChE activity remain largely unexplored. Recent evidence suggests CNIs possess neuroprotective properties, highlighting their potential for ND treatment. This study evaluated the binding affinities of FDA-approved CNIs-Tacrolimus (Tac), Pimecrolimus (Pim), Cyclosporine A (Csa), and Voclosporin (Voc)-to AChE via molecular docking and molecular dynamic simulation. AChE inhibition was assessed in vitro using the Ellman method and in H2O2-induced degenerative neuron-like SH-SY5Y cells via ELISA and qRT-PCR. Neuroprotection was examined through MTT assays and neurite analysis. Additionally, the antiapoptotic effect was examined by ELISA analysis measuring caspase-3. Docking studies confirmed strong AChE binding for all CNIs, with Voc exhibiting the highest affinity. Voc demonstrated superior in vitro AChE inhibition, surpassing galantamine at low concentrations. Cellular assays showed that CNIs, particularly Voc, significantly inhibited AChE expression at the gene level. Moreover, Voc markedly restored cell viability and reduced neuronal degeneration in H2O2-treated cells. These findings suggest CNIs, especially Voc, as promising candidates for ND treatment, targeting AChE overactivity and oxidative stress.},
}

@article {pmid40952592,
year = {2025},
author = {Chen, C and Wang, GQ and Li, DD and Zhang, F},
title = {Microbiota-gut-brain axis in neurodegenerative diseases: molecular mechanisms and therapeutic targets.},
journal = {Molecular biomedicine},
volume = {6},
number = {1},
pages = {64},
pmid = {40952592},
issn = {2662-8651},
support = {No. 82160690//National Natural Science Foundation of China/ ; No. ZK [2021]-014//Science and Technology Foundation of Guizhou Province/ ; No. 2020-39//Collaborative Innovation Center of Chinese Ministry of Education/ ; },
abstract = {The microbiota-gut-brain axis (MGBA) is an intricate bidirectional communication network that links intestinal microbiota with the central nervous system (CNS) through immune, neural, endocrine, and metabolic pathways. Emerging evidence suggests that dysregulation of the MGBA plays pivotal roles in the onset and progression of neurodegenerative diseases. This review outlines the key molecular mechanisms by which gut microbes modulate neuroinflammation, blood-brain barrier integrity, protein misfolding, and neuronal homeostasis. We discuss how microbial metabolites, such as short-chain fatty acids, tryptophan derivatives, and bile acids, interact with host to influence CNS functions. Disease-specific features are described across Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis, emphasizing the distinct and overlapping pathways through which gut dysbiosis may contribute to pathogenesis. We further explore the translational potential of microbiota-targeted therapies, including probiotics, fecal microbiota transplantation, dietary interventions, and small-molecule modulators. While preclinical results are promising, clinical trials reveal considerable variability, highlighting the need for personalized approaches and robust biomarkers. Challenges remain in deciphering causal relationships, accounting for inter-individual variability, and ensuring reproducibility in therapeutic outcomes. Future research should integrate multi-omics strategies, longitudinal human cohorts, and mechanistic models to clarify the role of the MGBA in neurodegeneration. Collectively, understanding the MGBA provides a transformative perspective on neurodegenerative disease mechanisms and offers innovative therapeutic avenues that bridge neurology, microbiology, and precision medicine.},
}

@article {pmid40952471,
year = {2025},
author = {Tomé, SO and Gawor, K and Ospitalieri, S and Ronisz, A and Otto, M and von Arnim, CAF and Ghebremedhin, E and Laureyssen, C and Sleegers, K and Vandenberghe, R and Nelson, PT and Thal, DR},
title = {Differences and overlaps in TDP-43 pathology of 'pure' LATE-NC compared to LATE-NC coexisting with Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {28},
pmid = {40952471},
issn = {1432-0533},
support = {1225725N//Fonds Wetenschappelijk Onderzoek/ ; G065721N//Fonds Wetenschappelijk Onderzoek/ ; PDMT2/21/069//KU Leuven/ ; AARF-24-1300693/ALZ/Alzheimer's Association/United States ; 22-AAIIA-963171/ALZ/Alzheimer's Association/United States ; A2022019F//BrightFocus Foundation/ ; 01ED1202A//EU Joint moodmarker/ ; 01ED1512//PreFrontAls/ ; FTLDc 01GI1007A//German Federal Ministry of Education and Research/ ; D.3830//Foundation of the State Baden-Württemberg/ ; D.5009//Boehringer Ingelheim Ulm University BioCenter/ ; ZN3553//Niedersächsisches Ministerium für Wissenschaft und Kultur/ ; 32.5.1140.0007.O/MA01//Robert-Bosch-Stiftung/ ; R01 NS118584/NH/NIH HHS/United States ; C14/17/107//Onderzoeksraad, KU Leuven/ ; TH-624-4-1, 4-2, 6-1//Deutsche Forschungsgemeinschaft/ ; 10810//Alzheimer Forschung Initiative/ ; },
abstract = {Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a common substrate of dementia in the elderly. LATE and Alzheimer's disease (AD) share similar clinical features, and their underlying neuropathological changes-LATE-NC and ADNC-commonly co-occur. However, the histomorphological and molecular features of TDP-43 pathology in LATE-NC with or without coexisting ADNC are not yet well understood. We performed immunohistochemistry in paraffin-embedded tissue from the hippocampus, amygdala, and temporal and frontal cortices of 108 human autopsy cases including 20 cognitively unimpaired controls, 20 AD dementia cases with moderate-high severity of ADNC without LATE-NC (ADNC group), 34 AD dementia cases with LATE-NC (ADNC + LATE-NC group), 17 dementia cases with LATE-NC but no/low ADNC (pure LATE-NC group), and 17 FTLD-TDP Type A cases. We assessed TDP-43 aggregate morphology and composition using antibodies against different TDP-43 epitopes: pS409/410, pS403/pS404, and C- and N-terminal TDP-43. We also investigated nuclear clearance of physiological TDP-43 and cytoplasmic colocalization of TDP-43 and tau proteins. Pure LATE-NC cases were on average 10 years older at death than ADNC + LATE-NC, had less cognitive impairment, higher prevalence of argyrophilic grain disease (AGD) pathology, aging-related tau astrogliopathy (ARTAG), and APOEε2 allele. They also tended to show lower APOEε4 frequencies, but similar frequencies of hippocampal sclerosis and LATE-NC stages. Importantly, LATE-NC predominantly displayed a mesh-like neuritic TDP-43 pattern in the hippocampus, extending from CA1/2 to subiculum. This mesh-like pattern was present in 81% of pure LATE-NC cases and only in 18% of ADNC + LATE-NC. This pattern was also observed in 53% of FTLD-TDP Type A cases. Moreover, the aggregate composition differed in pure LATE-NC and ADNC + LATE-NC, with LATE-NC cases exhibiting increased burdens of several phosphorylated and non-phosphorylated TDP-43 species, while only the pS409/pS410 epitope was significantly associated with ADNC + LATE-NC in the amygdala. Nuclear clearance patterns also tended to differ between pure LATE-NC and ADNC + LATE-NC. Similar to ADNC + LATE-NC, TDP-43 and tau proteinopathies colocalized in pure LATE-NC with comorbid primary age-related tauopathy (PART) or low ADNC. These data suggest that LATE-NC tends to be modified in the presence of moderate-high ADNC. These differences may reflect upstream influences (age, genetics, and environmental risk factors), direct protein-protein interactions, and/or other impacts of ADNC-related mechanisms on TDP-43 proteinopathy, potentially relevant for clinical trial design and future therapeutic applications.},
}

@article {pmid40952411,
year = {2025},
author = {Kanda, A and Rani, A and Mazumder, A},
title = {Exploring precision medicine by utilizing individual genetic information for the management of Alzheimer's disease.},
journal = {Pharmacogenomics},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/14622416.2025.2560296},
pmid = {40952411},
issn = {1744-8042},
abstract = {Alzheimer's Disease (AD) represents a formidable challenge in neurology, characterized by progressive neurodegeneration and cognitive decline. Traditional therapeutic approaches have failed to deliver significant outcomes, underscoring the need for innovative paradigms such as precision medicine. The review explores integrating genomic, biomarker-driven, and individualized therapeutic strategies to tackle AD. It examines the role of key genetic factors, including APOE and MTHFR polymorphisms, in influencing disease susceptibility and treatment responses. Advances in biomarker technologies, such as blood-based and imaging biomarkers, are highlighted for their potential in early diagnosis and patient stratification. Additionally, the review underscores the importance of tailoring interventions across different stages of AD, incorporating lifestyle modifications and emerging tools like artificial intelligence & recent patented technologies. Precision medicine offers a transformative pathway, aiming to deliver personalized, effective care that addresses the complex and multifactorial nature of AD. The paradigm shift promises improved clinical outcomes and enhanced patient quality of life.},
}

@article {pmid40952372,
year = {2025},
author = {Pizarro, M and Gomez-Gutierrez, R and Caviedes, A and Valdes, C and Woehlbier, U and Vargas, C and Hernandez, M and Duran-Aniotz, C and Morales, R},
title = {Infusion of blood from young and old mice modulates amyloid pathology.},
journal = {Aging},
volume = {17},
number = {},
pages = {},
doi = {10.18632/aging.206319},
pmid = {40952372},
issn = {1945-4589},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of misfolded proteins in the brain. Recently, the impact of blood components in the progression of this disease has come to attention. This study investigates the effects of infusing blood from young and old wild-type mice into transgenic mice that model AD brain amyloidosis. Impaired memory and Aβ accumulation were observed in mice infused with blood from old donors. A proteomic analysis in the brain of these mice identified alterations in components related to synaptogenesis and the endocannabinoid system. The α2δ2 protein, associated with neuronal calcium regulation, was validated as a possible mediator of the observed effects. This study highlights the influence of blood in AD pathology and the identification of potential therapeutic targets.},
}

@article {pmid40952136,
year = {2025},
author = {Frykman, H},
title = {Analytical considerations and clinical utility of plasma phosphorylated Tau217.},
journal = {Critical reviews in clinical laboratory sciences},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/10408363.2025.2551648},
pmid = {40952136},
issn = {1549-781X},
abstract = {Blood-based biomarkers are an easily available and practical tool for Alzheimer's disease (AD) screening and diagnosis. Plasma phosphorylated Tau217 (p-tau217) is the front-runner candidate for AD diagnosis due to its strong correlation with core AD pathology determined either by cerebrospinal fluid biomarker (CSF) and positron emission tomography (PET) or postmortem examination. While plasma p-tau217 is firmly associated with AD pathology, it is crucial to evaluate its performance in distinguishing AD from mixed pathologies, as brain autopsies have shown the coexisting of AD pathology with other related types of dementia. Moreover, the measurement of AD biomarkers will be a crucial element in defining eligibility for disease-modifying treatment in clinical practice. Moreover, plasma p-tau217 is a highly efficacious biomarker in the early detection of Aβ pathology, making it a feasible test for AD screening in clinical practice. Several assays, including the ALZpath p-tau217 assay and the Fujirebio plasma p-tau217 assay, have been made commercially available for research use. A few studies analytically and clinically have validated these immunoassays as laboratory diagnostic tests for AD diagnosis and differentiating from non-AD neurodegenerative disorders in clinical practice.},
}

@article {pmid40951978,
year = {2025},
author = {Trudel, L and Therriault, J and Macedo, AC and Servaes, S and Hosseini, SA and Bezgin, G and Rahmouni, N and Chan, T and Fernandez-Arias, J and Aumont, É and Wang, YT and Zheng, Y and Hall, B and Hopewell, R and Hsiao, CH and Toga, AW and Braskie, MN and Meeker, KL and Soucy, JP and Gauthier, S and Vitali, P and O'Bryant, SE and Pascoal, TA and Rosa-Neto, P},
title = {Rates of clinical progression according to biological Alzheimer's disease stages.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70624},
doi = {10.1002/alz.70624},
pmid = {40951978},
issn = {1552-5279},
support = {//Fonds de Recherche du Québec - Santé/ ; //Fondation Brain Canada/ ; /ALZ/Alzheimer's Association/United States ; /CAPMC/CIHR/Canada ; //Consortium canadien en neurodégénérescence associée au vieillissement/ ; //Weston Brain Institute/ ; },
abstract = {INTRODUCTION: Predicting the rate of cognitive decline and the likelihood of progression to dementia remains a critical unmet need in clinical settings.

METHODS: We assessed progression to mild cognitive impairment (MCI) and all-cause dementia in 492 individuals from the TRIAD, ADNI, and HABS-HD cohorts followed for an average of 2.49 years. Amyloid-positive participants were staged according to the Alzheimer's Association biological staging framework (A+T2-/A+T2MTL+/A+T2MOD+/A+T2HIGH+).

RESULTS: Cognitively unimpaired (CU) individuals in the A+T2MTL+, A+T2MOD+, and A+T2HIGH+ biological Alzheimer's disease (AD) stages were at significantly higher risk of clinical progression compared to non-AD CU individuals. In individuals with MCI, advanced tau stage was associated with an 83% likelihood of developing dementia over 4 years. Biological AD staging demonstrated superior accuracy in predicting clinical progression compared to amyloid-PET (positron emission tomography) status, tau-PET status, and demographic information. All tau-PET-positive individuals showed a significantly faster rate of cognitive decline than non-AD controls, with the A+T2HIGH+ stage showing the steepest rate of decline (p < 0.001).

DISCUSSION: Our results highlight the prognostic value of biological AD staging.

HIGHLIGHTS: Cognitively unimpaired (CU) individuals in all tau-PET (positron emission tomography)-positive biological Alzheimer's disease (AD) stages were at significantly higher risk of clinical progression compared to individuals without AD. In individuals with mild cognitive impairment (MCI), only the A+T2HIGH+ stage reached a point where 50% of individuals had progressed to all-cause dementia, after 2.36 years. Biological AD staging demonstrated superior accuracy in predicting clinical progression to dementia compared to other PET biomarkers and demographic information. All tau-PET-positive individuals showed a significantly faster rate of cognitive decline than individuals without AD, with the A+T2HIGH+ stage showing the steepest rate of decline.},
}

@article {pmid40951960,
year = {2025},
author = {Lao, P and Edwards, N and Flores-Aguilar, L and Alshikho, MJ and Smith, A and LeMay, R and Hahm, J and Rizvi, B and Tudorascu, D and Rosas, HD and Yassa, M and Christian, B and Mapstone, M and Handen, B and , and Gutierrez, J and Wilcock, D and Head, E and Brickman, AM},
title = {Longitudinal changes in white matter hyperintensity volume accelerate across the Alzheimer's continuum in adults with Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70679},
doi = {10.1002/alz.70679},
pmid = {40951960},
issn = {1552-5279},
support = {/TR/NCATS NIH HHS/United States ; UL1TR001873/NH/NIH HHS/United States ; F31AG090091/AG/NIA NIH HHS/United States ; U01AG051406/AG/NIA NIH HHS/United States ; U01AG051412/AG/NIA NIH HHS/United States ; U19AG068054/AG/NIA NIH HHS/United States ; RF1AG079519/AG/NIA NIH HHS/United States ; R00AG065506/AG/NIA NIH HHS/United States ; R25AG059557/AG/NIA NIH HHS/United States ; 23AARFD-1022715/ALZ/Alzheimer's Association/United States ; //Jerome Lejeune Foundation/ ; },
abstract = {INTRODUCTION: Cerebrovascular disease is elevated across the Alzheimer's disease (AD) continuum in adults with Down syndrome (DS), but regional change within individuals is unknown.

METHODS: Participants from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study (n = 187) had magnetic resonance imaging (MRI) scans quantified for white matter hyperintensity (WMH) volume. Annualized WMH change was assessed across cognitive diagnostic groups defined by progression or stability between two visits (78% remained cognitively stable (CS), 6% progressed from CS to mild cognitive impairment [MCI]-DS, 5% remained MCI-DS, 6% progressed from MCI-DS to AD, 4% remained AD).

RESULTS: Compared to those who remained CS, WMH changes, particularly in posterior regions, over time were faster in advanced diagnostic groups (i.e., MCI-DS to AD, AD at both timepoints). Monotonic increase across progressive diagnostic groups suggest an acceleration in WMH over time.

CONCLUSION: Posterior WMH accelerates with AD progression in adults with DS beginning at the progression from MCI-DS to AD.

HIGHLIGHTS: White matter hyperintensity (WMH) volume increased and decreased over time in adults with Down syndrome. WMH decreased over time in the cognitively stable group. WMH increased over time in advanced Alzheimer's disease diagnostic groups. Change in posterior WMH accelerated across progressive Alzheimer's disease groups.},
}

@article {pmid40951946,
year = {2025},
author = {Kang, M and Ang, TFA and Devine, SA and Sherva, R and Mukherjee, S and Trittschuh, EH and Scollard, P and Lee, M and Choi, SE and Klinedinst, B and Nakano, C and Dumitrescu, LC and Hohman, TJ and Cuccaro, ML and Saykin, AJ and Kukull, WA and Bennett, DA and Wang, LS and Mayeux, RP and Haines, JL and Pericak-Vance, MA and Schellenberg, GD and Crane, PK and Au, R and Lunetta, KL and Mez, J and Farrer, LA},
title = {Genome-wide pleiotropy analysis of longitudinal blood pressure and harmonized cognitive performance measures.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70681},
doi = {10.1002/alz.70681},
pmid = {40951946},
issn = {1552-5279},
support = {U19-AG068753/GF/NIH HHS/United States ; R01-AG048927/GF/NIH HHS/United States ; U54-AG052427/GF/NIH HHS/United States ; U01-AG058654/GF/NIH HHS/United States ; U01-AG032984/GF/NIH HHS/United States ; RF1-AG057519/GF/NIH HHS/United States ; U01-AG062602/GF/NIH HHS/United States ; P30-AG072878/GF/NIH HHS/United States ; U24-AG074855/GF/NIH HHS/United States ; U01-AG068057/GF/NIH HHS/United States ; U01-AG082665/GF/NIH HHS/United States ; U01-AG081230/GF/NIH HHS/United States ; R01-AG059716/GF/NIH HHS/United States ; U24-AG021886//National Cell Repository for Alzheimer's Disease/ ; U24-AG041689//National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site/ ; P30-AG10161//University of Pennsylvania, funded by NIA, and the Religious Orders Study/Rush Memory and Aging Project/ ; P30-AG72975//University of Pennsylvania, funded by NIA, and the Religious Orders Study/Rush Memory and Aging Project/ ; R01-AG15819//University of Pennsylvania, funded by NIA, and the Religious Orders Study/Rush Memory and Aging Project/ ; R01-AG17917//University of Pennsylvania, funded by NIA, and the Religious Orders Study/Rush Memory and Aging Project/ ; U01-AG46152//University of Pennsylvania, funded by NIA, and the Religious Orders Study/Rush Memory and Aging Project/ ; U01-AG61356//University of Pennsylvania, funded by NIA, and the Religious Orders Study/Rush Memory and Aging Project/ ; U24-AG074855//Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium/ ; U01-AG068057//Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium/ ; R01-AG059716//Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium/ ; U01-AG081230/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Identifying pleiotropy for blood pressure (BP) and cognitive performance measures may indicate mechanistic links between hypertension and Alzheimer's disease (AD).

METHODS: We performed a pleiotropy genome-wide association study (GWAS) for paired measures of systolic, diastolic, pulse, and mean arterial pressure with memory, executive function, and language scores using 116,075 exam data from 25,726 participants in clinic-based and prospective cohorts. Significant findings were evaluated by Bayesian colocalization and differential gene expression in brain tissue from pathologically confirmed AD cases with and without clinical symptoms.

RESULTS: Genome-wide significant pleiotropy for BP and cognitive performance with JPH2, GATA3, PAX2, LOC105371656, and SUFU in the total sample; RTN4, ULK2, SORBS2, and LOC100128993 in prospective cohorts; and ADAMTS3 and LINC02946 in clinic-based cohorts. Six pleiotropic loci influence cognition directly, and six genes were differentially expressed between pathologically confirmed AD cases with and without antemortem cognitive impairment.

DISCUSSION: Our results provide insight into mechanisms underlying hypertension and AD.

HIGHLIGHTS: Genome-wide significant pleiotropy in blood pressure (BP) and cognitive performance measures were identified with 11 novel loci: JPH2, GATA3, PAX2, LOC105371656, SUFU in the total sample; RTN4, ULK2, SORBS2, LOC100128993 in prospective cohorts; and ADAMTS3, LINC02946 in clinic-based cohorts. SUFU, RTN4, SORBS2, ADAMTS3, and GATA3 affected cognition directly rather than through BP. ACTR1A, HIF1AN, ADAMTS3, RTN4, SORBS2, and SUFU at pleiotropic loci were differentially expressed among controls and pathologically confirmed AD cases with and without clinical symptoms.},
}

@article {pmid40951943,
year = {2025},
author = {Yang, J and Liu, Z and Li, X and Qiu, Y and Liu, Q and Huang, X and Lian, L},
title = {IL7R[+] T Cell-Macrophage Crosstalk Links Asthma to Alzheimer's Pathogenesis: Integrating Mendelian Randomization and CellChat Analysis.},
journal = {Brain and behavior},
volume = {15},
number = {9},
pages = {e70809},
doi = {10.1002/brb3.70809},
pmid = {40951943},
issn = {2162-3279},
support = {82204985//National Natural Science Foundation of China/ ; },
abstract = {PURPOSE: Epidemiological investigation has revealed a higher incidence of Alzheimer's disease (AD) in individuals with severe asthma. However, the causality of this relationship remains uncertain. The current research aimed to examine the potential link between genetically predicted moderate to severe asthma and the risk of AD using Mendelian randomization (MR) analysis.

METHODS: Summary statistics obtained from genome-wide association studies of AD (n = 455,258) and moderate to severe asthma (n = 57,695) in individuals of European ancestry were utilized in this MR study. SMR analysis was also performed to investigate whether the expression of these genes was correlated with AD or moderate to severe asthma outcomes to detect a causal relationship between moderate to severe asthma and AD. Genome-wide genetic correlation between moderate to severe asthma and AD was estimated using linkage disequilibrium score regression (LDSC). Single-cell RNA sequencing (scRNA-seq) datasets of asthma-related peripheral blood mononuclear cell (PBMC) data and AD cerebrospinal fluid (CSF) were obtained to further investigate the crosstalk between the different biological pathways in asthma and AD.

RESULTS: The impact of moderate to severe asthma on AD risk persisted (ORIVW = 1.01, 95% CI = 1.00-1.02, p = 3.85 × 10[-3]) after controlling for confounder risk factors in multivariable MR analyses. Additionally, the study showed that 1.8% of the total effect (moderate to severe asthma) was mediated by eosinophils. SMR analysis and the gene-wide MR analysis revealed numerous gene targets linked to the susceptibility of AD and moderate to severe asthma. Among these targets, FPR1 (Formyl Peptide Receptor 1), IL1RAP (Interleukin 1 Receptor Accessory Protein), IL7R (Interleukin 7 Receptor), and IL18RAP (Interleukin 18 Receptor Accessory Protein) warrant additional exploration as potential therapeutic targets for AD and moderate to severe asthma. LDSC analysis revealed no significant overlap between asthma and AD (rg = 0.0436, SE = 0.0813, p = 0.592), suggesting distinct genetic architectures. Integrated single-cell RNA sequencing analysis of asthma PBMCs and AD CSF revealed IL7R may utilize the MIF-CD74-CXCR4 pathway to complete crosstalk between CD4 T cells and macrophages and contribute to AD disease development.},
}

@article {pmid40951940,
year = {2025},
author = {Gaynor, LS and Lopez, FV and Van Hulle, CA and Li, C and Vasunilashorn, SM and Andrews, SJ and Simone, SM and Mungas, DM},
title = {Measurement equivalence of the UDS version 2.0 and 3.0 neuropsychological batteries.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70720},
doi = {10.1002/alz.70720},
pmid = {40951940},
issn = {1552-5279},
support = {//Advanced Psychometric Methods in Cognitive Aging Research/ ; R13 AG030995/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: The present study examined the dimensional structure of the neuropsychological test batteries from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) versions 2.0 and 3.0 and measurement equivalence across UDS versions and race/ethnicity groups.

METHODS: There were 49,895 participants included in the present study. The best-fitting model was developed and tested in separate samples. Multiple group confirmatory factor analysis (CFA) evaluated measurement equivalence across UDS versions and race/ethnicity groups.

RESULTS: Results identified a best-fitting four-factor model with residual structure. Multiple group CFA supported partial scalar invariance by UDS version and race/ethnicity group. Regarding race/ethnicity groups, the Language and Attention domains had more non-invariant intercepts, which most affected the White group.

DISCUSSION: A four-factor model effectively summarizes the UDS neuropsychological test batteries across UDS versions and race/ethnicity groups. Crucial differences in measurement parameters must be accounted for in studies using these neuropsychological tests as outcomes.

HIGHLIGHTS: A four-factor model summarizes cognition across Uniform Data Set (UDS) versions and race/ethnicity groups. Measurement invariance exists across race/ethnicity groups. Model fit differs between cognitively impaired and unimpaired samples. Accounting for differences in measurement parameters across groups is essential. Tailored normative data are crucial for certain UDS tests, including category fluency.},
}

@article {pmid40951936,
year = {2025},
author = {Anagnostakis, F and Kokkorakis, M and Asvestis, C and Papadimopoulos, I and Nagarajan, S and Talbot, K and Li, L and Chen, Y and Nasrallah, IM and Wen, J and Davatzikos, C},
title = {Impact of cardiometabolic conditions on the progression from mild cognitive impairment to dementia: A large cohort study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70692},
doi = {10.1002/alz.70692},
pmid = {40951936},
issn = {1552-5279},
support = {RF1AG054409/GF/NIH HHS/United States ; U24NS130411/GF/NIH HHS/United States ; },
abstract = {INTRODUCTION: This study investigates the impact of cardiometabolic conditions, including type 2 diabetes, hyperlipidemia, hypertension, and obesity, on the progression of mild cognitive impairment (MCI) to dementia.

METHODS: The cohort included adults ≥ 50 years old with MCI and a cardiometabolic condition identified through electronic health records. Propensity score matching was applied to control for confounders, and Kaplan-Meier analysis was used to assess time-to-event outcomes.

RESULTS: During a 7-year median follow-up, type 2 diabetes was associated with the highest risk of all-cause dementia (hazard ratio [HR] 1.18, 95% confidence interval [CI]: 1.06 to 1.31), followed by hypertension and hyperlipidemia. For vascular dementia, type 2 diabetes conferred the greatest risk (HR 1.33, 95% CI: 1.07 to 1.64). Hyperlipidemia was the sole cardiometabolic factor significantly associated with Alzheimer's disease (AD) risk (HR 1.21, 95% CI: 1.11 to 1.32).

CONCLUSIONS: Hyperlipidemia is primarily associated with AD dementia risk, while type 2 diabetes is the major contributor to vascular dementia and all-cause risk in individuals with MCI.

HIGHLIGHTS: Type 2 diabetes, hypertension, and hyperlipidemia are associated with a high risk of developing all-cause dementia in participants already diagnosed with mild cognitive impairment (MCI). Type 2 diabetes was shown to pose a high risk for the progression from MCI to vascular dementia. Hyperlipidemia was associated with Alzheimer's disease progression in individuals with MCI.},
}

@article {pmid40951935,
year = {2025},
author = {Wei, Y and Li, H},
title = {The Efficacy and Safety of Amyloid Beta-Directed Monoclonal Antibodies for Alzheimer's Disease: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials.},
journal = {Human psychopharmacology},
volume = {40},
number = {5},
pages = {e70017},
doi = {10.1002/hup.70017},
pmid = {40951935},
issn = {1099-1077},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of mortality worldwide. One of the newer treatments for AD is amyloid beta (Aβ) directed monoclonal antibodies (mAbs). This systematic review and meta-analysis aimed to assess the efficacy and safety of this class of drugs.

METHODS: A comprehensive literature search was conducted across Scopus, Web of Science, PubMed, and the Cochrane Library until January 30, 2025, focusing on phase III randomized controlled trials (RCTs) evaluating anti-Aβ mAbs.

RESULTS: Twelve RCTs with 24 arms were included. Anti-Aβ mAbs significantly reduced the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score (mean difference (MD): -0.16, 95% confidence interval (CI) (-0.29, -0.04)), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score (MD: -0.87, 95% CI (-1.13, -0.60)), and amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR) (MD: -0.11, 95% CI (-0.19, -0.02)). They also significantly increased the Mini-Mental State Examination (MMSE) score (MD: 0.31, 95% CI (0.15, 0.46)) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score (MD: 1.21, 95% CI (0.89, 1.53)). However, they were associated with a significant increase in complications, including amyloid-related imaging abnormalities-edema/effusion (ARIA-E) (odds ratio (OR): 10.20, 95% CI (7.17, 14.50)), ARIA-hemosiderosis or microhemorrhage (ARIA-H) (OR: 1.75, 95% CI (1.22, 2.50)), and any adverse events (OR: 1.22, 95% CI (1.08, 1.38), I[2]: 48.59%)). The subgroup analysis showed that treatment administered in the early/preclinical stages of AD resulted in a greater reduction in CDR-SB and ADAS-Cog scores, as well as in amyloid burden.

CONCLUSIONS: Anti-Aβ mAbs offer modest clinical benefits, and pose some serious complications, necessitating a cautious approach to their prescription.},
}

@article {pmid40951925,
year = {2025},
author = {Detcheverry, FE and Senthil, S and Motue, WLK and Hosein, C and Arnaoutelis, R and Araujo, D and Fetco, D and Assemlal, HE and Antel, S and Arnold, DL and Near, J and Schipper, HM and Badhwar, A and Narayanan, S},
title = {Investigating the oxidative stress-vascular brain injury axis in mild cognitive impairment of the Alzheimer's type.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70456},
doi = {10.1002/alz.70456},
pmid = {40951925},
issn = {1552-5279},
support = {//Immunotec Inc./ ; #153005/CAPMC/CIHR/Canada ; //Courtois Foundation/ ; #283967//Fonds de Recherche du Québec - Santé/ ; #352199//Fonds de Recherche du Québec - Santé/ ; #332672//Fonds de Recherche du Québec - Santé/ ; },
abstract = {INTRODUCTION: Oxidative stress may contribute to brain injury in the Alzheimer's disease (AD) continuum. The antioxidant glutathione (GSH) can be assessed with magnetic resonance spectroscopy (MRS). Because the relationship between GSH and vascular brain injury is unknown in the AD continuum, we address this gap in mild cognitive impairment (MCI).

METHODS: 3T Magnetic resonance imaging (MRI)/MRS data were obtained from 31 patients with MCI. GSH and total N-acetylaspartate (tNAA; neuroaxonal integrity marker) were measured in posterior cingulate cortex (PCC) and frontal white matter (FWM). Cerebrovascular injury was assessed using white matter hyperintensity (WMH) volume. Global and regional brain tissue integrity were assessed using normalized brain (NBV) and hippocampal volumes.

RESULTS: Significant associations were reported in FWM between GSH/total creatine (tCr) and tNAA/tCr, and between GSH and both WMH and NBV. tNAA, GSH/tCr, and tNAA/tCr were higher in PCC than in FWM.

DISCUSSION: Our results suggest that oxidative stress contributes to vascular brain injury in MCI.

HIGHLIGHTS: Neuronal, vascular, and oxidative injuries occur in the Alzheimer's disease (AD) spectrum. Glutathione (GSH) is the main endogenous antioxidant in the brain. Brain GSH can be measured with magnetic resonance spectroscopy (MRS). We measured brain GSH level in people with mild cognitive impairment (MCI). Low GSH level was associated with vascular brain injury, neuroaxonal damage, and atrophy.},
}

@article {pmid40951924,
year = {2025},
author = {Gibson, LL and Grinberg, LT and Paes, VR and Mueller, C and Leite, REP and Nunes, PV and Justo, AFO and Pasqualucci, CA and Ferriolli, E and Aarsland, D and Suemoto, CK},
title = {Co-pathology in Alzheimer's disease and Lewy body disease and its association with neuropsychiatric symptoms.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70693},
doi = {10.1002/alz.70693},
pmid = {40951924},
issn = {1552-5279},
support = {21/14171-8//Fundação de Apoio a Pesquisa do Estado de São Paulo/ ; AARG-20-678884/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: Mixed neuropathology is common in dementia, but the clinical implications for neuropsychiatric symptoms (NPSs) are not well characterized.

METHODS: In a population-based post mortem study, cases with Alzheimer's disease neuropathological change (ADNC) and Lewy body disease (LBD) were identified with any comorbid neuropathology (limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy neuropathological change (LATE-NC), cerebrovascular disease, LBD, and ADNC, respectively). Post mortem interviews collected information regarding NPSs and cognition to explore associations between each co-pathology and NPSs across the whole cohort, as well as in participants without dementia.

RESULTS: Co-existing neuropathology was frequent, even among individuals without clinical dementia. In cases with ADNC, comorbid neocortical LBD pathology was associated with hallucinations, regardless of cognitive status. However, ADNC co-pathology in LBD was linked to a greater NPS burden in the full cohort but not in individuals without dementia.

DISCUSSION: Lewy bodies are associated with hallucinations independent of cognitive impairment, whereas ADNC co-pathology may contribute to NPS only when widespread and associated with cognitive dysfunction.

HIGHLIGHTS: Neuropathological heterogeneity is high even in clinical stages without dementia. Neocortical but not limbic or brainstem LBD co-pathology is associated with hallucinations. LBs are associated with hallucinations independent of cognitive status. ADNC co-pathology is not associated with NPSs in LBD without dementia. LATE co-pathology is associated with increased risk of dementia but not NPS. Vascular co-pathology is associated with increased risk of delusions in ADNC.},
}

@article {pmid40951923,
year = {2025},
author = {Buongiorno, M and Sánchez-Benavides, G and Caruana, G and Elias-Mas, A and Artero, C and Cullell, N and Delgado, P and Giraldo, DM and Marzal-Espí, C and Grau-Rivera, O and de la Sierra, A and Delgado-Sanchez, A and Ray, NJ and Krupinski, J},
title = {Abnormal sleep blood pressure patterns are associated with the diffusion tensor imaging along the perivascular space index in cognitively impaired individuals.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1578270},
pmid = {40951923},
issn = {1663-4365},
abstract = {INTRODUCTION: Blood pressure (BP) physiologically dips during sleep, and a lack of dipping is associated with adverse health outcomes and cognitive decline. Vascular pulsatility is the primary driver of glymphatic cerebrospinal fluid (CSF) transport, which removes metabolic waste products from the brain during sleep. We hypothesized that abnormal sleep BP patterns may affect glymphatic system health and that this relationship may result in lower diffusion tensor imaging along the perivascular space (DTI-ALPS) indices, a proposed neuroimaging index of glymphatic health.

METHODS: A total of 21 participants with mild-to-moderate cognitive impairment underwent 24-h ambulatory BP monitoring (ABPM), DTI-MRI, and Alzheimer's disease (AD) biomarker assessments. Of them, eight participants were classified as dippers (≥10%) and 13 as non-dippers (< 10%), using the sleep/awake systolic BP (SBP) percentage of change.

RESULTS: We found that the non-dippers had lower DTI-ALPS indices, even after adjusting for age and clinical stage (p = 0.013). Stiffness measures (pulse wave velocity) were negatively correlated with DTI-ALPS (r = -0.5), but the association disappeared after adjusting for age. Positive AD biomarkers were more frequently observed in the individuals who were classified as non-dippers for both systolic and diastolic BP (DBP), compared to the systolic and diastolic dippers (p = 0.041).

DISCUSSION: Our findings suggest that deviations from the physiological BP dipping sleep pattern may be related to poorer glymphatic function and increased AD pathology.},
}

@article {pmid40951922,
year = {2025},
author = {Leng, K and Maze, M and Barreto Chang, OL},
title = {Emerging biomarkers of postoperative delirium at the intersection of neuroinflammation and neurodegeneration.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1632947},
pmid = {40951922},
issn = {1663-4365},
abstract = {Postoperative delirium (POD) is a common and severe neuropsychiatric complication affecting older adults after surgery. POD is characterized by fluctuating cognitive disturbances, impaired attention, and altered consciousness, resulting in increased morbidity and mortality, prolonged hospital stays, and higher healthcare costs. Systemic inflammation induced by surgical trauma is implicated in the pathophysiology of POD, although the subsequent mechanisms that produce blood-brain barrier (BBB) dysfunction, neuroinflammation, and interactions with underlying dementia neuropathology have not been resolved. Recent advances in biomarker research have shed light on predictive and diagnostic tools for POD. Biomarkers linked to dementia neuropathology (e.g., hyperphosphorylated tau, amyloid beta), neuronal injury (e.g., total tau, neurofilament light chain), glial activation (e.g., glial fibrillary acidic protein), and systemic inflammation (e.g., interleukin-6) have shown promise. The feasibility of measuring the above biomarkers in easy-to-obtain biofluids such as blood is enhanced by technologies like single-molecule array immunoassays, enabling sensitive detection of central nervous system markers at femtomolar concentrations. Emerging evidence highlights associations between POD risk and these biomarkers, although findings often vary due to cohort heterogeneity and methodological differences. This review critically examines the existing literature on POD biomarkers, focusing on their relevance to dementia neuropathology, neuronal injury, neuroinflammation, and BBB integrity. While significant strides have been made, gaps in knowledge persist, emphasizing the need for larger, more standardized studies. Developing robust biomarkers could transform POD prediction, diagnosis, and management, ultimately improving outcomes for vulnerable surgical populations.},
}

@article {pmid40951730,
year = {2025},
author = {Besin, V and Humardani, FM and Yudiarto, FL and Ong, PA and Putra, SED and Ningrum, RA},
title = {Amyloid-Related Imaging Abnormality (ARIA) Beyond the APOE-ε4 Allele.},
journal = {Chronic diseases and translational medicine},
volume = {11},
number = {3},
pages = {186-196},
pmid = {40951730},
issn = {2589-0514},
abstract = {Monoclonal antibodies (mAbs) have made significant progress in the treatment of Alzheimer's disease (AD). However, mAbs are associated with adverse effects, including Amyloid-Related Imaging Abnormality (ARIA), which manifests as edema or effusion (ARIA-E) and hemorrhage (ARIA-H). The mechanisms behind these effects are not yet fully understood. Moreover, spontaneous ARIA has been insufficiently explored, and mAb therapies, particularly lecanemab, have mainly focused on patients with the APOE-ε4 allele carrier. This review aims to address this gap by examining the mechanisms of spontaneous ARIA, ARIA induced by mAbs, and the influence of genetic variants on ARIA development. The autoantibody-Aβ-mediated immune response targets excessive Aβ deposits, increasing immune activity through microglial reactivity. The heightened immune response, driven by Aβ accumulation in blood vessels, promotes angiopathy and inflammation, potentially contributing to spontaneous ARIA. The APOE-ε4 allele carrier is more strongly associated with ARIA-E because it redistributes Aβ deposition from the brain to blood vessels, influencing microglial reactivity. The redistribution enhances vascular integrity and reduces the risk of ARIA-H. However, it also increases the likelihood of ARIA-E due to Aβ accumulation in the vasculature, triggering inflammation. In contrast, the development of ARIA-H is linked to increased TREM2 expression and microglial reactivity, leading to impaired vascular integrity and disrupted matrix remodeling, which worsens the condition. Additionally, the adverse effects of mAbs may extend beyond the APOE-ε4 allele, possibly impacting other genetic variants involved in microglial reactivity, Aβ redistribution, and vascular integrity.},
}

@article {pmid40951709,
year = {2025},
author = {Cui, CX and Shao, XN and Li, YY and Qiao, L and Lin, JT and Guan, LH},
title = {Therapeutic potential of mesenchymal stem cells in neurodegenerative diseases.},
journal = {World journal of stem cells},
volume = {17},
number = {8},
pages = {107717},
pmid = {40951709},
issn = {1948-0210},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, are characterized by the progressive loss of neuronal function and structure, leading to severe morbidity and mortality. Current therapeutic approaches are ineffective at stopping or reversing disease progression. Stem cell therapy has emerged as a promising candidate in research and treatment. Mesenchymal stem cells (MSCs) are considered ideal candidates for regenerative medicine because of their high proliferation rate and multi-differentiation potential. MSCs can differentiate into neurons and glial cells, modulate immune responses, and reduce inflammation, and their exosomes can promote neural repair and regulate neuronal function; thus, MSCs offer unique advantages for treating neurodegenerative diseases. However, challenges remain in optimizing cell delivery methods, ensuring the long-term survival and integration of transplanted cells, and fully understanding their therapeutic effects. This article primarily outlines the functions of MSCs in neurodegenerative diseases, with the intention that further research will fully harness their potential and translate these findings into clinical applications, offering new hope for patients suffering from neurodegenerative diseases.},
}

@article {pmid40951706,
year = {2025},
author = {Shan, XQ and He, MH and Gao, WL and Li, YJ and Liu, SZ and Liu, Y and Wang, CL and Zhao, L and Xu, SX},
title = {Mesenchymal stem cell-derived exosomes: Shaping the next era of Alzheimer's disease treatment.},
journal = {World journal of stem cells},
volume = {17},
number = {8},
pages = {109006},
pmid = {40951706},
issn = {1948-0210},
abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disease for which effective disease-modifying therapies are lacking. Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as a promising therapeutic approach due to their unique biological functions and favorable biocompatibility. This review systematically explores the mechanism of action of MSC-Exos in AD therapy, including the removal of β-amyloid via the delivery of degradative enzymes, modulation of neuroinflammation, and promotion of neural regeneration. Meanwhile, this paper summarizes recent advances in preclinical and clinical studies, and analyzes the challenges in production standardization, safety assessment, and long-term efficacy validation of exosome therapies. Finally, several innovative strategies are proposed to enhance the therapeutic potential of MSC-Exos, including exosome functionalization and targeting optimization, gene editing techniques. This aims to promote the translation of exosomes from basic research to clinical application.},
}

@article {pmid40951640,
year = {2025},
author = {Khan, MS and Hu, Q and Okeibunor, K and Ma, L and Bopassa, JC},
title = {Targeting ferroptosis for neuroprotection: potential therapeutic avenues in neurodegenerative and neuropsychiatric diseases.},
journal = {Frontiers in physiology},
volume = {16},
number = {},
pages = {1641323},
pmid = {40951640},
issn = {1664-042X},
abstract = {Ferroptosis is an iron-dependent programmed cell death that plays an important role in neurodegenerative and neuropsychiatric diseases. In the present study, we have highlighted how different risk factors are involved in the induction of ferroptosis in brain cells. In addition, we also demonstrated how ferroptosis plays an important role in different brain diseases. In our study why we focused and elaborated on the mechanisms of ferroptosis only in brain cells (Neurons, oligodendrocytes, and microglia) because they are particularly vulnerable to such kind of cell death. Additionally, brain cells are more dependent on mitochondrial function, iron regulation, and high levels of polyunsaturated fatty acids (PUFAs) as compared to peripheral body cells. Highlighting ferroptosis is more important because it has demonstrated several important mechanisms of neuronal injury and dysfunction which provides a deep understanding of the etiology of various brain diseases that were not sufficiently described by other programmed cell death pathways. Therefore, it has led to the exploration of new therapeutic strategies against various brain diseases and thus targeting ferroptosis-related proteins opens a new therapeutic window for several incurable brain diseases, and various ferroptosis regulators are now under clinical trials. However, their validation as a preclinical therapeutic agent is needed. Interestingly, here in our study we also summarize the most recent potential therapeutic targets and promising interventions which will provide a beam of light for future therapies against major brain diseases.},
}

@article {pmid40951469,
year = {2025},
author = {Widaja, E and Pawitan, JA and Ramli, Y},
title = {Therapeutic potential of hUC-MSC secretome preconditioned with IFN-γ and/or TNF-α: An in vitro study on Alzheimer's neuronal cell models.},
journal = {Narra J},
volume = {5},
number = {2},
pages = {e2281},
pmid = {40951469},
issn = {2807-2618},
abstract = {Alzheimer's disease is a progressive neurodegenerative disease that is characterized by toxic Amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). Treatment options include the use of human umbilical cord mesenchymal stem cell (hUC-MSC)-based therapy. Its secretome contains healing substances such as neprilysin (CD10), which breaks down Aβ42; anti-inflammatory cytokines, which lower inflammation; and growth factors, which promote neuronal regeneration. The aim of this study was to produce hUC-MSC secretomes preconditioned with tumor necrosis factor-alpha (TNF-α) and/or interferon-gamma (IFN-γ) to enhance the secretion of these healing substances. hUC-MSCs were sub-cultured in T-25 flasks at a seeding density of 5×103 cells/cm[2] in 10 mL xeno-free medium. hUC-MSCs were preconditioned with TNF-α only, IFN-γ only, and a combination of TNF-α and IFN-γ. This study used 10 ng/mL TNF-α and 20 ng/mL IFN- γ. The secretome was harvested after 48 hours of preconditioning and then filtered through a 0.22 µm filter. In vitro tests were conducted to assess the effects of the secretome on neuronal survival using the neuroblastoma SH-SY5Y cell line. These cells were differentiated with retinoic acid (RA) and then exposed to Aβ42 to mimic Alzheimer's disease neurons. Secretome therapy was applied at concentrations of 5%, 10%, and 20% to evaluate neuroprotective effects. Four types of secretome were tested: unpreconditioned, TNF-α preconditioned, IFN-γ preconditioned, and a combination of TNF-α and IFN-γ. High levels of CD10 (neprilysin) expression were observed in hUC-MSCs treated with IFN-γ and TNF-α, although they did not release sufficient soluble neprilysin (sNEP). Viability results indicated that secretomes preconditioned with IFN-γ at 10% and 20% concentrations provided the highest increase in cell viability after 72 hours post-therapy. The combination of TNF-α and IFN-γ preconditioned secretome exhibited synergistic effects, particularly at 5% and 10% doses at 24- and 72-hours post- therapy. In conclusion, preconditioned hUC-MSC secretome represents a promising therapeutic approach for Alzheimer's disease, as it enhances neuronal cell viability and promotes neuronal regeneration. However, further studies are required to optimize sNEP release and maximize therapeutic efficacy in in vivo models.},
}

@article {pmid40951465,
year = {2025},
author = {Cynthia, C and Nugraha, J and Hamdan, M and Dharma, R and Limempouw, SF},
title = {Associations between plasma beta amyloid and cognitive decline: A systematic review and meta-analysis.},
journal = {Narra J},
volume = {5},
number = {2},
pages = {e2268},
pmid = {40951465},
issn = {2807-2618},
abstract = {Alzheimer's disease is a leading neurodegenerative disorder characterized by progressive cognitive decline. Early prediction is crucial for enabling timely interventions. Plasma amyloid β-peptides (Aβ), particularly the Aβ-42/Aβ-40 ratio, have been proposed as potential non-invasive biomarkers for cognitive decline and Alzheimer's disease risk. However, conflicting findings and methodological variability have hindered consensus regarding their clinical utility. The aim of this study was to evaluate whether the plasma Aβ levels predict dementia, Alzheimer's disease, and cognitive decline. Studies were eligible for inclusion if they measured at least one plasma Aβ species (Aβ-40, Aβ-42, or the Aβ-42/Aβ-40 ratio) and reported outcomes related to dementia, Alzheimer's disease, or cognitive change. Only human studies published in peer-reviewed journals were included. A comprehensive search of six databases (PubMed, PMC, SSRN, Scopus, BioRxiv, and MedRxiv) was conducted up to December 1, 2024. Risk of bias was assessed using the ROBINS-E tool, and pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random-effects meta-analysis. A total of 25 studies were included in the systematic review, with four contributing to the meta-analysis. Lower plasma Aβ-42/Aβ-40 ratio was not significantly associated with Alzheimer's disease risk (pooled HR=0.8; 95%CI: 0.62-1.04), and substantial heterogeneity was observed (I2=70%, p=0.02). Individual studies varied in their findings: while some reported that lower Aβ-42/Aβ-40 ratio predicted increased Alzheimer's disease risk, others found no association or even opposing trends. Methodological heterogeneity-including differences in sample handling, measurement techniques, and study designs-likely contributed to these inconsistencies. Overall, this review suggests that plasma Aβ-42/Aβ-40 ratio is not reliable predictors for the onset of Alzheimer's disease or dementia. However, the substantial heterogeneity observed underscores the need for further research to clarify the potential of plasma Aβ as a preclinical biomarker.},
}

@article {pmid40951388,
year = {2025},
author = {Muñoz-Najar, A and Montemurro, M and Tejada, MDC and Rivera-Fernández, C and Sánchez-Fernández, M and Custodio, N and Possin, KL and Tsoy, E and Lanata, S and Soto-Añari, M},
title = {Peruvian validation and standardization of the TabCAT-brain health assessment.},
journal = {Frontiers in public health},
volume = {13},
number = {},
pages = {1600131},
pmid = {40951388},
issn = {2296-2565},
abstract = {INTRODUCTION: Detecting cognitive impairment in low-educated and marginalized populations may result in under- or over-estimation of diagnoses due to reliance on non-validated approaches and normative data. This study validates and standardizes TabCAT-BHA for older adults living in the Andean region of Peru using regression-based normalization.

METHODS: Two hundred fifty-eight participants were assessed with the MMSE, RUDAS, and TabCAT-BHA. Classified as either cognitively healthy or impaired based on Clinical Dementia Rating criteria.

RESULTS: By incorporating sex, place of residence, age, and years of education as covariates, the TabCAT-BHA demonstrated greater accuracy in detecting cognitive impairment (AUC = 75.3%) compared to the MMSE (AUC = 66.4%) and RUDAS (AUC = 71.4%). After incorporating only significant sociodemographic predictors, TabCAT-BHA obtained better AUC (77.4%) compared to MMSE (66.6%) and RUDAS (71.9%).

DISCUSSION: The TabCAT-BHA proves to be a valid tool for detecting cognitive impairment, and incorporating sociodemographic factors improves its accuracy in marginalized settings of Peru.},
}

@article {pmid40951286,
year = {2025},
author = {Lill, C and Homann, J and Korologou-Linden, R and Viallon, V and Morgan, S and Dobricic, V and Deecke, L and Schessner, J and Smith-Byrne, K and Birtles, D and Zhao, Y and Wuu, J and Artaud, F and Hajizadah, F and Huerta, J and Ohlei, O and Lebedev, M and Kolijn, P and Eslava, MG and Jiménez-Zabala, A and Sánchez, MJ and Trobajo-Sanmartín, C and Colorado-Yohar, S and Alonso-Martin, S and Petrova, D and Sieri, S and Berger, K and Peters, S and Wareham, N and Kaaks, R and Travis, R and Vermeulen, R and Consortium, GNPCGN and Tzoulaki, I and Elbaz, A and Mann, M and Sacerdote, C and Masala, G and Katkze, V and Benatar, M and Bertram, L and Middleton, L and Riboli, E and Gunter, M and Robinson, O and Ferrari, P},
title = {Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7452736/v1},
pmid = {40951286},
issn = {2693-5015},
abstract = {Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form. Methods: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM). Findings: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson's and Alzheimer's disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance. Interpretation: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention.},
}

@article {pmid40950807,
year = {2025},
author = {Ahmmad, MR and Hossain, E and Khan, MTF and Paudel, S},
title = {Using machine learning to identify risk factors for Alzheimer's disease among older adults in the United States: The role of chronic and behavioral health.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251377691},
pmid = {40950807},
issn = {2542-4823},
abstract = {BACKGROUND: The interactions between behavioral disturbances, chronic diseases, and Alzheimer's disease (AD) risk are not fully understood, particularly in the context of the COVID-19 pandemic.

OBJECTIVE: This study aimed to identify key demographic, behavioral, and health-related predictors of AD using machine learning approaches.

METHODS: We conducted a cross-sectional analysis of 3257 participants from the National Health and Aging Trends Study (NHATS) and its COVID-19 supplement. Predictors included demographic, behavioral, and chronic disease variables, with self-reported physician-diagnosed AD as the outcome. LASSO and random forest (RF) models identified significant predictors, and regression tree analysis examined interactions to estimate individual AD risk profiles and subgroups.

RESULTS: Stroke, diabetes, osteoporosis, depression, and sleep disturbances emerged as key predictors of AD in both LASSO and RF models. Regression tree analysis identified three risk subgroups: a high-risk subgroup with a history of stroke and diabetes, showing a 68% AD risk among females; an intermediate-risk subgroup without stroke but with osteoporosis and positive COVID-19 status, showing a 30% risk; and a low-risk subgroup without stroke or osteoporosis, with the lowest risk (∼10%). Female patients with both stroke and diabetes had significantly higher AD risk than males (68% versus 10%, p = 0.029). Among patients without stroke but with osteoporosis, COVID-19 positivity increased AD risk by 20% (30% versus 10%, p = 0.006).

CONCLUSIONS: Machine learning effectively delineates complex AD risk profiles, highlighting the roles of vascular and metabolic comorbidities and the modifying effects of sex, osteoporosis, and COVID-19. These insights support targeted screening and early intervention strategies to improve outcomes in older adults.},
}

@article {pmid40950806,
year = {2025},
author = {Li, M and Wang, Y and Kazis, L and Weng, J and Xia, W},
title = {Comorbidities and apolipoprotein E genotypes of patients with mild cognitive impairment in transition to Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251353209},
pmid = {40950806},
issn = {2542-4823},
abstract = {BACKGROUND: Three common chronic diseases in the elderly: diabetes, hypertension, and hypercholesterolemia, associate with mild cognitive impairment (MCI) and Alzheimer's disease (AD).

OBJECTIVE: We will examine the association of apolipoprotein E (APOE) ε4 allele, diabetes, hypertension, and hypercholesterolemia (in combination) with the transition of MCI to AD.

METHODS: We examine patients from the National Alzheimer's Coordinating Center database from June 2005 to May 2021. AD converted from MCI, stable MCI, and non MCI/AD control subjects were analyzed using Cox proportional hazard models with propensity score weights on matching demographic information and medications prescribed at baseline.

RESULTS: With MCI time of diagnosis as the index date, MCI patients with diabetes and hypertension carried a higher risk of developing AD (HR = 1.17, 95%CI (1.04, 1.31), p = 0.01) compared to MCI patients with a single condition. A similar observation was found among MCI patients with diabetes and hypercholesterolemia (HR = 1.20, 95%CI (1.07, 1.36), p = 0.002). Compared to MCI patients who had a single condition and without APOE ε4 allele, MCI patients with APOE ε4/4 and both diabetes and hypertension have a significantly higher risk of AD onset (HR = 7.6, 95%CI (5.02, 11.5), p < 0.0001). Those with APOE ε3/4 also have a significantly high risk (HR = 2.3, 95%CI (1.92, 2.75), p < 0.0001). Comparable outcomes were found among those with diabetes and hypercholesterolemia.

CONCLUSIONS: The combination of diabetes with hypertension or hypercholesterolemia have a significant association with the progression of MCI to AD, and APOE ε4 allele enhances the association of these selected comorbidities in promoting this conversion.},
}

@article {pmid40950727,
year = {2025},
author = {Applications, BCA},
title = {RETRACTION: Inhibition of Glycogen Synthase Kinase and the Neuroprotective Function of Conjugated ZnO-Osthol Nanoparticles in Alzheimer's Disease.},
journal = {Bioinorganic chemistry and applications},
volume = {2025},
number = {},
pages = {9754654},
doi = {10.1155/bca/9754654},
pmid = {40950727},
issn = {1565-3633},
abstract = {[This retracts the article DOI: 10.1155/2022/1401995.].},
}

@article {pmid40950506,
year = {2025},
author = {Toyli, A and Zhao, C and Su, KJ and Shen, H and Deng, HW and Chen, QH and Sha, Q and Zhou, W},
title = {Phenotypic and Genetic Associations Between Cardiovascular Disease Subtypes and Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.29.25334750},
pmid = {40950506},
abstract = {BACKGROUND: Cardiovascular disease (CVD) and Alzheimer's disease (AD) are major public health concerns that share overlapping risk factors and potential mechanistic pathways. While vascular contributions to cognitive decline are well-documented, the specific relationships between AD and different CVD subtypes remain poorly understood.

METHODS: We examined associations between AD and 11 CVD subtypes using logistic regression models in two large biobanks: the UK Biobank (n = 502,133) and the All of Us Research Program (n = 287,011). Models were adjusted for demographic, lifestyle, and clinical covariates. We also explored genetic overlap between AD and CVD traits through colocalization of significant single nucleotide polymorphisms (SNPs) (p < 5×10 [-8]) using genome-wide association study (GWAS) data.

RESULTS: Most CVD subtypes were significantly associated with AD in both cohorts. Hypotension had the strongest and most consistent association, followed by hypertension and cerebral infarction. Acute myocardial infarction was the only subtype not significantly linked to AD. Genetic analyses revealed shared loci between AD and CVD-related traits, particularly in regions near APOE, MAPT , and genes influencing myocardial structure and vascular function.

CONCLUSIONS: This study identifies subtype-specific CVD associations with AD across two diverse cohorts and highlights shared genetic architecture underlying heart-brain interactions. These findings underscore the importance of vascular health in AD risk and suggest that certain CVD subtypes, especially hypotension, may play underrecognized roles in cognitive decline.},
}

@article {pmid40950503,
year = {2025},
author = {Ersözlü, E and Meyer, F and Preis, L and Arslan, O and Gref, D and von Droste, L and Hellmann-Regen, J and , },
title = {An explorative analysis of plasma biomarkers associated with cerebral amyloid angiopathy.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.03.25334994},
pmid = {40950503},
abstract = {BACKGROUND: Cerebral amyloid angiopathy (CAA) remains diagnostically challenging, particularly in asymptomatic individuals. While CAA often co-exists with Alzheimer's disease (AD), it may even have a direct impact on AD pathophysiology and the cognitive decline within the clinical course of AD. While fluid biomarkers are well-established for AD pathology, reliable markers to improve the characterization of CAA are lacking.

METHODS: We analyzed two subsets of participants from the Alzheimer's Disease Neuroimaging Initiative: one with available T2*-weighted gradient echo magnetic resonance imaging (MRI) (n=21) and another with postmortem neuropathological data (n=24), all with available plasma biomarkers from a 145-analyte multiplex immunoassay panel. We defined CAA as two or more lobar microbleeds in MRI or moderate to severe neocortical amyloid angiopathy in neuropathological examination. Plasma analytes were assessed twice per subject, one year apart, with the earlier sample obtained up to 6.6 years prior to either the first MRI or neuropathological examination. Non-parametric correlation and receiver operating characteristic curves were mainly reported.

RESULTS: In both cohorts, various markers related to inflammation, lipid metabolism, and cell adhesion were associated with CAA proxy measures. Specifically, both increased (Osteopontin, VCAM-1) and decreased (vitronectin or endothelial growth factor) biomarker levels were associated with MBs, while increased apolipoproteins (ApoAII, ApoCI and ApoCIII, ApoE and clusterin) and decreased AXL were associated with CAA severity in neuropathology. Ratios between inversely associated markers enhanced correlation strength and discriminated CAA status.

CONCLUSIONS: Several candidate plasma biomarkers of CAA were identified in individuals with either MRI or neuropathological indicators of CAA.},
}

@article {pmid40950481,
year = {2025},
author = {Lathika Rajendrakumar, A and Arbeev, KG and Bagley, O and Yashin, AI and Ukraintseva, S and , },
title = {Lower Hippocampal Volume Partly Mediates the Association Between rs6859 in the NECTIN2 Gene and Alzheimer's Disease: New Findings from Causal Mediation Analysis of ADNI Data.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.02.25334930},
pmid = {40950481},
abstract = {Infections may contribute to neurodegeneration, including Alzheimer's disease (AD). Polymorphism in the NECTIN2 gene has been linked to both AD and vulnerability to infections. We hypothesized that neurodegeneration may mediate the connection between this polymorphism and AD. To test this hypothesis, we conducted a causal mediation analysis (CMA) using the Alzheimer's Disease Neuroimaging Initiative (ADNI) data. We found that smaller hippocampal volume (HV), a biomarker of neurodegeneration, significantly mediated the association between rs6859 in NECTIN2 and AD risk. For the right HV, the mediated effect was 42.75%, while for the left HV, it was 49.76%. In linear mixed models (LMM), carrying the rs6859 risk alleles (A) was associated with a reduction in right HV (β = -0.16, p = 0.03), left HV (β = -0.14, p = 0.04), and total HV (β = -0.15, p = 0.04). In this data, the rs6859 (A) was a risk factor for AD only in men. Our results suggest that hippocampal atrophy may substantially mediate the association between NECTIN2 polymorphism and AD risk.},
}

@article {pmid40950465,
year = {2025},
author = {Du, L and Yu, L and Wang, T and Boyle, PA and Barnes, LL and Marquez, DX and Bennett, DA},
title = {Lifetime risk of incident dementia and incident mild cognitive impairment in older adults.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.29.25334749},
pmid = {40950465},
abstract = {BACKGROUND AND OBJECTIVES: To estimate the lifetime risk of dementia and mild cognitive impairment (MCI) from age 55 to 105, accounting for competing risk of death, and to examine differences by sex and race.

METHODS: We analyzed data from five harmonized longitudinal cohort studies at the Rush Alzheimer's Disease Center, including 4611 community dwelling older adults for lifetime dementia risk estimation and 3915 for lifetime MCI risk estimation. Incident dementia and MCI were identified through annual clinical evaluations.Nonparametric cumulative incidence function curves estimated lifetime risk, adjusting for competing risk of death and left truncation. Additional analyses assessed lifetime risk from index ages 55, 65, 75, and 85 and examined differences by sex and race.

RESULTS: The lifetime risk of incident dementia after age 55 was 43% (95% CI: 38-47), with a median age at diagnosis of 88 years(IQR: 83-92). For MCI, the lifetime risk was 62% (95% CI: 57-67), with a median age at diagnosis of 86 years(IQR: 80-90). Females had higher lifetime risks than males for both dementia (45% vs. 39%) and MCI (63% vs. 60%). Racial differences were smaller for dementia (45% in Black vs. 44% in White participants). For MCI, Black adults had higher lifetime risk before age 90.

DISCUSSION: These findings extend dementia lifetime risk estimation beyond age 90 among diverse older adults to provide lifetime risk estimates for MCI while accounting for the competing risk of death, highlighting the importance of prevention, and equitable public health strategies to reduce the burden of cognitive impairment.},
}

@article {pmid40950451,
year = {2025},
author = {Thakur, LS and Bharj, G and Sangabattula, L and Malik, B},
title = {ci-fGBD: Cluster-Integrated Fast Generalized Bruhat Decomposition for Multimodal Data Clustering in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.03.25334761},
pmid = {40950451},
abstract = {Multimodal biomedical datasets, such as those from neurodegenerative disease cohorts, present significant challenges in stratifying heterogeneous patient populations due to missing values, high dimensionality, and modality-specific biases. Traditional clustering methods often require extensive preprocessing and fail to integrate heterogeneous data types effectively. We introduce ci-fGBD(Cluster-Integrated Fast Generalized Bruhat Decomposition), a novel matrix factorization and clustering framework that natively operates on block-structured, multimodal datasets. ci-fGBD extends the classical Bruhat decomposition by jointly learning latent representations and patient clusters while automatically harmonizing contributions across diverse modalities, including neuroimaging, cognitive assessments, genomics, wearable sensors, and environmental exposures. Benchmarking against standard methods on real datasets demonstrates that ci-fGBD consistently identifies clinically meaningful subgroups, capturing subtle biological, cognitive, and demographic heterogeneity in Alzheimer disease cohorts with superior interpretability and robustness.},
}

@article {pmid40950430,
year = {2025},
author = {Qian, H and Wu, C and Li, B and Rosenzweig, A and Wang, M},
title = {Plasma Proteomics Linking Primary and Secondary diseases: Insights into Molecular Mediation from UK Biobank Data.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.29.25334726},
pmid = {40950430},
abstract = {Diabetes, hypertension, and dyslipidemia are major risk factors for cardiovascular (CVD), cerebral, and renal diseases (RD). However, the underlying molecular mechanisms, particularly the biological paths linking these primary conditions to downstream diseases remain incompletely understood. In this study, we investigated the role of plasma proteins as mediators of secondary disease development using data from ∼50,000 UK Biobank participants. Across three primary diseases and 18 subsequent conditions, we identified 1,461 significant mediation pathways involving 395 unique plasma proteins. Notable examples included GDF15 consistently mediating the diabetes-CVD link and ADM mediating the hypertension-pulmonary disease pathway. Protein mediators of secondary disease development were highly enriched in immune, metabolic, and cytokine-related pathways. Mendelian randomization supported causal roles for 84 proteins, highlighting their potential as therapeutic targets. Moreover, the identified mediating proteins improved predictive accuracy for secondary disease risk compared to other proteins and traditional clinical risk factors from machine learning methods. For example, in individuals with hypertension, the inclusion of top mediating proteins improved prediction accuracy for glomerular disease risk by approximately 14% measured by C-index. Stratified analyses based on disease severity revealed additional disease progression pathways and mediating proteins, such as APOE mediating the association between severe diabetes and Alzheimer's disease. Together, these findings implicate plasma proteins as central molecular mediators linking these primary diseases to subsequent development of a secondary condition and nominate promising targets for biomarker development and therapeutic intervention.},
}

@article {pmid40950425,
year = {2025},
author = {Brown, CA and Cousins, KAQ and Korecka, M and McGrew, E and Chen-Plotkin, A and Detre, JA and McMillan, CT and Lee, EB and Das, SR and Mechanic-Hamilton, D and Yushkevich, PA and Nasrallah, IM and Shaw, LM and , and Wolk, DA},
title = {Temporal Modeling of Amyloid and Tau Trajectories in Alzheimer's Disease using PET and Plasma Biomarkers.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.04.25334935},
pmid = {40950425},
abstract = {OBJECTIVE: To compare PET and plasma-based temporal modeling of amyloid and tau biomarkers in Alzheimer's disease.

METHODS: Longitudinal amyloid PET, [18] F-flortaucipir tau-PET, and Fujirebio Lumipulse plasma p-tau 217 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and University of Pennsylvania Alzheimer's Disease Research Center (Penn ADRC) were used to generate biomarker trajectory models using Sampled Iterative Local Approximation (SILA). SILA models using plasma p-tau 217 were compared to amyloid and tau PET-based models to estimate tau onset age (ETOA) and estimate amyloid onset age (EAOA), and factors influencing ETOA and time from ETOA to dementia were evaluated for PET and plasma-based models.

RESULTS: Plasma-based models generated similar results to PET for EAOA and ETOA, with stronger model agreement for ETOA than EAOA. Accuracy of estimated onset age compared to actual onset age was high within modality with slightly greater error when comparing across modalities (i.e. plasma to PET). For both plasma and PET models, earlier ETOA was associated with younger EAOA, female sex, and ≥1 ApoE ε4 allele. Earlier dementia onset after ETOA was associated with later ETOA for both plasma and PET models, while male sex was associated with shorter tau to dementia gap in plasma models.

INTERPRETATION: Temporal modeling of plasma biomarkers provides comparable information to PET-based models, particularly for tau onset age. Plasma-based temporal modeling can serve as a widely accessible tool for clinical assessment of biological disease duration that places the patient on the disease timeline, which may allow for improved discussion of prognosis and treatment decisions.},
}

@article {pmid40950202,
year = {2025},
author = {Jhaldiyal, A and Kumari, M and Tripathi, T and Khan, R and Wang, J and Guttman, L and Biswas, D and Pasupuleti, A and Aggarwal, A and Pandya, S and Chou, SC and Panicker, N and Monghekar, A and Albert, M and Bekris, L and Leverenz, J and Kam, TI and Dawson, T and Dawson, VL},
title = {Poly(ADP-ribose) Polymerase 1 Deficiency Attenuates Amyloid Pathology, Neurodegeneration, and Cognitive Decline in a Familial Alzheimer Disease Model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {40950202},
issn = {2692-8205},
abstract = {Poly(ADP-ribose) (PAR) polymerase-1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimer disease (AD), yet its role in amyloid-β (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive ELISA, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. In vitro, oligomeric Aβ 1-42 activated PARP1 and induced DNA damage, while genetic or pharmacological inhibition of PARP1 conferred neuroprotection. In vivo, PARP1 knockout in the 5XFAD mouse model of amyloidosis led to reduced amyloid plaque burden, preserved synaptic and neuronal integrity, attenuated glial activation and neuroinflammation, and rescued cognitive deficits. Mechanistically, PARP1 deficiency decreased amyloid precursor protein (APP) and BACE1 levels, altered γ-secretase complex composition, and enhanced Aβ degradation via neprilysin. These findings position PARP1 as a critical mediator of Aβ toxicity and neurodegeneration, suggesting its inhibition as a promising therapeutic strategy for AD.},
}

@article {pmid40950201,
year = {2025},
author = {Ivan, T and Timon, L and Hans-Wolfgang, K and Mohammed Mehedi, H and Annik, S and Barbara, M and Sebastian, B and Lars, VW and Thomas, L and Jochen, W and Hermann, S and Jens, W and Oliver, W and Olaf, J and Hans-Michael, M},
title = {Aggregation-Dependent Epitope Sequence and Modification Fingerprints of Anti-Aβ Antibodies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.02.26.640323},
pmid = {40950201},
issn = {2692-8205},
abstract = {A hallmark of Alzheimer's disease (AD), the most common form of dementia, is the progressive accumulation of amyloid-beta (Aβ) peptides across distinct brain regions. Anti-Aβ antibodies (Aβ-Abs) targeting specific Aβ variants are essential tools for AD research, diagnostics, and therapy. The monoclonal antibodies Aducanumab, Lecanemab, and Donanemab have recently been approved as the first disease-modifying treatments for early AD, highlighting the clinical importance of their exact binding profiles. In this study, we systematically characterized the binding and modification requirements of 20 Aβ-Abs, including biosimilars of Aducanumab, Lecanemab, and Donanemab, across monomeric, oligomeric, and aggregated Aβ forms. Array-based analysis of 20,000 modified Aβ peptides defined binding epitopes at single-residue resolution and revealed the impact of sequence variation, including familial AD mutations, as well as diverse post-translational modifications (PTMs). Notably, genetic variants such as H6R impaired binding of therapeutic Aβ-Abs like Aducanumab. Donanemab showed strong preference for pyroglutamate-modified AβpE3-10, while Lecanemab and Aducanumab exhibited aggregation- and sequence-context-dependent binding requirements. Comparison of peptide binding profiles with binding of full-length and aggregated Aβ via immunoprecipitation-mass spectrometry, capillary immunoassays, Western blotting, and immunohistochemistry on AD brain tissue revealed distinct aggregation-dependent binding behaviours. The valency- and context-dependence of Aducanumab binding, together with its preference for Ser8-phosphorylated Aβ, supports a dimerization-mediated binding mechanism. For Lecanemab, our data suggest that additional structural contributions beyond the minimal N-terminal epitope are required for binding to aggregated Aβ, which remain to be fully resolved. Together, this work provides the most comprehensive dataset to date on aggregation-dependent sequence and modification selectivity of Aβ-Abs. By integrating mutational, PTM, and aggregation contexts in a unified experimental framework, we establish a resource that enables rational selection of antibodies for research and diagnostic applications, and offers mechanistic insights that may inform the design and optimization of future therapeutic antibodies in AD.},
}

@article {pmid40950166,
year = {2025},
author = {Wang, Y and Anchipolovsky, S and Bhuiyan, P and Sato, L and Liang, G and Chuang, DM and Wei, H},
title = {Lithium Chloride Inhibits Iron Dysregulation and Ferroptosis in Induced Pluripotent Stem Cells with ApoE4/E4 from a sporadic Alzheimer's disease patient.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.28.672956},
pmid = {40950166},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD), particularly its sporadic form (SAD, 95% AD patients), is strongly associated with the apolipoprotein E4 ApoE4 genotype and characterized by oxidative stress, iron dysregulation, and increased susceptibility to ferroptosis. Lithium, a well-established neuroprotective agent, has shown potential to mitigate several pathological mechanisms in AD, including ferroptosis. This study investigates the therapeutic potential of lithium chloride in human induced pluripotent stem cells (iPSCs) derived from a SAD patient with ApoE4/E4 genotype, and compared effects with those of isogenic gene-edited ApoE3/E3 control. Lithium treatment significantly improved cell viability in ApoE4/E4 iPSCs. It also reversed key ferroptosis phenotypes, including elevated cytosolic Fe [2+] , increased expression of divalent metal transporter 1, reduced level of glutathione peroxidase 4, enhanced lipid peroxidation, and excessive ROS production. Moreover, lithium normalized mitochondrial respiration and reduced proton leak, indicating preservation of mitochondrial function and protection against mitochondrial damage and cell death. Lithium also reduced the expression of type 1 InsP3 receptor (InsP3R-1) protein, a Ca [2+] channel located on the endoplasmic reticulum (ER) membrane. Together, these findings highlight lithium's inhibition of ferroptosis through modulation of iron metabolism, antioxidant defenses, and inhibition of disrupted Ca [2+] signaling. Given its demonstrated efficacy in reversing ApoE4-driven cellular vulnerabilities, lithium salt warrants further investigation for the treatment of AD.},
}

@article {pmid40950140,
year = {2025},
author = {Yu, L and Yokomizo, S and Doan, TH and Zhao, Q and Ganne, A and Balasubramaniam, M and Kastanenka, KV},
title = {Zolpidem restores sleep and slows Alzheimer's progression in a mouse model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.31.673377},
pmid = {40950140},
issn = {2692-8205},
abstract = {INTRODUCTION: Deficits in Non-Rapid Eye Movement (NREM) sleep facilitate Alzheimer's disease (AD) progression. Enhancing GABAergic signaling can restore sleep. Unbiased computational analysis identified zolpidem as high-affinity GABA receptor modulator facilitating chloride transport that could slow AD.

METHODS: Zolpidem's effects on sleep and Alzheimer's progression were evaluated in young APP/PS1 mice. Sleep was monitored with EEG/EMG telemetry. Widefield imaging with voltage-sensitive dyes was used to track sleep-dependent brain rhythms. Multiphoton microscopy allowed assessments of amyloid plaque load and basal neuronal calcium levels. Behavioral assays were used to measure memory and cognitive function.

RESULTS: Zolpidem restored NREM sleep and rescued sleep-dependent brain rhythm, slow oscillation. Zolpidem administration reduced cortical amyloid plaque burden, mitigated neuronal calcium overload, and enhanced sleep-dependent memory consolidation without adverse effects on locomotion.

DISCUSSION: Zolpidem effectively slowed Alzheimer's progression in young APP/PS1 mice. This supports zolpidem's therapeutic promise as an intervention strategy at early stages of AD.},
}

@article {pmid40950136,
year = {2025},
author = {Saunders, D and Sultan, F and Vialle, RA and Kearns, NA and Ng, B and Clark, EM and Vyas, H and Tissera, S and Xu, J and Bennett, DA and Wang, Y},
title = {Stress-Responsive Transcriptomic Signatures in Human iPSC-Derived Microglia Reveal Links to Alzheimer's Disease Risk Genes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.30.673269},
pmid = {40950136},
issn = {2692-8205},
abstract = {Cellular stress responses are essential for maintaining homeostasis in the face of environmental or internal challenges. In the central nervous system, microglia serve as key stress sensors and immune responders, shaping neuroinflammatory processes and disease progression. However, the molecular programs engaged by distinct stressors and their impact on microglial viability remain incompletely understood. In this study, we used human induced pluripotent stem cell-derived microglia-like cells to investigate stress responses to amyloid beta (Aβ), a chronic Alzheimer's disease-related stressor, and lipopolysaccharide (LPS), a classical acute inflammatory stimulus. Using single-cell RNA sequencing, we mapped the transcriptional programs activated by each condition and benchmarked these states against reference microglial datasets from mouse and human brains. In parallel, we performed a pooled CRISPR interference screen targeting Alzheimer's disease-associated microglial genes to identify genetic determinants of microglial survival. We found that Aβ and LPS elicit partially overlapping but distinct transcriptional responses. Aβ induced more focused and disease-associated gene expression changes, while LPS triggered broad inflammatory activation and stronger cell death signatures. A subset of genes activated by stress overlapped with Alzheimer's disease risk genes and with hits from the survival screen, suggesting that disease-associated microglial genes may contribute to stress adaptation and cellular fitness. These results demonstrate that iPSC-derived microglia-like cells can recapitulate in vivo-like stress-responsive states and offer a tractable platform to investigate genetic and environmental influences on microglial behavior. Together, our findings reveal transcriptional programs that link stress sensing, survival regulation, and Alzheimer's disease-associated gene networks, providing a foundation for future efforts to enhance microglial resilience in neurodegenerative disease contexts.},
}

@article {pmid40950115,
year = {2025},
author = {Zhang, L and Franceschi, AM and Crary, JF and Provenzano, FA and , },
title = {Structural Compression and Entorhinal Vulnerability: Linking Tentorial Adjacency to Tau Burden and Dementia Progression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.02.670249},
pmid = {40950115},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is a growing public health crisis. The disease is defined neuropathologically by accumulation of amyloid-β plaques and neurofibrillary tangles (NFTs) composed of abnormal tau protein in the brain. Early neurofibrillary degeneration in the entorhinal cortex (EC) is a hallmark of AD and a critical initiating event in the hierarchical pathoanatomical progression. However, the factors triggering initial tau deposition in the EC remain unclear. We propose a novel biomechanical cascade hypothesis, positing that the unique anatomical inferomedial positioning of the EC, including proximity to the tentorial incisura (TI) and other skull base structures, renders it susceptible to very mild yet persistent age-related mechanical stress, analogous to the effects of repetitive mild traumatic brain injury, triggering tau pathology. To test this hypothesis, we developed a method to quantify Entorhinal-Tentorial (EC-TI) proximity and applied it to multimodal imaging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n =47). Based on this neuroanatomical contact coefficient (NCC), participants were heuristically stratified into high (n =24) and low (n =23) adjacency groups. When controlling for other risk factors, tau PET signal in the EC predicted conversion from mild cognitive impairment to AD only in the high-adjacency group (LLR p =0.009, tau PET in EC p =0.036). These findings identify EC-TI proximity as a novel and anatomically grounded biomarker of AD progression risk. More broadly, they suggest a previously unrecognized biomechanical contribution to the initiation of tau pathology in aging and sporadic AD, opening new avenues for early detection, risk stratification, and mechanistically targeted prevention strategies.},
}

@article {pmid40950111,
year = {2025},
author = {Ma, F and Özbay, PS and Bilgic, B and Hedden, T and Delman, B and Balchandani, P and Alipour, A},
title = {Optimized Quantitative Susceptibility Mapping at 7T MRI for Assessing Iron deposition in Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.31.673334},
pmid = {40950111},
issn = {2692-8205},
abstract = {INTRODUCTION: Elevated brain iron levels are common in Alzheimer's disease (AD). Quantitative Susceptibility Mapping (QSM) is an advanced MRI technique for assessing iron accumulation. The optimized QSM at 7 Tesla (7T) MRI may further improve the sensitivity to detect subtle susceptibility changes in AD.

METHODS: We optimized a QSM processing pipeline for 7T MRI by systematically comparing multiple reconstruction algorithms. Evaluation criteria included image quality, artifact suppression, and anatomical clarity. The finalized pipeline was applied to individuals with AD and healthy controls (HCs).

RESULTS: The results revealed significantly elevated magnetic susceptibility values in the globus pallidus and dentate nucleus of the AD group compared to HCs. These findings were confirmed through both visual inspection and quantitative analysis of high-resolution QSM maps.

DISCUSSION: Our results highlight the importance of optimizing QSM pipelines at 7T for accurate susceptibility quantification. We identified an optimal pipeline suitable for future applications in patients with AD and other neurological conditions.},
}

@article {pmid40950072,
year = {2025},
author = {Webster, JM and Yang, YT and Miller, AT and Zane, A and Scholz, K and Stone, WJ and Mudium, N and Corbin-Stein, NJ and Won, WJ and Stoll, AC and Greathouse, KM and Cooper, NH and Long, LF and Manuel, PN and Herskowitz, JH and Yacoubian, TA and Tyrrell, DJ and Sandoval, IM and Manfredsson, FP and Kordower, JH and Harms, AS},
title = {Tau, amyloid-beta and alpha-synuclein co-pathologies synergistically enhance neuroinflammation and neuropathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.10.13.618101},
pmid = {40950072},
issn = {2692-8205},
abstract = {Alzheimer's and Parkinson disease pathology often co-occur, with amyloid-β and phosphorylated tau, found in 30-50% of idiopathic Parkinson disease cases. α-synuclein inclusions, a hallmark of Parkinson disease, are present in 50% of Alzheimer's cases and the co-expression of these pathologies is linked to faster cognitive decline and earlier death. Immune activation is a hallmark of both diseases, but current model systems primarily examine each pathology in isolation. As such, how these co-pathologies interact to drive inflammation and neuronal loss remain poorly understood. To address this, we developed a co-pathology mouse model combining tau, amyloid-β, and α-synuclein. Here, we show that co-pathologies synergistically trigger a distinct and amplified neuroimmune response, marked by robust expansion of CD4 [+] and CD8 [+] tissue-resident memory T cells and increased CD68 [+] microglia, a population of activated, phagocytosing microglia, compared to single pathology brains. These changes were abundant in the hippocampus and cortex, regions showing elevated amyloid-β protein pathology load and enhanced neuronal loss with co-pathology expression. Our findings demonstrate that co-pathologies act synergistically to enhance immune activation prior to neurodegeneration. This model provides a platform for assessing mixed-pathology mechanisms and identifies key immune cell populations that may drive disease acceleration across Alzheimer's, Parkinson disease and their related dementias.},
}

@article {pmid40950069,
year = {2025},
author = {Simpson, D and Morrone, CD and Wear, D and Khani, A and Liu, F and Gutierrez, J and Yu, WH},
title = {Brain large artery dilatation increases the risk for Alzheimer's disease pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.29.672901},
pmid = {40950069},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) and related dementia cases are increasing globally, emphasizing the urgent need to clarify disease mechanisms for translational application in diagnoses and treatment. Vascular alterations represent a major pathological feature of AD, and beyond the well-established roles of small vessel disease and large artery atherosclerosis, our group has previously demonstrated that brain large artery dilatation is associated with elevated risk of dementia and Alzheimer pathology. The most severe manifestation of this non-atherosclerotic arterial phenotype is dolichoectasia, an enlargement of large blood vessels (Gutierrez et al., 2019; Melgarejo et al., 2024). Despite consistent epidemiological evidence across populations, the mechanistic link between arterial dilatation and AD remains poorly understood. To address this gap, we induced dolichoectasia in App [NL-G-F] mice, a model of amyloid pathology, by injecting elastase into the cisterna magna. After three months, brains were examined using biochemical and immunohistochemical methods. Elastase-treated mice exhibited a significant increase in amyloid plaques in the hippocampus (p = 0.021) and cortex (p = 0.029) compared with vehicle-treated controls. Neuronal loss was evident in the CA1 region of the hippocampus (p = 0.036), with a trend towards neurodegeneration in CA3 (p = 0.055). We also observed elevated p62 in the hippocampus and cortex (p = 0.009 and p = 0.001 , respectively), suggesting impaired protein or autophagic-lysosomal clearance. Although no overt increase in neuroinflammation or astrogliosis was detected at this time point, matrix metalloproteinase-9 (MMP-9) levels were trending towards elevated levels (p = 0.058). Combined, these findings indicate successful elastase-induced brain arterial dilatation accelerates AD-related pathology in App [NL-G-F] mice, providing mechanistic evidence that large artery dilatation may contribute directly to Alzheimer's disease progression.},
}

@article {pmid40950061,
year = {2025},
author = {Liu, C and Sakha, KA and Anton, J and Cardenas-Rivera, A and Yaseen, MA},
title = {Systemic inflammation reduces astrocyte Ca [2+] and neurovascular coupling in a mouse model of Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.31.673380},
pmid = {40950061},
issn = {2692-8205},
abstract = {Neuroinflammation and neurovascular dysfunction are two major pathologies in Alzheimer's disease (AD), yet their interplay remains poorly understood. Astrocytes are central players in both brain immunity and neurovascular coupling. In this study, we induced neuroinflammation through systemic administration of lipopolysaccharide (LPS) in 12-month-old APP/PS1dE9 mice and simultaneously monitored the astrocyte Ca [2+] signaling and the brain hemodynamics with two-photon microscopy. We showed that the spontaneous release of Ca [2+] in astrocytes was elevated in AD mice and decreased by 14 days of LPS administration. The effects of LPS-induced inflammation on astrocytic Ca [2+] signaling varied substantially between brief 3 sensory stimulation and sustained 30 second sensory stimulation with modest effects on vascular responses. These findings highlight the nuanced impact of neuroinflammation on astrocytic Ca [2+] dynamics and brain hemodynamics in AD, shedding light on mechanisms that link these pathologies.},
}

@article {pmid40950052,
year = {2025},
author = {Pericak-Vance, MA and Nam, Y and DeRosa, BA and Ramirez, AM and Ayele, BA and Whitehead, PG and Adams, LD and Golightly, CG and Starks, TD and Laverde-Paz, J and Cukier, HN and Akinyemi, R and Sarfo, F and Akpalu, A and Cuccaro, ML and Williams, S and Caban-Holt, A and Reitz, C and Haines, JL and Goldie, BS and Rajabli, F and Dykxhoorn, DM and Young, JI and Vance, JM},
title = {Disrupted Lipid Homeostasis as a Pathogenic Mechanism in ABCA7-Associated Alzheimers Disease Risk.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.03.673792},
pmid = {40950052},
issn = {2692-8205},
abstract = {INTRODUCTION: ABCA7 (ATP-binding cassette sub-family A member 7) encodes a lipid transporter linked to Alzheimers disease (AD). While common variants confer modest risk in Europeans, a 44-base pair deletion (rs142076058; p.Arg578Alafs) is a strong risk factor in African Americans (AA). Despite this, the biological consequences of this ancestry-specific variant are not well understood.

METHODS: We expressed the truncated ABCA7 protein in HEK and HepG2 cells to assess localization and lipid metabolism. Additionally, induced pluripotent stem cell (iPSC)-derived neurons carrying the deletion were compared with isogenic controls.

RESULTS: The truncated ABCA7 localized to the plasma membrane similarly to wild type but induced significant lipid droplet accumulation in HepG2 cells and iPSC-derived neurons.

DISCUSSION: These findings show that the AA-specific ABCA7 deletion disrupts lipid regulation despite normal localization, suggesting a mechanistic link between impaired lipid homeostasis and increased AD risk. This work underscores the importance of ancestry-specific studies in AD research.},
}

@article {pmid40950010,
year = {2025},
author = {De La Cruz, PM and Lockett, A and Gomes, MT and Banerjee, S and Razee, A and Fisher, A and Cook, T and Lloyd, CD and Magaki, S and Umar, S and Oblak, AL and Machado, RF},
title = {Pulmonary Hypertension Promotes Neuroinflammation and Neurodegeneration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.02.673803},
pmid = {40950010},
issn = {2692-8205},
abstract = {INTRODUCTION: Pulmonary arterial hypertension (PAH) is associated with neurocognitive deficits and abnormal brain MRI. Little is known about the mechanisms underlying these clinical observations. TDP-43 is a proteinopathy associated with frontotemporal lobar degeneration (FTLD), Alzheimer's Disease, and Amyotrophic Lateral Sclerosis (ALS). In this study, we hypothesize PAH will result in gliosis, reduced neuronal density, and increased TDP-43 mislocalization.

METHODS: Sprague Dawley rats were randomly assigned to receive Vehicle (DMSO) Monocrotaline, or Sugen/Hypoxia to induce PH. Right heart catheterization was used to confirm PAH. Brain tissue was fixed and probed for microglia (Iba1), astrocytes (GFAP), neurons (NeuN), and TDP-43. Human PH vs control brain tissue was also probed for NeuN and TDP-43.

RESULTS AND CONCLUSIONS: We identify an increase in microglia and astrocyte density in the frontal cortex along with reduced neuronal density and neuronal TDP-43 mislocalization in rat models of PH. In addition, human PH frontal cortex demonstrated neuronal TDP-43 mislocalization. This is the first evidence of TDP-43 proteinopathy in PH.},
}

@article {pmid40950002,
year = {2025},
author = {Häkkinen, S and Beckett, A and Walker, E and Huber, LR and Feinberg, DA},
title = {Functional imaging of hippocampal layers using VASO and BOLD on the Next Generation (NexGen) 7T Scanner.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.29.673151},
pmid = {40950002},
issn = {2692-8205},
abstract = {Spatial accuracy and venous biases are a central concern in mesoscale fMRI, with subcortical brain regions facing additional challenges due to lower contrast-to-noise ratio (CNR), high physiological noise, and complicated vasculature. Here, we optimized CBV VASO on the NexGen 7T scanner for layer-specific investigations of the hippocampus. The presence of venous biases in VASO and BOLD (from the same acquisition) was then compared by using an established autobiographical memory task. While VASO and BOLD based activation patterns converged at macroscale, layer-specific differences emerged in the hippocampal subiculum, consistent with venous bias in the inner layers of the subiculum which can be explained by the unique two-sided venous drainage. Further, both VASO and BOLD showed sensitivity to short blocks (elaboration > construction), revealing an anterior-posterior distinction consistent with stronger involvement of the posterior hippocampus. Hippocampal cortical connectivity revealed brain circuitry between subcortical and cortical regions. Thus, hippocampal fMRI allows mapping layer function with high accuracy, made possible by sequence timing optimization on the high performance NexGen 7T scanner. The improved MR imaging has been developed to enable precision mapping of subcortical brain gray matter. By capturing changes of neural information flow within and across the microcircuitry of the hippocampus, it can provide deeper insights into a number of neuropsychological phenomena and the early changes occurring in Alzheimer's disease (AD) and mild cognitive impairment (MCI).},
}

@article {pmid40949984,
year = {2025},
author = {Drew, EE and Nyvall, HG and Parson, MAH and Talus, RK and Burke, JE and Hansen, SD},
title = {SH2-mediated steric occlusion of the C2 domain regulates autoinhibition of SHIP1 inositol 5-phosphatase.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.02.673847},
pmid = {40949984},
issn = {2692-8205},
abstract = {The Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1) is an immune cell specific enzyme that regulates phosphatidylinositol-(3,4,5)-trisphosphate signaling at the plasma membrane following receptor activation. SHIP1 plays an important role in processes such as directed cell migration, endocytosis, and cortical membrane oscillations. Alterations in SHIP1 expression have been shown to perturb myeloid cell chemotaxis and differentiation. In the brain, SHIP1 regulate microglial cell behaviors, which has been linked to Alzheimer's disease. Understanding the structural and functional relationships of SHIP1 is critical for developing ways to modulate SHIP1 membrane localization and lipid phosphatase activity during immune cell signaling. Recently, we discovered that the N-terminal SH2 domain of SHIP1 suppresses lipid phosphatase activity. SHIP1 autoinhibition can be relieved through interactions with receptor-derived phosphotyrosine (pY) peptides presented on membranes or in solution. Using hydrogen-deuterium exchange mass spectrometry (HDX-MS) we identified intramolecular contacts between the N-terminal SH2 domain and CBL1 motif of the C2 domain that limit SHIP1 membrane localization and activity. Single molecule measurements of purified SHIP1 on supported lipid bilayers and in neutrophil-like cells support a model in which the SH2 domain blocks membrane binding of the central catalytic module. Mutations that disrupt autoinhibition enhance the membrane binding frequency and increase the catalytic efficiency of SHIP1. Although dimerization of SHIP1 enhances membrane localization and the apparent phosphatase activity, it is not required for SHIP1 autoinhibition. Overall, our results provide new insight concerning SHIP1's structural organization, membrane binding dynamics, and the mechanism of autoinhibition.},
}

@article {pmid40949966,
year = {2025},
author = {Chattopadhyay, T and Mehendale, G and Thomopoulos, SI and Joshi, H and Venkatasubramanian, G and John, JP and Ambite, JL and Ver Steeg, G and Thompson, PM},
title = {Generating diffusion MRI scalar maps from T1-weighted images using Reversible GANs.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.08.27.672677},
pmid = {40949966},
issn = {2692-8205},
abstract = {Diffusion tensor imaging (DTI) provides valuable insights into brain tissue microstructure, but acquiring high-quality DTI data is time-intensive and not always feasible. To mitigate data scarcity and enhance accessibility, we investigate the generation of synthetic DTI scalar maps-specifically mean diffusivity (MD)-from structural 3D volumetric T1-weighted brain MRI using a reversible generative adversarial network (RevGAN). Unlike conventional pipelines requiring multiple steps, our approach enables a single-step translation from T1 to diffusion-derived measures. We assess the quality and utility of the synthetic maps in two downstream tasks: sex classification and Alzheimer's disease classification. Performance comparisons between models trained on real and synthetic DTI maps demonstrate that RevGAN-generated images retain meaningful microstructural features and offer competitive accuracy, underscoring their potential for data augmentation and analysis in neuroimaging workflows. We also examine how well models trained on these data generalize to a new population dataset from India (NIMHANS cohort).},
}

@article {pmid40949928,
year = {2024},
author = {Macaulay, O and Servilla, M and Arredondo, D and Virupakshappa, K and Hu, Y and Tafoya, L and Zhang, Y and Sahu, A},
title = {MedGraphNet: Leveraging Multi-Relational Graph Neural Networks and Text Knowledge for Biomedical Predictions.},
journal = {Proceedings of machine learning research},
volume = {261},
number = {},
pages = {162-182},
pmid = {40949928},
issn = {2640-3498},
abstract = {Genetic, molecular, and environmental factors influence diseases through complex interactions with genes, phenotypes, and drugs. Current methods often fail to integrate diverse multi-relational biological data meaningfully, limiting the discovery of novel risk genes and drugs. To address this, we present MedGraphNet, a multi-relational Graph Neural Network (GNN) model designed to infer relationships among drugs, genes, diseases, and phenotypes. MedGraphNet initializes nodes using informative embeddings from existing text knowledge, allowing for robust integration of various data types and improved generalizability. Our results demonstrate that MedGraphNet matches and often outperforms traditional single-relation approaches, particularly in scenarios with isolated or sparsely connected nodes. The model shows generalizability to external datasets, achieving high accuracy in identifying disease-gene associations and drug-phenotype relationships. Notably, MedGraphNet accurately inferred drug side effects without direct training on such data. Using Alzheimer's disease as a case study, MedGraphNet successfully identified relevant phenotypes, genes, and drugs, corroborated by existing literature. These findings demonstrate the potential of integrating multi-relational data with text knowledge to enhance biomedical predictions and drug repurposing for diseases. MedGraphNet code is available at https://github.com/vinash85/MedGraphNet.},
}

@article {pmid40949843,
year = {2025},
author = {Guo, AY and Laporte, JP and Singh, K and Bae, J and Bergeron, K and de Rouen, A and Fox, NY and Zhang, N and Carino-Bazan, I and Faulkner, ME and de Cabo, R and Benjamini, D and Gong, Z and Bouhrara, M and , },
title = {Machine learning diagnosis of mild cognitive impairment using advanced diffusion MRI and CSF biomarkers.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {3},
pages = {e70182},
pmid = {40949843},
issn = {2352-8729},
abstract = {INTRODUCTION: Machine learning applied to neuroimaging can help with medical diagnosis and early detection by identifying biomarkers of subtle changes in brain structure and function. The effectiveness of advanced diffusion MRI (dMRI) methods for pre-dementia classification remains largely unexplored, particularly when combined with CSF biomarkers.

METHODS: We implemented XGBoost machine learning models to evaluate the classification potential of dMRI parameters (derived using NODDI, C-NODDI, MAP, or SMI), CSF biomarkers of Alzheimer's pathology (Tau, pTau, Aβ42, Aβ40), and pairwise dMRI + CSF combinations in distinguishing cognitive normality from mild cognitive impairment.

RESULTS: MAP-RTAP (AUC = 0.78) and pTau/Aβ42 (AUC = 0.76) were the best performing individual biomarkers. Combining C-NDI derived using C-NODDI and Aβ42/Aβ40 achieved the highest performance (AUC = 0.84) and accuracy (0.84), while other combinations optimized either sensitivity (0.93) or specificity (0.88).

DISCUSSION: dMRI biomarkers demonstrate comparable performance to CSF biomarkers, with notable improvements achieved when combined. This study highlights dMRI's effectiveness for enhancing early AD detection.

HIGHLIGHTS: Advanced multishell diffusion MRI provides equivalent performance as CSF biomarkers in classifying MCICombining diffusion MRI and CSF biomarkers improves classification performanceStatistical diffusion MRI models perform best when used individually to classify MCIThe pTau/Aβ42 ratio outperforms other individual CSF biomarkers in MCI diagnosisBiophysical diffusion MRI models achieve the best performance when combined with CSF data.},
}

@article {pmid40949788,
year = {2025},
author = {Alzenaidi, F and Aldoweesh, O and Alghofaili, S and Fadel, A and Ali Awad Lasloom, R and Alharbi, D and Almalki, F and Ahmad Alkhairi, A and Alharbi, M and Ahmed Alhamdan, N and Azzam, AY},
title = {Selective serotonin reuptake inhibitors and glucose metabolism in Alzheimer's disease and related dementias: A systematic review and meta-analysis of brain metabolic and adverse event data.},
journal = {Metabolism open},
volume = {27},
number = {},
pages = {100389},
pmid = {40949788},
issn = {2589-9368},
abstract = {INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression in Alzheimer's disease (AD), however their effects on glucose metabolism remain poorly understood. We conducted a systematic review and meta-analysis to evaluate SSRI effects on brain glucose metabolism and metabolic adverse events in AD patients.

METHODS: Following PRISMA 2020 guidelines, we searched multiple databases up to July 11, 2025 for studies investigating SSRI effects on glucose-related outcomes in AD patients. Despite significant heterogeneity in study designs and populations, we performed meta-analyses for adverse events and coordinate-based meta-analysis for neuroimaging data. We performed meta-analyses for adverse events and coordinate-based meta-analysis for neuroimaging data. Advanced Bayesian hierarchical modeling and Markov simulations projected long-term metabolic outcomes.

RESULTS: Twelve studies with total included 7143 participants met our inclusion criteria, including nine randomized controlled trials and three observational studies. Brain FDG-PET revealed SSRI use restored dorsal raphe nucleus hypometabolism (standardized mean difference 0.87, 95 % CI: 0.52-1.22, P-value = 0.001). Meta-analysis demonstrated increased gastrointestinal adverse events (risk ratio 2.15, 95 % CI: 1.68-2.76, P-value<0.001, with moderate between-study heterogeneity), with sertraline showing highest rates. Citalopram 30 mg provided significant weight loss protection (risk ratio 0.13, 95 % CI: 0.02-0.98, P-value = 0.02), though this exceeds the recommended 20 mg maximum dose for elderly patients due to cardiac safety considerations. Long-term diabetes incidence showed no increased risk (hazard ratio 0.75, 95 % CI: 0.50-1.12, P-value = 0.15). Bayesian modeling revealed 85 % probability of beneficial brain metabolic effects and 89 % probability of citalopram superiority for weight protection.

CONCLUSIONS: SSRIs restore brain glucose metabolism in AD patients while causing manageable peripheral metabolic effects. Citalopram appears the best for weight-sensitive patients, while sertraline requires gastrointestinal monitoring. These findings support SSRI safety for metabolic outcomes in AD treatment, however longer-term studies with controlled metabolic outcomes are needed to confirm our findings. The observed citalopram weight protection benefit was documented at 30 mg daily, which exceeds recommended dosing limits for elderly patients due to cardiac safety concerns.},
}

@article {pmid40949676,
year = {2025},
author = {Cai, H and Hu, J and Zhao, C and Lin, J},
title = {Wearable devices in neurological disorders: a narrative review of status quo and perspectives.},
journal = {Annals of translational medicine},
volume = {13},
number = {4},
pages = {46},
pmid = {40949676},
issn = {2305-5839},
abstract = {BACKGROUND AND OBJECTIVE: Neurological disorders are a group of diseases involving motor, sensory, cognitive, and autonomic functions, among which stroke, Alzheimer's disease (AD), and Parkinson's disease (PD) are prevalent. Their management, especially in conditions with chronic courses or long-term sequelae, remains a substantial unmet need. With the growing comprehension of neuroscience, the development of digital technology, and the rising demand for quality of life, wearable devices offer a promising solution for disease management. The review aimed to evaluate the application and prospect of wearable devices in neurological disorders.

METHODS: We conducted the review by searching papers on the application of wearable devices and wearable technology in neurology and neurological disorders using multiple databases. We summarized the present development status of wearable devices, and outlined the potential value and future direction for further research.

KEY CONTENT AND FINDINGS: Existing wearable devices for neurological diseases can be applied to diagnosis and follow-up, as an electronic biomarker detector capturing subtle and objective changes in motor, sensory, and cognitive function. The devices can also be utilized for treatment and rehabilitation, mainly through exoskeletons and brain-computer interface. The application of wearable devices in neurology currently faces several critical limitations, including technical bottlenecks in the detection of fine motor and sensory functions, a lack of industry standards, and a limited sample size.

CONCLUSIONS: This review demonstrates the potential of wearable technology in people with neurological disorders, enabling disease management and clinical trials outside clinical settings in the future. Nevertheless, further research is required to develop lighter, more user-friendly devices with various functions. It is believed that with increasing demand and technical support, wearable devices would have a promising range of applications.},
}

@article {pmid40949612,
year = {2025},
author = {Gao, L and Wang, J and Bi, Y},
title = {Nanotechnology for Neurodegenerative Diseases: Recent Progress in Brain-Targeted Delivery, Stimuli-Responsive Platforms, and Organelle-Specific Therapeutics.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {11015-11044},
pmid = {40949612},
issn = {1178-2013},
abstract = {Neurodegenerative diseases-including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis-are characterized by progressive neuronal loss and complex pathological mechanisms such as protein aggregation, mitochondrial dysfunction, and neuroinflammation. Conventional therapies offer limited efficacy due to the blood-brain barrier (BBB) and lack of targeted delivery. Nanotechnology has emerged as a transformative strategy for precise brain-targeted treatment. This review summarizes recent advances in nanoparticle-based drug delivery systems, including polymeric nanoparticles, liposomes, inorganic nanomaterials, and biomimetic carriers, highlighting their design features, BBB-penetration mechanisms, and disease-specific applications. Emphasis is placed on stimuli-responsive nanocarriers that react to pH, reactive oxygen species, or enzyme activity, enabling site-specific drug release. Additionally, organelle-targeting strategies-particularly those directed at mitochondria and lysosomes-are explored for their role in subcellular precision therapy. The integration of diagnostic and therapeutic modalities in theranostic nanoplatforms is also discussed. By consolidating preclinical progress and emerging technologies, this review offers insights into the future of nanomedicine in treating neurodegenerative diseases and lays the groundwork for clinical translation.},
}

@article {pmid40949219,
year = {2025},
author = {Van, DTT and Hoang, TLH and Tran, TVT and Le, TH and Le, LS and Nguyen, QM and Nguyen, THH and Bich, TTN and Nguyen, THC and Phan, CU and Nguyen, CC},
title = {Structural Characterizations and In Vitro Bioactivities of a d‑Fructose-Rich Polysaccharide from Gymnopetalum cochinchinense as a Potential Candidate for Alleviating Alzheimer's Disease.},
journal = {ACS omega},
volume = {10},
number = {35},
pages = {40342-40353},
pmid = {40949219},
issn = {2470-1343},
abstract = {The presented investigation attempts to unveil the structural characteristics, bioactivities, and potential application of Gymnopetalum cochinchinense-derived d-fructose-rich heteropolysaccharide (denoted as PS-HB5) for the treatment of Alzheimer's disease (AD). Structural analyses of the PS-HB5 evaluated by FT-IR, GC-MS, and NMR techniques reveal a novel repeating unit composed of d-glucose and d-fructose linked through (1 → 6)-glucosyl, (2 → 6)-fructosyl, and (2 → 4)-fructosyl bonds, and possesses a molecular weight of 1.217 × 10[5] Da. The PS-HB5 exhibits strong antioxidant activity, as evidenced by its DPPH and ABTS radical scavenging rates of 84.12% and 74.14%, associated with the IC50 values of 0.80 and 3.06 mg.mL[-1], respectively. In addition, the PS-HB5 shows an inhibition rate of 78.37% (IC50 = 221.96 μg.mL[-1]) toward nitric oxide (NO) production in LPS-stimulated macrophages. Cytotoxicity assays indicate selective inhibition of the PS-HB5 against HepG2 and KB cancer cell lines (IC50 = 449.95 and 408.34 μg/mL), with minimal impact on MCF-7 and SK-LU-1. Interestingly, PS-HB5 demonstrates an outstanding AChE inhibitory effect, achieving 41.01% inhibition at 500 μg.mL[-1], placing it among the most active AChE-inhibitory polysaccharides. These findings unveil the PS-HB5 potential as a candidate for the treatment of Alzheimer's Disease.},
}

@article {pmid40949178,
year = {2025},
author = {Nivethitha, A and Manigandan, T},
title = {A hybrid deep learning architectures and feature extraction techniques for alzheimer disease recognition.},
journal = {Cognitive neurodynamics},
volume = {19},
number = {1},
pages = {146},
pmid = {40949178},
issn = {1871-4080},
abstract = {Alzheimer's disease (AD) is one of the common forms of dementia and is tremendously increasing throughout the world. There are many biomarkers currently available to detect the AD progression. In AD, brain cell death occurs, leading to memory loss, impaired calculation ability, and difficulty in remembering recent events. Early detection of AD is crucial for managing the symptoms and providing effective medical intervention. AD symptoms usually develop gradually and become worse over time, and interfere with daily activities. Hence, this research proposes the Fuzzy scoring based ResNet-Convolutional Neural Network (FS-ResNet CNN) to discriminate AD patients having AD, Mild Cognitive Impairment (MCI), and cognitively normal (CN) using a hybrid deep learning architecture to leverage more complete spatial information from the ADNI data. Initially, the pre-processing is carried out using the z-score normalization. To reduce the time complexity and to select the prominent features, the Adaptive Grey Wolf Optimization Algorithm (AGWOA), harnessing the swarm intelligence, has been proposed. Finally, the Hybrid Deep Learning Architecture is applied for the classification of AD. Specifically, the proposed method introduces a novel method known as the Fuzzy Scoring to optimize the network performance. Furthermore, the proposed FS-ResNet CNN model is computationally efficient, less sensitive to noise, and efficiently saves memory. Experimental results demonstrate the effectiveness of the proposed method on the ADNI dataset, showing high classification accuracy of 97.89%, surpassing the other state-of-the-art methods.},
}

@article {pmid40949174,
year = {2025},
author = {Lu, Y and Xu, H and Sun, Y and Ihejirika, SA and Chiang, CW and Darst, BF and Song, S and Shen, Y and Ye, K},
title = {Gene-Diet Interaction Analysis in UK Biobank Identified Genetic Loci That Modify the Association Between Fish Oil Supplementation and the Incidence of Dementia.},
journal = {Current developments in nutrition},
volume = {9},
number = {9},
pages = {107524},
pmid = {40949174},
issn = {2475-2991},
abstract = {BACKGROUND: Dementia is a common disease influenced by both genetic and environmental factors. APOE ε4 is well-known to increase risk of dementia, and it has been shown to attenuate the protective association of fish oil supplements (FOS) and the incidence of dementia.

OBJECTIVES: To identify additional genetic factors with modifying effects, we performed a genome-wide scan.

METHODS: We performed genome-wide association studies (GWAS) of incident all-cause dementia, Alzheimer's disease, and vascular dementia in 357,631 participants from UK Biobank and the FOS subgroups. Single-nucleotide polymorphisms (SNPs) suggestively associated with dementia (P < 1 × 10[-5]) were then evaluated for their interactions with fish oil status in Cox regression models. Furthermore, we conducted gene set enrichment analysis to identify the relevant cell types for these interaction signals.

RESULTS: Time-to-event GWAS identified 6, 5, and 2 genome-wide significant loci (P < 5 × 10[-8]) for the incidence of all-cause dementia, Alzheimer's disease, and vascular dementia, respectively. Most of them overlapped with previously known GWAS loci for Alzheimer's disease and related dementia. A total of 178 suggestive GWAS loci (P < 1 × 10[-5]) were passed onto interaction analysis, and 43 of them were found to significantly modify the association between FOS and dementia incidence (P < 2.8 × 10[-4] with Bonferroni correction). One locus overlapped with a known Alzheimer's disease GWAS locus (EED/PICALM) and 2 with GWAS loci for circulating ω-3 fatty acids (SRSF4 and PSMG1). Candidate interacting genes exhibited cell-type-specific expression in the nervous system.

CONCLUSIONS: In total, 43 genetic loci modify the association between FOS and dementia. These findings indicate a need for genome-informed personalized nutrition of FOS for the purpose of dementia prevention.},
}

@article {pmid40949164,
year = {2025},
author = {Roczkowsky, A and Rachubinski, RA and Hobman, TC and Power, C},
title = {Peroxisomes as emerging clinical targets in neuroinflammatory diseases.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1642590},
pmid = {40949164},
issn = {1662-5099},
abstract = {Peroxisomes are membrane-bounded organelles that contribute to a range of physiological functions in eukaryotic cells. In the central nervous system (CNS), peroxisomes are implicated in several vital homeostatic functions including, but not limited to, reactive oxygen species signaling and homeostasis; generation of critical myelin sheath components (including ether phospholipids); biosynthesis of neuroprotective docosahexaenoic acid; breakdown of neurotoxic metabolites (such as very-long chain fatty acids); and, intriguingly, glial activation and response to inflammatory stimuli. Indeed, peroxisomes play a critical role in modulating inflammatory responses and are key regulators of the mitochondrial antiviral signaling (MAVS) protein-mediated response to infections. The importance of peroxisomes in CNS physiology is exemplified by the peroxisome biogenesis disorders (PBDs), a spectrum of inherited disorders of peroxisome assembly and/or abundance, that are characterized in part by neurological manifestations ranging from severe cerebral malformations to vision and hearing loss, depending on the individual disorder. Recently, peroxisome dysfunction has been implicated in neurological diseases associated with neuroinflammation including Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson's disease while also contributing to the pathogenesis of neurotropic viruses including SARS-CoV-2, Human Pegivirus, HIV-1 and Zika virus. In the present review, we examine the diverse roles that peroxisomes serve in CNS health before reviewing more recent studies investigating peroxisome dysfunction in inflammatory brain disorders and also highlight potential peroxisomal targets for diagnostic biomarkers and therapeutic interventions.},
}

@article {pmid40949132,
year = {2025},
author = {Han, X and Meng, X and Wu, Y and Xia, W and Xue, S and Liu, X and Lyu, C and Li, Z and Yan, X and Won Jung, H and Zhang, S},
title = {Systems pharmacology identifies ajugol-mediated NF-κB/caspase-3 inhibition and isoacteoside-driven p62/mTOR-mediated autophagy as key mechanisms of Rehmanniae Radix and its processed form in Alzheimer's treatment.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1644847},
pmid = {40949132},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the deposition of senile plaques, neurofibrillary tangles, and neuronal dysfunction, resulting in severe cognitive and memory decline. The root of the Scrophulariaceae plant Rehmannia glutinosa (Gaertn.) DC. (Rehmanniae radix; RR) and its product Rehmanniae radix praeparata (RRP) possess high nutritional and medicinal value. Both show therapeutic potential for AD in traditional medical settings. However, the differences in their bioactive components and the mechanisms of action underlying their anti-AD effects remain unclear.

METHODS: In this study, APP/PS1 mice were used as the animal model of AD. Ultra-high-performance liquid chromatography coupled with Q-Exactive tandem mass spectrometry (MS/MS) (UPLC-QE-MS/MS), network pharmacology, proteomics, molecular docking, and 16S rRNA sequencing were used to investigate the differences in the medicinal components of RR and RRP and their mechanisms of action in the treatment of AD. The mechanisms of action of two identified critical components, ajugol and isoacteoside, were further verified in the D-galactose/AlCl3-induced Institute of Cancer Research (ICR) mouse model of AD-with cognitive function evaluated using the Morris water maze and open-field tests-and the amyloid-beta (Aβ)-induced BV2 cell model of inflammation.

RESULTS: Ajugol and isoacteoside were identified as the key anti-AD bioactive compounds in RR and RRP, respectively, through UPLC-QE-MS/MS. Integrated network pharmacology, proteomics, and 16S rRNA sequencing implicated neuroinflammation, apoptosis, and autophagy as critical pathways for their anti-AD effects. Subsequently, in vivo and in vitro experiments demonstrated that ajugol exerted its effects mainly by modulating the TLR/NF-κB/NLRP3 and BCL-2/BAX/cytochrome C/caspase-3 pathways, while isoacteoside primarily acted via the LC3-Ⅱ/P62/p-mTOR/mTOR pathway. Ajugol and isoacteoside mitigated cognitive impairment in AD models, decreased Aβ plaque accumulation in hippocampal tissues, and attenuated inflammatory injury-induced cytotoxicity in BV2 microglia, thereby suppressing AD progression.

CONCLUSION: In this work, we systematically elucidated the differential mechanisms underlying the anti-AD effects of ajugol and isoacteoside. We found that ajugol primarily acts via the TLR/NF-κB/NLRP3 and BCL-2/BAX/cytochrome C/caspase-3 pathways, while isoacteoside acts via the LC3-II/P62/p-mTOR/mTOR pathway. These findings establish a foundation for developing RRP-based complementary medicines and functional foods.},
}