@article {pmid41325816,
year = {2025},
author = {Farhana, F and Sultana, MA and Hia, RA and Hegde, V},
title = {Postmenopausal Sarcopenia and Alzheimer's disease: The interplay of Mitochondria, Insulin resistance, and Myokines.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106501},
doi = {10.1016/j.neubiorev.2025.106501},
pmid = {41325816},
issn = {1873-7528},
abstract = {As life expectancy increases, cognitive impairments such as Alzheimer's disease (AD) create serious problems for older adults. Women regardless of ethnicity and age group, are disproportionately affected, accounting for two-thirds of AD cases, with post-menopausal women representing over 60% of those affected. Sarcopenia, defined by gradual reduction of skeletal muscle mass, strength, and activities, is increasingly correlated with an elevated risk of cognitive decline in post-menopausal women. Menopause-related hormonal decline (particularly estrogen loss) and aging contribute to sarcopenia, characterized by muscle mitochondrial dysfunction, oxidative stress, and insulin resistance. This sarcopenia-driven reduction in muscle mass and functional capacity further reduces the production of myokines (e.g., BDNF, irisin), impairing neuronal proliferation, adult neurogenesis, and spatial learning/memory. These pathophysiological changes show a contributing link between sarcopenia and AD progression in post-menopausal women. This review is unique in that it discusses the triangular interplay between menopause, sarcopenia, and AD, offering an integrated mechanistic framework that links hormonal decline, muscle loss, and neurodegeneration. We aim to clarify the pathophysiological causes behind the muscle-brain axis and suggest viable treatment approaches to slow down sarcopenia and cognitive deterioration in postmenopausal women based on current evidence. The formulation of targeted strategies for enhancing the quality of life and lessening healthcare expenditures in this expanding population depends on the advancement of understanding this complex interconnection between menopause, sarcopenia and cognition.},
}

@article {pmid41325358,
year = {2025},
author = {Qin, R and Zhao, H and Gao, H and Liu, H},
title = {Global trends in Alzheimer's disease and other dementias: A comprehensive analysis of incidence, socio-demographic variations, and future projections.},
journal = {PloS one},
volume = {20},
number = {12},
pages = {e0338018},
doi = {10.1371/journal.pone.0338018},
pmid = {41325358},
issn = {1932-6203},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/epidemiology ; Incidence ; Aged ; Middle Aged ; *Dementia/epidemiology ; Aged, 80 and over ; Global Health ; Global Burden of Disease/trends ; Bayes Theorem ; Socioeconomic Factors ; Adult ; },
abstract = {BACKGROUND: Alzheimer's disease and other dementias (ADRD) are significant global health concerns, with rising incidence rates and substantial social and economic implications due to population aging.

METHODS: We investigated trends in ADRD incidence from 1992 to 2021 across age, sex, and socio-demographic index (SDI) regions, utilizing data from the Global Burden of Disease (GBD) 2021 platform. An age-period-cohort (APC) model was employed to analyze the effects of age, period, and birth cohort on ADRD incidence, and a Bayesian age-period-cohort (BAPC) model was used to predict future trends.

RESULTS: Globally, the age-standardized incidence rates (ASIR) remained relatively steady. However, the total number of ADRD cases witnessed a remarkable 141.25% increase, with 9,837,056 cases (95% UI: 8,620,519-11,163,700) in 2021. High SDI regions exhibited higher ASIR, whereas high-middle SDI regions showed the greatest growth, particularly among females. The net drift of ADRD incidence ranged from 0.43% per year in China to -0.68% per year in Denmark. Age effect was consistent across SDI regions, increasing exponentially with age. The 60-64 age group experienced the fastest annual incidence growth. High-middle SDI regions faced unfavorable period and cohort effects.

CONCLUSION: Although progress in ADRD globally, significant regional and sex disparities persist. Strengthened surveillance and management of adults over 60 are urgently needed. Targeted public health policies and interventions are essential to address the escalating global dementia burden.},
}

Humans
Female
Male
*Alzheimer Disease/epidemiology
Incidence
Aged
Middle Aged
*Dementia/epidemiology
Aged, 80 and over
Global Health
Global Burden of Disease/trends
Bayes Theorem
Socioeconomic Factors
Adult

@article {pmid41325201,
year = {2025},
author = {Zhao, N and Wang, Y and Yang, S and Guo, W and Li, Z and Cao, H and Zhang, Z and Li, Y and Chen, D and Xia, S and Xie, Z and Qu, Y and Wu, Y and Li, J and Yi, L and Wang, G and Guo, M},
title = {Surgical Protocols for Deep Cervical Lymphovenous Anastomosis in a Rat Model: Lymph Node and Lymphatic Vessel Anastomoses.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {225},
pages = {},
doi = {10.3791/69201},
pmid = {41325201},
issn = {1940-087X},
mesh = {Animals ; *Lymphatic Vessels/surgery ; *Anastomosis, Surgical/methods ; Rats ; *Lymph Nodes/surgery ; Neck/surgery ; *Veins/surgery ; Female ; },
abstract = {Deep cervical lymphovenous anastomosis (dcLVA) has become a promising treatment strategy for Alzheimer's disease (AD), offering significant improvements compared to the current limited treatment options. However, the underlying mechanism of dcLVA remains unclear. Although clinical trials are ongoing, animal models simulating dcLVA provide a valuable tool for exploring its mechanism. This study aims to develop a standardized protocol for creating dcLVA models in animals to facilitate basic research and address clinical challenges. We describe the surgical procedures and key steps for anastomosing the deep cervical lymph node (dcLN) and its afferent lymphatic vessel (ALV) with the posterior facial vein (PFV), detailing these two distinct surgical methods: deep cervical lymph node-vein anastomosis (dcLnVA) and deep cervical lymphatic vessel-vein anastomosis (dcLaVA). Beyond promoting lymphatic drainage, the comparison of these two surgical methods also helps us to understand and explore the role of the deep cervical lymph node and deep cervical lymphatic system in the pathogenesis of AD. Overall, the complete and clear presentation of the surgical procedure and key anatomical landmarks in the rat helps to standardize the surgical protocol, which can minimize confounding factors and reduce inter-experimental variability, thus laying a solid methodological foundation for a deeper understanding of the mechanisms involved.},
}

Animals
*Lymphatic Vessels/surgery
*Anastomosis, Surgical/methods
Rats
*Lymph Nodes/surgery
Neck/surgery
*Veins/surgery
Female

@article {pmid41325114,
year = {2025},
author = {Dharia, SY and Liu, Q and Smith, SD and Valderrama, CE},
title = {A Novel Approach for the Early Identification of Genetic Risk Factors for Alzheimer's Disease Using EEG and Psychometric Data.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2025.3639217},
pmid = {41325114},
issn = {2168-2208},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with impairments in memory and executive functions. Despite significant advancements in identifying genetic risk factors, the high cost and limited accessibility of genetic testing remain major barriers. In this work, we propose a cost-effective screening approach that leverages EEG recordings and psychometric test scores to predict an individual's genetic risk for AD. Our Convolutional Neural Network (CNN) model shows promising performance: it achieved an F1 score of 72.21% in distinguishing APOE-ϵ4/PICALM GG non-carriers (N) from APOE-ϵ4 carriers with the risky PICALM GG alleles (A+P+). It reached an F1 score of 60.78% for differentiating non-carriers (N) from APOE-ϵ4 carriers without the risky alleles (A+P-), and 65.12% when separating A+P- from A+P+. To enhance interpretability, we employ Grad-CAM, which reveals that EEG features contribute more significantly to gene prediction than psychometric measures. Notably, our model also identifies three key psychometric tests, MINI COPE (which assesses emotional coping skills), the California Verbal Learning Test (CVLT), and NEO Neuroticism, as associated with higher AD risk, consistent with prior research. Moreover, our results align with earlier findings reporting increased theta-band power among high-risk individuals. Finally, Higuchi Fractal Dimension (HFD) features drove most of the EEG-based prediction capability, as shown through our ablation study. This study highlights the potential of integrating neurophysiological and cognitive assessments to develop accessible and reliable screening tools for AD genetic risk, enabling earlier diagnoses. The code has been released at https://github.com/ Shyamal-Dharia/EEG-Psycho-Genes-AD.},
}

@article {pmid41324966,
year = {2025},
author = {Grill, JD},
title = {Disclosing Alzheimer Biomarkers to Motivate Brain Health Behaviors.},
journal = {JAMA network open},
volume = {8},
number = {12},
pages = {e2545780},
doi = {10.1001/jamanetworkopen.2025.45780},
pmid = {41324966},
issn = {2574-3805},
}

@article {pmid41324953,
year = {2025},
author = {Jiao, D and Wu, L and Zhang, W and Dou, J and Li, S and Zhao, Q and Yang, C and Nie, J and Ding, Y and Zhang, B and Li, M},
title = {Bicarbonate, blood urea nitrogen and cognitive function among us older adults, NHANES 2011-2014.},
journal = {Psychology, health & medicine},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/13548506.2025.2597470},
pmid = {41324953},
issn = {1465-3966},
abstract = {Alzheimer's disease and kidney health have become serious and urgent public health issues. Bicarbonate and blood urea nitrogen is closely related to kidney function but the relationship of the bicarbonate, blood urea nitrogen and cognitive function which is one of the most important symptoms of Alzheimer's disease is still unclear. In this study we aimed to examine the association of the bicarbonate, blood urea nitrogen and cognitive function. This study used the NHANES database, from which 2681 eligible individuals over 60 years of age were selected. We also extracted cognitive related tests, bicarbonate and blood urea nitrogen concentration to statistically analyze. Logistic regression and restricted cubic splines (RCS) were performed with confounding variables such as gender, age, race, body mass index (BMI), and alcohol intake. After adjusting for multiple factors, statistical analyses indicated significant correlations between bicarbonate, blood urea nitrogen, and cognitive function tests, with varying strengths across different tests. A stratified analysis by gender revealed that there are also differences in the results by gender. Based on the research, we concluded that bicarbonate, blood urea nitrogen are correlated with cognitive function in older Americans. This effect varied across populations.},
}

@article {pmid41324931,
year = {2025},
author = {Grill, JD},
title = {Blood Tests for Alzheimer Disease-What to Do With the Holy Grail.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.4726},
pmid = {41324931},
issn = {2168-6157},
}

@article {pmid41324928,
year = {2025},
author = {Malek-Ahmadi, M and Sharma, S and Stipho, F and Denkinger, M and Singh, A and Brum, WS and Ashton, NJ},
title = {Plasma Phosphorylated Tau 217 and Amyloid Burden in Older Adults Without Cognitive Impairment: A Meta-Analysis.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.4721},
pmid = {41324928},
issn = {2168-6157},
abstract = {IMPORTANCE: Blood-based biomarkers (BBMs) demonstrate high accuracy in detecting Alzheimer disease (AD) pathological changes in symptomatic individuals. In autosomal dominant AD and in individuals with Down syndrome, both populations with near-universal development of AD pathology, elevations in BBMs are detectable years before clinical onset, supporting their utility for identifying preclinical disease in these cases. Among BBMs, plasma phosphorylated tau 217 (p-tau217) exhibits strong concordance with established in vivo markers of AD pathology. However, its ability to identify older adults without cognitive impairment who are amyloid-positive remains variable across studies and settings.

OBJECTIVE: To assess the standardized effect size of mean differences and classification accuracy of p-tau217 for published studies that compared amyloid-positive and amyloid-negative older adults without cognitive impairment.

DATA SOURCES: PubMed, Embase, and EBSCOhost databases from inception to September 1, 2025.

STUDY SELECTION: Observational studies or randomized clinical trials with baseline data on individuals without cognitive impairment who were classified as either amyloid positive or amyloid negative and reported numeric data for p-tau217 levels.

DATA EXTRACTION AND SYNTHESIS: The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guideline was used for this study. Two authors independently carried out literature searches to identify studies with older adults without cognitive impairment who were classified as either amyloid positive or amyloid negative where p-tau217 was quantified.

MAIN OUTCOME AND MEASURE: The standardized mean difference (Hedges g) was used to characterize differences in mean p-tau217 levels. A pooled area under the curve (AUC) value was used to summarize the diagnostic accuracy of p-tau217 in identifying amyloid-positive individuals. Between-study heterogeneity was investigated using subgroup and sensitivity analyses. Publication bias was assessed using Egger tests.

RESULTS: Data for 7834 participants (2533 amyloid positive, 5301 amyloid negative) from 18 publications were analyzed. A large effect size was observed for p-tau217 (Hedges g = 1.50; 95% CI, 1.33-1.68). Values for p-tau217 also demonstrated high accuracy for identifying amyloid-positive individuals without cognitive impairment (AUC = 0.87; 95% CI, 0.85-0.90).

CONCLUSION AND RELEVANCE: These findings demonstrate that plasma p-tau217 can reliably detect AD pathology in the preclinical stage. These findings support the clinical utility of plasma p-tau217 as a scalable, minimally invasive tool for early identification of AD, particularly in settings where timely intervention with disease-modifying therapies may offer the greatest benefit in slowing or preventing disease progression.},
}

@article {pmid41324873,
year = {2025},
author = {Mousavi, MA and Salarvandian, S and Rafiee, S and Mohammadi, M and Khodagholi, F and Javadpour, P},
title = {The interactions of copper, glutamate, and cuproptosis: insights into brain health and Alzheimer's disease pathology.},
journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine},
volume = {},
number = {},
pages = {},
pmid = {41324873},
issn = {1572-8773},
support = {43014492-1//Neuroscience Research Center, Shahid Beheshti University of Medical Sciences/ ; },
abstract = {Copper (Cu) is a vital trace element essential for numerous neurological functions, such as neurotransmission and antioxidant defense mechanisms. Nevertheless, Cu dyshomeostasis has been increasingly associated with neurodegenerative diseases, particularly Alzheimer's disease (AD).This review provides an overview of the intricate mechanisms of Cu homeostasis in the brain, detailing the pathways through which Cu enters neural tissues and its subsequent metabolic roles. We also discuss the emerging concept of cuproptosis, a Cu-dependent regulated cell death mechanism, and highlight its relevance to AD pathophysiology. Furthermore, we examine the interplay between glutamate, a key excitatory neurotransmitter, and cuproptosis, illustrating how alterations in glutamate levels may exacerbate Cu toxicity and contribute to neuronal degeneration in AD. Additionally, we review several compounds with the potential to modulate Cu concentrations, emphasizing their therapeutic implications for restoring Cu balance and mitigating neurodegenerative processes.By integrating current findings on Cu metabolism, cuproptosis, and glutamate interactions, this review provides novel insights into potential therapeutic interventions that may help prevent or slow AD progression.},
}

@article {pmid41324859,
year = {2025},
author = {Shi, C and Dong, J and Hui, X and Xu, Z and Zhao, Z and Dong, L},
title = {Production, Mechanisms, and Therapeutic Strategies of Tryptophan Metabolites in CNS Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {226},
pmid = {41324859},
issn = {1559-1182},
support = {22XYJ0002//Xi'an Innovation Capability Strong Foundation Plan/ ; },
mesh = {Humans ; *Tryptophan/metabolism ; Animals ; *Central Nervous System Diseases/metabolism/therapy/drug therapy ; Gastrointestinal Microbiome/physiology ; },
abstract = {Tryptophan (TRP) metabolites, which are produced from TRP via three pathways-kynurenine, 5-hydroxytryptamine, and indole-are key signaling molecules of the gut-brain axis and are involved in a variety of central nervous system (CNS) disease processes, such as Alzheimer's disease, depression, and schizophrenia by orchestrating inflammatory responses, redox imbalances, neurotransmitter dynamics, mitochondrial dysfunction, and apoptotic/autophagic pathways. However, TRP metabolites exhibit bidirectional modulatory effects, combining different neuroprotective and neurotoxic substances, depending on their metabolic environment and concentration thresholds, posing significant challenges for therapeutic strategies. Therefore, it is important to modulate TRP metabolite production factors, including the regulation of key enzymes in metabolic pathways, the gut microbiota, hormones, and the disease pathology microenvironment, to promote the production of neuroprotective metabolites and inhibit neurotoxic metabolite production. In this review, we detail the influencing factors affecting TRP metabolite production, the regulatory role of TRP metabolites in CNS disorders, and therapeutic strategies related to TRP metabolites for CNS disorders. Targeting TRP metabolizing enzymes or remodeling the ecology of the gut microbiota could be a new strategy for the treatment of CNS diseases, providing a theoretical basis for future precision intervention in CNS diseases.},
}

Humans
*Tryptophan/metabolism
Animals
*Central Nervous System Diseases/metabolism/therapy/drug therapy
Gastrointestinal Microbiome/physiology

@article {pmid41324805,
year = {2025},
author = {Kang, M and Kim, H and Jeon, Y and Shin, YK and Park, HT and Shin, JE},
title = {APLP1 Interacts with SARM1 and Regulates Axonal Maintenance and Post-Injury Degeneration.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {225},
pmid = {41324805},
issn = {1559-1182},
support = {RS-2023-00218515//National Research Foundation of Korea/ ; 2020R1C1C1011074//National Research Foundation of Korea/ ; 2021R1A6C101A425//National Research Facilities and Equipment Center/ ; },
mesh = {*Armadillo Domain Proteins/metabolism ; Animals ; *Axons/metabolism/pathology ; *Cytoskeletal Proteins/metabolism ; *Nerve Degeneration/metabolism/pathology ; *Amyloid beta-Protein Precursor/metabolism ; Protein Binding ; Humans ; Mice ; Mice, Inbred C57BL ; Sciatic Nerve/pathology/metabolism ; Sensory Receptor Cells/metabolism/pathology ; },
abstract = {Amyloid beta precursor-like protein 1 (APLP1), a member of the APP protein family, has been associated with the pathogenesis of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. However, its role in the peripheral nervous system remains unclear. Here, we demonstrate that APLP1 binds to sterile alpha and TIR motif-containing 1 (SARM1), an NAD[+] hydrolase critical for peripheral axonal degeneration, and plays a role in axonal maintenance and post-injury degeneration. To identify potential regulators of SARM1-dependent axonal degeneration, we performed yeast two-hybrid screening using the SARM1 auto-inhibitory domain as bait and identified APLP1 as a SARM1-binding protein. We observed a significant increase in APLP1 levels after axonal injury in the proximal axon segments of cultured sensory neurons and mouse sciatic nerve. Knockdown of Aplp1 in vitro reduced neuronal NAD[+] levels and caused spontaneous axon degeneration in a SARM1-dependent manner. Furthermore, Aplp1 knockdown also accelerated injury-induced axonal degeneration. Collectively, these results show that APLP1 interacts with SARM1 and contributes to axonal maintenance in the peripheral nervous system.},
}

*Armadillo Domain Proteins/metabolism
Animals
*Axons/metabolism/pathology
*Cytoskeletal Proteins/metabolism
*Nerve Degeneration/metabolism/pathology
*Amyloid beta-Protein Precursor/metabolism
Protein Binding
Humans
Mice
Mice, Inbred C57BL
Sciatic Nerve/pathology/metabolism
Sensory Receptor Cells/metabolism/pathology

@article {pmid41324786,
year = {2025},
author = {Abushakra, S and Doraiswamy, PM and Hey, JA and Tosun, D and Barkhof, F and Barakos, J and Petrella, J and Kesslak, JP and Power, A and Sabbagh, M and Porsteinsson, A and Cohen, S and Gauthier, S and Ritchie, C and Watson, D and McSweeney, E and Boada, M and Liang, E and Bracoud, L and McLaine, R and Flint, S and Schaefer, JF and Yu, J and Bray, M and Hendrix, S and Dickson, S and Durrant, A and Albayrak, A and Tolar, M},
title = {Hippocampal Atrophy on Magnetic Resonance Imaging as a Surrogate Marker for Clinical Benefit and Neurodegeneration in Early Symptomatic Alzheimer's Disease: Synthesis of Evidence from Observational and Interventional Trials.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {41324786},
issn = {1179-1934},
abstract = {Amyloid-plaque reduction is currently the only recognized surrogate outcome for Alzheimer's disease (AD) trials, allowing accelerated approval of plaque-clearing amyloid antibodies. However, plaque reduction does not facilitate the development of new non-plaque-clearing treatments. The hippocampus is among the first brain regions affected by AD pathology, exhibiting synaptic dysfunction and neurodegeneration that manifests as hippocampal atrophy and memory decline. We evaluated hippocampal volume (HV) as a potential surrogate outcome that can predict clinical benefit in disease-modification trials. Using published data from observational and interventional studies that examined both cognition and HV on volumetric magnetic resonance imaging (vMRI), we evaluated the cross-sectional correlations of HV to cognitive performance, the longitudinal correlations of HV atrophy to cognitive decline, HV sensitivity to drug effects, and the correlations between drug effects on HV atrophy and cognitive decline. We also examined the magnitude of HV protection that corresponds to meaningful clinical benefit. Analyses from 30 observational studies encompassing 13,187 individuals (2633 cognitively normal; 10,554 early AD) showed significant cross-sectional correlations between baseline HV and cognition, and longitudinal correlations between HV atrophy and cognitive decline over ≥ 1 year. The relationship of HV-cognitive drug effects was examined at the group level in nine placebo-controlled trials of five antiamyloid agents that evaluated HV in early AD trials of at least 18 months' duration. These trials included four amyloid antibodies (aducanumab, lecanemab, donanemab, and gantenerumab) and one oral anti-oligomer agent (valiltramiprosate). Individual-level HV-cognition relationships were examined in two valiltramiprosate studies, one of which included diffusion tensor imaging (DTI) providing microstructural correlates of HV drug effects and helping distinguish neuroprotection from brain edema. Across these anti-amyloid drug trials (total N ~10,000), there was a linear relationship between drug effects on slowing of cognitive decline and slowing of HV atrophy. Two anti-oligomer trials (valiltramiprosate) reported significant subject-level correlations between drug effects on HV and cognition over 18-24 months (r = -0.40 to -0.44, p < 0.005, N = 50/69), with significant correlations of drug effects on brain microstructure (decreased mean diffusivity) with both HV and cognitive benefits, supporting reduced neurodegeneration. The minimal HV preservation at the mild cognitive impairment (MCI) stage that is associated with clinical benefit is estimated to be ≥ 40 mm[3] or ≥ 10% of atrophy in the placebo arm over 18 months. Our findings demonstrate that hippocampal atrophy is an early indicator of cognitive decline in AD, linked to amyloid and tau-related neurodegeneration. HV on standardized vMRI is sensitive to anti-amyloid treatments, demonstrating strong correlations between slowed hippocampal atrophy and slowed cognitive decline. Data from over 23,000 subjects over three decades support HV as a surrogate marker for predicting clinical benefit in early symptomatic AD.},
}

@article {pmid41324750,
year = {2025},
author = {Zhang, L and Zhang, L and Zhao, J and Zhang, W and Zhang, H},
title = {Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Alzheimer's Disease: Recent Advances and Controversies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {231},
pmid = {41324750},
issn = {1559-1182},
mesh = {*Alzheimer Disease/metabolism/enzymology/pathology ; Humans ; *Proprotein Convertase 9/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Cholesterol/metabolism ; },
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by the gradual deterioration of memory, imposes a significant global socioeconomic burden. Despite mechanistic insights into amyloid-β (Aβ) and tau pathways, effective therapies remain elusive. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism, has emerged as a multifunctional player in neurodegenerative processes. Initially studied for its role in cardiovascular health, recent evidence implicates PCSK9 in AD pathogenesis through mechanisms involving Aβ clearance, neuroinflammation, and receptor-mediated cholesterol trafficking. However, conflicting genetic and clinical data complicate its therapeutic potential. This review synthesizes current knowledge on PCSK9's role in AD, highlighting molecular pathways, clinical controversies, and implications for therapeutic development. Resolving these complexities could advance targeted diagnostics and disease-modifying therapies.},
}

*Alzheimer Disease/metabolism/enzymology/pathology
Humans
*Proprotein Convertase 9/metabolism
Animals
Amyloid beta-Peptides/metabolism
Cholesterol/metabolism

@article {pmid41324281,
year = {2025},
author = {Bozoki, A and Jain, H and Olivarez, M and Gallant, S and Reeder, S and Huntington-Alfano, K},
title = {Feasibility of an Alzheimer's Disease Care Pathway: Findings from an Educational Pilot in 2 Healthcare Systems.},
journal = {Journal of primary care & community health},
volume = {16},
number = {},
pages = {21501319251394537},
doi = {10.1177/21501319251394537},
pmid = {41324281},
issn = {2150-1327},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; Pilot Projects ; Feasibility Studies ; Referral and Consultation ; *Primary Health Care/organization & administration ; Male ; North Carolina ; Female ; *Critical Pathways/organization & administration ; Aged ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) impacts an estimated 7.2 million people aged 65 and older in the United States and remains undiagnosed in numerous additional patients. Earlier detection requires awareness and established care pathways for timely screening, diagnosis, and referrals in the primary care setting.

METHODS: A consensus AD care pathway was developed by 8 multidisciplinary clinicians and piloted across 2 health systems representing 3 geographies, University of North Carolina at Chapel Hill (NC) and Midwestern University (AZ and IL). Twenty primary care practitioners (PCP) completed baseline surveys before receiving disease state and care pathway education. Subsequent 1- and 3-month surveys assessed understanding, confidence, and experience diagnosing, screening, referring, and implementing suggested AD practices.

RESULTS: At baseline, 15% of respondents felt sufficiently trained on AD referral guidance, and 10% felt trained on the use of noninvasive tests to inform referrals. After 3 months, 85% agreed or strongly agreed receiving sufficient training on appropriate referrals for patients with suspected AD, and 90% agreed or strongly agreed receiving sufficient training on utilizing noninvasive tests to inform referrals and detect AD.

CONCLUSION: A standardized AD care pathway improved PCP disease awareness and confidence assessing patients suspected of having AD. Earlier AD detection in primary care may enable prompt intervention and resource accessibility.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
Pilot Projects
Feasibility Studies
Referral and Consultation
*Primary Health Care/organization & administration
Male
North Carolina
Female
*Critical Pathways/organization & administration
Aged

@article {pmid41323809,
year = {2025},
author = {Horgan, NG and Djurovic-Topalovic, A and Ademoye, TA and Reyes-Charles, HI and Kobayashi, N and Plascencia-Villa, G and Perry, G and Murakami, T and Fortin, JS},
title = {Epigallocatechin-3-Gallate: A potential amyloid Fibril Disaggregator of Serum amyloid A1.},
journal = {Biochemistry and biophysics reports},
volume = {44},
number = {},
pages = {102365},
pmid = {41323809},
issn = {2405-5808},
abstract = {Serum amyloid A1 (SAA1) is a 122-amino acid protein that, after cleavage, matures into a 104-amino acid form. Its N-terminus is responsible for binding high-density lipoprotein (HDL), while the C-terminus maintains its structural integrity. As an acute-phase protein, SAA1 is produced by the liver in response to acute inflammation. SAA1 is also a precursor to amyloid A (AA), and its accumulation can lead to AA amyloidosis-a condition secondary to chronic inflammation that causes tissue damage and organ dysfunction. Our study explores methods to disaggregate SAA1 fibrils isolated from the cat spleen, chicken liver, and cow liver. Specifically, we investigate the use of epigallocatechin-3-gallate (EGCG), a polyphenolic flavonoid extracted from green tea known for its anti-inflammatory and antioxidant properties, to disaggregate these fibrils. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to analyze these fibrils after treatment with 1 % DMSO and 400 μM of EGCG in 10 mM PBS (pH 7.4). The results demonstrated that EGCG effectively reduced fibril size, as confirmed by DLS characterization, with the disappearance or diminished prominence of the 10[3-4] nm peak. Additional TEM results confirmed that EGCG disaggregated amyloid-beta fibrils isolated from Alzheimer's disease brains. These findings suggest that compounds like EGCG could be valuable in treating inflammatory and neurodegenerative conditions by disaggregating amyloid fibrils.},
}

@article {pmid41323723,
year = {2025},
author = {Dewangan, B and Swain, P and Patra, S and Bodhe, PR and Kulkarni, N and Sahu, B},
title = {Synthesis and evaluation of HFIP bearing triazolo-amides as amyloid-β aggregation inhibitors and suppressors of aggregation induced neuroinflammation.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41323723},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease with biological signatures of amyloid beta (Aβ) aggregated plaques and increased levels of bio-metals like copper (Cu), zinc (Zn), and iron (Fe). Aβ-induced lysosomal membrane permeabilization is a key event in neuronal injury in AD. Aβ aggregation also modulates mitochondria membrane potential (MMP), activates interleukin 1β and NLRP3 inflammasome eventually leading to increased reactive oxygen species (ROS) production, neuronal apoptosis and mitochondrial dysfunction. Here, we report a multi-functional compound (2f) identified through structure-activity relationship study from a series of polyfluorinated triazole compounds. Compound 2f suppressed metal induced aggregation, downregulated NLRP3 inflammasome and IL-1β expression. It has maintained the lysosomal acidic pH and restored mitochondrial membrane potential. HFIP bearing triazolo amide (2f) was found to chelate with Cu(ii) and Zn(ii) selectively in the presence of a range of other physiologically relevant metals. Further, a molecular dynamics (MD) simulation study revealed 2f disrupted the aggregation via interacting with chain A of pentameric Aβ. Therefore the HFIP bearing triazole amides may serve as potential scaffolds for drug development towards the treatment of AD.},
}

@article {pmid41323657,
year = {2025},
author = {Lv, L and Guo, H and Zhao, Z and Zhao, X},
title = {Structural and microstructural changes in white and gray matter across the Alzheimer's disease continuum.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1693840},
pmid = {41323657},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive brain atrophy, with pathological progression accompanied by significant structural alterations in both gray matter (GM) and white matter (WM). This review summarizes the neuroimaging features and clinical implications of brain volumetric changes across distinct the clinical phases of the AD continuum [preclinical phase, subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia phase]. Our analysis reveals a key conceptual advance: the spatiotemporal pattern of WM volume loss is not merely a consequence of GM degeneration but an active and complementary contributor to clinical decline. We identify specific, underappreciated WM tracts whose atrophy rates offer unique prognostic value beyond hippocampal volume. The primary contribution of this work is a unified model of AD neuroanatomy, which challenges the isolated view of GM and WM pathology. This refined understanding is critical for developing the next generation of biomarkers and underscores the imperative to leverage artificial intelligence for analyzing these complex, multi-tissue interactions. Future research should further integrate artificial intelligence and multi-omics data to refine personalized predictive models.},
}

@article {pmid41323653,
year = {2025},
author = {Lee, BC and Choe, YM and Kim, JH and Choi, HJ and Suh, GH and Kim, SG and Kim, HS and Hwang, J and Yi, D and Kim, JW},
title = {Self-reported hopefulness and cognitive function: the moderating effect of physical activity in older adults without cognitive impairment.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1646298},
pmid = {41323653},
issn = {1663-4365},
abstract = {BACKGROUND: With dementia cases rising globally, identifying modifiable psychological factors that support cognitive resilience is crucial. Hopefulness, an optimistic emotional state, may serve as a protective factor against cognitive decline. However, its role in cognitively normal (CN) individuals remains underexplored. We aim to investigate the association between self-reported hopefulness and overall cognitive function in CN older adults and to examine the moderating effect of physical activity on this relationship.

METHODS: A total of 152 CN adults aged 65-90 years were included in the General Lifestyle and Alzheimer's Disease (AD) study. Hopefulness was assessed by the Geriatric Depression Scale item "Are you hopeful about the future?," with "Yes" and "No" responses defining the hopefulness and non-hopefulness groups. Cognitive function was measured using the total score (TS) of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery. Physical activity was evaluated using the Physical Activity Scale for the Elderly.

RESULTS: Participants in the hopefulness group showed significantly higher TS scores compared to the non-hopefulness group (B = 5.009, p = 0.003). Physical activity moderated this relationship, with a stronger positive association observed in individuals with high-to-moderate activity levels (B = 7.409, p < 0.001).

CONCLUSION: Self-reported hopefulness, defined as optimism about the future, is positively associated with cognitive function in CN older adults, particularly among those with high-to-moderate physical activity levels. Interventions promoting both emotional well-being and physical activity may offer synergistic benefits for cognitive health.},
}

@article {pmid41323652,
year = {2025},
author = {Zhang, H and Chen, W and Yuan, S and Cai, B and Ding, S and Bao, H and Sun, J and Lu, W and Zhu, H},
title = {Integrated analysis of N-glycosylation and Alzheimer's disease: identifying key biomarkers and mechanisms.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1597511},
pmid = {41323652},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly, imposing a significant societal burden. Current therapeutic approaches primarily address symptoms, underscoring the critical need to elucidate its pathogenesis and identify robust early biomarkers. N-glycosylation, a critical post-translational modification, is dysregulated in neurodegenerative disorders, yet its role in AD and diagnostic potential remain underexplored.

OBJECTIVE: This investigation aimed to characterize the interplay between N-glycosylation and AD through multi-dimensional bioinformatics analysis, identify core differentially expressed genes (DEGs) associated with this crosstalk, and evaluate their diagnostic efficacy in early AD detection.

METHODS: A bibliometric analysis of Web of Science literature spanning 2001-2025 was performed using VOSviewer, CiteSpace, and R. Transcriptomic data were analyzed with LIMMA to identify DEGs. Feature prioritization and molecular interaction decoding were achieved through Lasso, Random Forest, XGBoost, and SHAP analysis.

RESULTS: Bibliometric analysis highlighted a shift toward granular molecular mechanisms, with "bisecting GlcNAc" and "GNT-III (MGAT3)" emerging as key research topics. Differential expression profiling identified 6,845 DEGs, including TMEM59, MLEC, and MAX. Machine learning algorithms consistently prioritized these three genes as core N-glycosylation-related biomarkers, alongside APP as a key associated molecule. Among transcription factors, MAX was identified as a central regulator, with a subset of 8 factors (including MAX and BRD9) pinpointed as critical modulators of N-glycosylation and glial activation in AD. Diagnostic models demonstrated strong performance: logistic regression achieved an AUC of 0.947 with MAX, APP, and MLEC; Random Forest and XGBoost attained perfect AUC = 1.0 in primary analyses; and a clinical nomogram integrating core genes yielded an AUC of 0.899. SHAP analysis confirmed MAX, APP, MLEC, and TMEM59 as top predictors, revealing significant positive interactions between MLEC and TMEM59 (p = 0.00019) and a negative interaction between MAX and MGAT3 (p = 0.0288). Notably, MAX alone served as a impactful single-gene biomarker, with AUC values ranging from 0.644 to 0.898 across external validation.

CONCLUSION: MAX, MLEC, and TMEM59 represent key N-glycosylation-linked diagnostic biomarkers for AD. This integrative framework provides novel insights into AD pathogenesis and lays the foundation for personalized diagnostic tools and therapies, warranting experimental validation.},
}

@article {pmid41323574,
year = {2025},
author = {Sonko, S and Houssam, MI and Bissadu, KD and O'Connor, B and Hossain, G},
title = {Scoping the Landscape of Deep Learning for Alzheimer's Disease Stage Classification: Methods, Challenges, and Opportunities.},
journal = {BME frontiers},
volume = {6},
number = {},
pages = {0202},
pmid = {41323574},
issn = {2765-8031},
abstract = {Deep learning (DL) models have been widely applied for Alzheimer's disease (AD) stage classification. This scoping review synthesizes recent research to evaluate current performance benchmarks, identify methodological limitations, and highlight translational barriers. DL has potential to augment diagnostic accuracy and accelerate early intervention in AD, but translation requires models that generalize across datasets and integrate into real-world clinical workflows. Following scoping review methodology, 18 peer-reviewed studies published between 2018 and 2024 were analyzed. We extracted dataset sources, preprocessing strategies, model architectures, performance metrics, and translational considerations. Most studies employed convolutional neural networks (CNNs) or transfer learning (TL) backbones with accuracies frequently reported above 90%. Comparative synthesis revealed that TL and custom CNNs achieved similar headline accuracies, with differences of less than one percentage point. Reported performance was highly sensitive to task framing (cross-sectional vs. progression) and dataset provenance, with curated subsets often yielding near-ceiling internal accuracies but limited generalizability. Only one study implemented true external validation, underscoring a critical translational gap. Cost-effectiveness was rarely discussed explicitly; however, several studies indicated that open datasets reduce financial barriers, while adapting pipelines for EMR, or multisite data entails substantial resource demands. DL for AD classification shows consistent high accuracy but limited robustness, with external validation and financial cost-effectiveness remaining underreported. Future progress depends on standardized evaluation protocols, explicit reporting of financial costs, and the development of clinically interpretable, workflow-integrated models.},
}

@article {pmid41323451,
year = {2025},
author = {Nanthasi, W and Rattanabannakit, C and Wongkom, N and Dujada, P and Raksthaput, A and Chaichanettee, S and Phoyoo, P and Wachirutmanggur, L and An, SSA and Senanarong, V},
title = {The Utility of CSF Biomarkers in Diagnosing Alzheimer's Disease: A Thai Cohort Study.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {15},
number = {1},
pages = {162-173},
pmid = {41323451},
issn = {1664-5464},
abstract = {INTRODUCTION: Cutoff values for cerebrospinal fluid biomarkers vary by analytic technique and population, which complicates the differentiation of Alzheimer's disease (AD) from non-AD dementias. We aimed to establish local cerebrospinal fluid biomarker cutoffs within a Thai cohort.

MATERIALS AND METHODS: We recruited 68 patients with various forms of dementia from the Memory Clinic at Siriraj Hospital, Thailand. Each patient underwent clinical subtyping for dementia, and their cerebrospinal fluid levels of Aβ42, p-tau181, and t-tau were quantified using the Fujirebio INNOTEST ELISA. We then employed a data-driven approach, specifically a Z-score-based Gaussian Mixture Model, to define intersection cutoffs for Aβ42, p-tau181, t-tau, and the p-tau181/Aβ42 ratio. These established biomarker cutoffs were subsequently incorporated with clinical manifestations to refine the clinicobiological diagnoses.

RESULTS: Our study included 67 patients (mean age 65.5 ± 7.4 years, 61.2% female). Using a data-driven approach, we established the following CSF biomarker cutoffs for identifying AD in this Thai cohort: Aβ42 at 492.67 pg/mL, p-tau181 at 44.00 pg/mL, t-tau at 545.97 pg/mL, and the p-tau181/Aβ42 ratio at 0.057. After incorporating these CSF biomarker results with clinical profiles, the diagnoses changed in 17.9% of the patients.

CONCLUSIONS: In this study, CSF cutoffs for differentiating AD from non-AD dementia were established through a data-driven approach, which has been demonstrated as a valid alternative methodology. The integration of clinical and biological profiles is paramount in achieving accurate dementia diagnoses.},
}

@article {pmid41323450,
year = {2025},
author = {Hashimoto, M and Matsuzaki, K and Matsuda, C and Wakatsuki, H and Hossain, S and Ohno, M and Kato, S and Ohata, S and Yamashita, K and Yamaguchi, S and Nagai, A and Shido, O},
title = {Impact of the Apolipoprotein E ε4 Allele on Cognition and Omega-3 Fatty Acid Levels in the Plasma Membrane of Red Blood Cells in Healthy Elderly Japanese Population.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {15},
number = {1},
pages = {140-151},
pmid = {41323450},
issn = {1664-5464},
abstract = {INTRODUCTION: The ε4 allele of the apolipoprotein E (APOE4) gene is a well-known risk factor for the onset and development of late-onset Alzheimer's disease (AD). Lipid metabolism also plays a key role in AD. However, data on the association between APOE4, cognitive function, and blood lipid metabolism, particularly fatty acid metabolism, in the healthy elderly Japanese population are lacking.

METHODS: We analyzed the baseline data of 506 healthy elderly Japanese individuals (mean age: 73 ± 0.4 years) from Shimane Prefecture, Japan, who participated in six intervention trials conducted between 2008 and 2020. Among them, participants with mild cognitive impairment (MCI) were divided into the following two groups: APOE4 carriers (n = 104) and noncarriers (n = 321).

RESULTS: Compared with the noncarriers, the APOE4 carriers had significantly lower scores in the "recalling five objects" sub-item of Hasegawa's Dementia Scale-Revised and longer total times in the Cognitive Assessment for Dementia, iPad version. The ratio of docosahexaenoic acid (DHA)-to-arachidonic acid was significantly decreased, and the erythrocyte eicosapentaenoic acid (EPA) and DHA levels tended to be reduced in APOE4 carriers.

CONCLUSION: These findings suggest a possible association between the APOE4 allele and reduced erythrocyte EPA and DHA levels, even in healthy elderly Japanese individuals with high ω-3 fatty acid intake. Such alterations in lipid metabolism may be linked to cognitive vulnerability in older adults and individuals with MCI.},
}

@article {pmid41323288,
year = {2025},
author = {Wang, W and Hou, S and Wang, B and Sun, D and Liu, H and Zhao, T and Wang, Q and Xu, S and Li, T and Quan, M},
title = {Machine learning-derived biomarker cutoffs for Alzheimer's disease: Validation and application in preclinical and prodromal phases.},
journal = {iScience},
volume = {28},
number = {11},
pages = {113895},
pmid = {41323288},
issn = {2589-0042},
abstract = {This study aims to derive biomarker cutoffs in Alzheimer's disease dementia (ADD) and validate their concordance in preclinical and prodromal stages. 341 sporadic and 103 familial participants were selected from the China Cognition and Aging Study (COAST) and the Chinese Familial Alzheimer's Disease Network (CFAN) cohorts, separately. Machine learning was used to generate prediction models and biomarker cutoffs for identifying ADD. Agreement test was used in cognitive normal and mild cognitive impairment (CN + MCI) participants. For COAST, the optimal regression model was CSF Aβ42/40, ptau and left medial temporal atrophy (MTA-L), with area under the curve (AUC) of 0.841. The optimal decision tree model was CSF Aβ42/ptau, Aβ42/ttau, and MTA-L (AUC = 0.820). For CFAN, the optimal regression model was left precuneus relative volume and MTA-L (AUC = 0.935). The optimal decision tree model was left hippocampal and precuneus relative volume (AUC = 0.806). They showed significant concordance in CN + MCI participants with cutoff-based diagnosis in ADD. Machine learning-enhanced thresholds could improve participant stratification in early Alzheimer's disease (AD) trials.},
}

@article {pmid41323221,
year = {2025},
author = {Kang, J and Chen, J and Li, P and Zhao, S and Jing, F and Xie, J and Dong, C},
title = {Study on the relationship between insomnia disorder, PET/CT, and gut microbiota in patients with Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1669835},
pmid = {41323221},
issn = {1664-2295},
abstract = {OBJECTIVE: Previous studies on Alzheimer's disease (AD) have focused on the relationships between brain pathology and gut microbiota, brain pathology and sleep, and sleep and gut microbiota, but no study has explored the relationship between these three factors. Therefore, we integrated these three factors into a unified framework and aimed to provide a reference for treating insomnia disorders (ID) in patients with AD.

PATIENTS/METHODS: The 65 patients diagnosed with AD were categorized into ID group (n = 30) and non-ID group (n = 35) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. [18]F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) and [18]F-florbetapir (AV45)-PET scan were performed. Fecal samples were analyses using 16S rRNA amplicon sequencing. Basic data, PET, and gut microbiota were compared between the ID and non-ID groups. Finally, the relationships among the data, with differences including PSQI, were analyses. All p-values were corrected using the False Discovery Rate (FDR) method to obtain q-values.

RESULTS: Data with significant differences (p < 0.05 or q < 0.05) included PSQI, left middle frontal cortex-FDG, left Broca's area-FDG, right thalamus (rTh)-FDG, left thalamus (lTh)-FDG, Roseburia, Prevotella 7, and Bifidobacterium. However, no differences were found between groups in AV45-PET. In the ID group, PSQI scores were significantly correlated with rTh-FDG (r = -0.612, q < 0.05), lTh-FDG (r = -0.585, q < 0.05), and Bifidobacterium (r = -0.637, q < 0.05). Partial least squares structural equation modeling revealed that Thalamic-FDG exerted a partial mediating effect in the association between Bifidobacterium and PSQI scores.

CONCLUSION: In AD patients with ID, there may be both a direct and an indirect association between Bifidobacterium and sleep quality, with thalamic glucose metabolism mediating the indirect association, indicating that treatments aimed at enhancing brain metabolism and probiotic supplementation may improve sleep quality in this population.},
}

@article {pmid41323104,
year = {2025},
author = {Kaplan, JM and Gibbs, E and Coutts, JA and Zhao, B and Mackenzie, IR and Plotkin, SS and Cashman, NR},
title = {Relationship between efficacy and preferential targeting of soluble Aβ aggregates.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70184},
pmid = {41323104},
issn = {2352-8737},
abstract = {INTRODUCTION: Amyloid beta (Aβ)-directed antibodies have shown varying degrees of efficacy against Alzheimer's disease (AD). This study explored the relationship between targeting of Aβ molecular species and therapeutic efficacy/adverse effects.

METHODS: Surface plasmon resonance was used to measure binding of various Aβ-directed antibodies to monomers and soluble oligomers from AD brains. Plaque reactivity was assessed by immunohistochemistry and immunofluorescence. Antibody PMN310 was tested in AD mouse models.

RESULTS: Pan-Aβ reactive antibodies that failed in the clinic lost the ability to bind AD brain oligomers when competing with monomers. Lecanemab, aducanumab, and donanemab, which slowed cognitive decline, and early stage PMN310 and ACU193 showed a greater ability to withstand monomer competition. All antibodies bound plaque except for PMN310. In mouse models, PMN310 protected cognition and was not associated with microhemorrhages.

DISCUSSION: These results suggest that selectivity for soluble toxic oligomers correlates with clinical efficacy, potentially attenuating monomer competition and amyloid-related imaging abnormalities (ARIA).

HIGHLIGHTS: Selectivity for toxic Aβ oligomers has potential to maximize efficacy and safety.Avoidance of Aβ monomers increases binding to toxic AD brain oligomers.Avoidance of Aβ plaque/vascular deposits reduces the risk of ARIA.},
}

@article {pmid41322563,
year = {2025},
author = {Dias, AJ and Sena Oliveira, A and Silva, AC and Braga, AL},
title = {Rational Design and Greener Synthesis of Selenylated Indolamides as Potential Anti-Alzheimer's Agents.},
journal = {ACS omega},
volume = {10},
number = {46},
pages = {56334-56348},
pmid = {41322563},
issn = {2470-1343},
abstract = {This study presents the rational design and sustainable synthesis of selenylated indolamides as potential therapeutic agents for Alzheimer's disease. Through computational approaches, including molecular docking and pharmacokinetic analyses, we identified key structural modifications that improve acetylcholinesterase inhibition, a critical target for AD treatment. We employed an environmentally benign I2/DMSO oxidation system to optimize the synthetic protocol, enabling the efficient selenylation of 27 indolamide derivatives (5a-6a) via a straightforward and practical transformation, delivering high yields of up to 99%. Importantly, the methodology proved scalable, delivering an 88% yield on a gram-scale reaction. In silico ADMET predictions using the pkCSM platform indicated that C2-selenylated indolamides possess an improved safety profile and promising pharmacokinetic properties, suggesting their potential for further drug development. In particular, compounds 5a and 5y demonstrated the best balance between reaction yield and docking score (94% and 86.17; 98% and 93.71, respectively). These findings highlight the significance of incorporating green chemistry principles alongside advanced in silico methodologies to drive innovation in drug discovery.},
}

@article {pmid41322478,
year = {2025},
author = {Irfan, B and Sirvent, R and Abbasian, H and Khweis, S},
title = {Defining healthy longevity and dementia prevention campaigns have been tied to the ability to work.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251403463},
pmid = {41322478},
issn = {2542-4823},
abstract = {Contemporary dementia-prevention campaigns inherit a century-old coupling of health with economic productivity. By framing "healthy longevity" as the capacity to sustain waged labor, they cast risk reduction as a personal duty to insure future workforce participation and overlook the structural inequities-precarious work, environmental hazards, racialized stressors-that shape brain health. We trace this genealogy, critique the individualized cognitive-reserve paradigm, and argue for prevention strategies co-created with cultural interlocutors and paired with material reforms such as fair wages, housing, and caregiver support. Decoupling health from productivity is essential for an ethically coherent dementia-prevention agenda.},
}

@article {pmid41322409,
year = {2025},
author = {Weidling, H and Motta, E and Kuhrt, LD and Krüger, C and Figueiredo, CA and Wallach, T and Frahm, S and Diecke, S and Wolf, SA and Kettenmann, H and Lehnardt, S},
title = {Extracellular microRNAs modulate human microglial function through TLR8.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1645062},
pmid = {41322409},
issn = {1664-3224},
mesh = {Humans ; *Toll-Like Receptor 8/metabolism/genetics ; *Microglia/metabolism/immunology ; *MicroRNAs/genetics/metabolism ; Toll-Like Receptor 7/metabolism/genetics ; Alzheimer Disease/genetics/metabolism/immunology ; Induced Pluripotent Stem Cells/metabolism ; Glioma/genetics/metabolism/immunology ; Phagocytosis ; Cells, Cultured ; Neurons/metabolism ; Coculture Techniques ; Signal Transduction ; Cytokines/metabolism ; },
abstract = {OBJECTIVE: MicroRNAs (miRNAs) are abundantly expressed in the brain and are specifically dysregulated in central nervous system (CNS) diseases. They act as post-transcriptional gene regulators but can also serve as ligands for Toll-like receptors (TLRs). This study aims to investigate CNS disease-associated miRNAs as signaling molecules for human microglia.

METHODS: Using a machine learning algorithm and the disease-linked database PhenoMiR, we identified Alzheimer's disease (AD)- and glioma-associated miRNAs as ligands for TLR7 and TLR8. Expression of human TLR7 and TLR8 in iPSC-derived human microglia-like cells (iMGLs) was validated by RT-qPCR. Using ELISA, scratch assay, and FACS, we investigated the miRNAs' potential to modulate iMGL function, including cytokine release, motility, and phagocytosis, respectively. The selective human TLR8 antagonist CU-CPT9a was used to determine the role of this receptor in miRNA-induced modulation of human microglial activity. Co-cultures of iMGLs and iPSC-derived human cortical neurons (iNeurons) were analyzed by Neurotrack imaging to assess the effects of miRNAs on human neurites.

RESULTS: We identified AD- and glioma-associated miR-9-5p, miR-132-5p, miR-340-3p, miR-30e-3p, miR-501-3p, and let-7b as ligands for human TLR7 and TLR8. Exposure of iMGLs to select miRNAs, including miR-9-5p, miR-132-5p, and miR-340-3p, led to interleukin-6 (IL-6) and tumor necrosis factor (TNF) mRNA expression and protein release in a sequence-dependent fashion. Also, these miRNAs acting as signaling molecules, modulated iMGL motility and phagocytosis activity. The miRNA-induced effects on iMGLs were abolished by CU-CPT9a. Extracellular delivery of miR-132-5p and miR-9-5p to co-cultures of iNeurons and iMGLs resulted in reduced neurite length.

DISCUSSION: Our data establish that distinct CNS disease-associated miRNAs serve as signaling molecules for human microglia via TLR8, thereby controlling the diverse microglial functions and modulating the neuroinflammatory response.},
}

Humans
*Toll-Like Receptor 8/metabolism/genetics
*Microglia/metabolism/immunology
*MicroRNAs/genetics/metabolism
Toll-Like Receptor 7/metabolism/genetics
Alzheimer Disease/genetics/metabolism/immunology
Induced Pluripotent Stem Cells/metabolism
Glioma/genetics/metabolism/immunology
Phagocytosis
Cells, Cultured
Neurons/metabolism
Coculture Techniques
Signal Transduction
Cytokines/metabolism

@article {pmid41322377,
year = {2025},
author = {Hojjati, SH and Butler, TA and Zare, SJM and Reihanian, A and Khalafi, M and Foldi, N and Shah, S and Jafari, H and Li, Y and Zhou, L and Dartora, W and Wartchow, K and McIntire, LBJ and Chiang, GC and , },
title = {Diagnostic utility of plasma p-tau217 differs by Alzheimer's disease tau-based subtypes.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70227},
pmid = {41322377},
issn = {2352-8729},
abstract = {INTRODUCTION: Blood-based biomarkers, most notably plasma phosphorylated tau (p-tau)217, have transformed the diagnostic landscape of Alzheimer's disease (AD).

METHODS: We applied an unsupervised machine learning approach to tau positron emission tomography (PET) imaging in 606 participants (age 73.95 ± 7.72; 309 female) to identify AD subtypes. Within each subtype, we evaluated plasma p-tau217 levels, their association with regional tau PET uptake, differences between cognitively unimpaired (CU) and cognitively impaired (CI) individuals, and relationships to cognitive performance.

RESULTS: Four subtypes were identified: limbic, medial temporal lobe (MTL) sparing, posterior, and lateral temporal (l temporal). Plasma p-tau217 was elevated in CI versus CU in limbic, posterior, and l temporal subtypes and strongly associated with tau deposition and cognitive performance. In the MTL-sparing subtype, p-tau217 showed a significant association with tau but no elevation in CI and no relationship to cognition.

DISCUSSION: These findings indicate that p-tau217's diagnostic utility varies across AD subtypes, reflecting distinct biological mechanisms not captured by current blood biomarkers.

HIGHLIGHTS: Plasma phosphorylated tau (p-tau)217 differentiated cognitively unimpaired from impaired individuals in most subtypes, with the notable limitation of the medial temporal lobe (MTL)-sparing group.P-tau217 level was linked to regional tau accumulation as measured by tau positron emission tomography, across all subtypes.The MTL-sparing subtype appeared to be unique, as p-tau217 was not elevated in cognitively impaired individuals, and there was no clear relationship between p-tau217 levels and cognitive performance.},
}

@article {pmid41322376,
year = {2025},
author = {Blotenberg, I and Thyrian, JR},
title = {Toward targeted dementia prevention: Population attributable fractions and risk profiles in Germany.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70225},
pmid = {41322376},
issn = {2352-8729},
abstract = {INTRODUCTION: Effective dementia prevention requires understanding the distribution of modifiable risk factors and identifying high-risk subgroups. We estimated the prevention potential in Germany and identified risk profiles to inform precision public health.

METHODS: We analyzed nationally representative data from the 2023 German Aging Survey (n = 4992). Population attributable fractions and potential impact fractions were computed for established modifiable risk factors. Relative risks were taken from meta-analyses. Latent class analysis identified risk profiles.

RESULTS: An estimated 36% of dementia cases in Germany are attributable to modifiable risk factors. Reducing their prevalence by 15%-30% could prevent 170,000-330,000 cases by 2050. We identified four risk profiles-metabolic, sensory impairment, alcohol, and lower-risk-each associated with demographic and regional characteristics.

DISCUSSION: Our findings highlight considerable national prevention potential and reveal population subgroups with shared risk patterns. These profiles provide a foundation for designing targeted, equitable, and efficient dementia prevention strategies.

HIGHLIGHTS: 36% of dementia cases in Germany are linked to modifiable risk factors.A 15% reduction in risk factor prevalence could prevent 170,000 cases by 2050.Key contributors: depression, hearing loss, low education, and obesity.Data-driven risk profiles identified (e.g., metabolic, sensory, low-risk).Risk profiles strongly associated with sociodemographic characteristics.},
}

@article {pmid41322353,
year = {2025},
author = {Sanghai, N and Barzegar Behrooz, A and Latifi-Navid, H and Fahanik Babaei, J and Tranmer, GK},
title = {Phosphoproteomics-guided tau biomarker discovery in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD).},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1714196},
pmid = {41322353},
issn = {1662-4548},
}

@article {pmid41322352,
year = {2025},
author = {Liu, S and Zhao, M and Liu, Y and Yang, X and Yan, H and Xu, H and Wu, Y and Xu, Y},
title = {Comparative efficacy and safety of symptomatic therapy and disease-modifying therapy for Alzheimer's disease: a systematic review and network meta-analysis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1656906},
pmid = {41322352},
issn = {1662-4548},
abstract = {BACKGROUND: The management of Alzheimer's disease has shifted toward disease-modifying therapies aimed at delaying disease progression rather than focusing solely on symptomatic treatment. This study summarizes the latest evidence regarding the benefits and harms of anti-Alzheimer's disease drugs.

METHODS: We conducted a comprehensive review of randomized controlled trials from PubMed, Embase, Cochrane Library, Web of Science databases, and other sources up to April 2025. Two researchers independently reviewed the literature and analyzed the data. A network meta-analysis was performed using Review Manager version 5.3 and Stata version 18.0 to calculate mean differences (MDs) and 95% confidence intervals (CIs) for direct and indirect comparisons. Treatment efficacy was evaluated using the Surface Under the Cumulative Ranking Curve (SUCRA). Bias was assessed using the Revised Cochrane Risk of Bias Tool version 2.0, and publication bias was analyzed with funnel plots.

RESULTS: The network meta-analysis included 23 randomized controlled trials with 16,010 participants, evaluating nine pharmacological interventions ranging from traditional symptomatic therapies to four United States Food and Drug Administration- and National Medical Products Administration-approved disease-modifying therapies, notably anti-amyloid beta monoclonal antibodies. Aducanumab significantly improved ADAS-cog scores compared with placebo (MD -5.97, 95%CI -10.33, -1.61; SUCRA: 93.0%) and demonstrated notable improvements in ADCS-ADL scores (MD 4.99, 95%CI 2.27, 7.72; SUCRA: 98.6%). Memantine ranked highest for neuropsychiatric symptoms (SUCRA: 80.8%). Aducanumab also had the highest SUCRA for CDR-SB (91.5%) and showed moderate superiority in MMSE scores (MD 3.55, 95%CI 1.35, 5.75; SUCRA: 98.2%).

CONCLUSION: Symptomatic treatments, especially memantine for neuropsychiatric symptoms, remain effective. However, the network meta-analysis indicates that, for patients with mild cognitive impairment or mild Alzheimer's disease, aducanumab demonstrates the greatest potential for cognitive and clinical improvement (MMSE, ADAS-cog, ADCS-ADL), despite associated risks such as adverse events and amyloid-related imaging abnormalities linked to disease-modifying therapies. Lecanemab provides moderate benefits, while donanemab appears less effective. Thus, clinicians should apply disease-modifying therapies cautiously and individually, carefully balancing potential risks and benefits for each patient.

PROSPERO [CRD42025637730], https://www.crd.york.ac.uk/PROSPERO/.},
}

@article {pmid41322351,
year = {2025},
author = {Xing, H and Hu, WL and Bao, SY},
title = {Acupuncture modulates the microbiota-gut-brain axis: a novel therapeutic strategy for amnestic mild cognitive impairment.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1710066},
pmid = {41322351},
issn = {1662-4548},
abstract = {Amnestic mild cognitive impairment (aMCI) represents a critical prodromal stage of Alzheimer's disease (AD), yet effective therapeutic interventions to prevent or delay this conversion remain an unmet clinical need. Growing evidence implicates dysregulation of the microbiota-gut-brain axis (MGBA)-a complex bidirectional communication network involving neural, immune, and endocrine pathways-in the pathogenesis of neurodegenerative disorders. This perspective proposes that acupuncture, as a multi-target therapeutic approach, may modulate gut microbiota composition and restore MGBA homeostasis, thereby potentially decelerating the progression from aMCI to AD. A systematic understanding of the precise mechanisms through which acupuncture influences the MGBA carries substantial implications for both neuroscience and clinical practice. Future investigations should prioritize the elucidation of these mechanisms and the generation of robust clinical evidence through well-controlled experimental designs.},
}

@article {pmid41322300,
year = {2025},
author = {Domínguez-Fernández, C and Kumar, A and Kumar, R and Darreh-Shori, T},
title = {From heart to brain: cognitive potential of propranolol and diltiazem through cholinergic enhancement via butyrylcholinesterase inhibition.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1694610},
pmid = {41322300},
issn = {1663-9812},
abstract = {BACKGROUND: Butyrylcholinesterase (BChE) has emerged as a promising therapeutic target in the treatment of Alzheimer's disease (AD), particularly in its later stages when acetylcholinesterase (AChE) activity declines. Drug repurposing offers a strategic approach to identify novel BChE inhibitors among existing FDA-approved compounds.

OBJECTIVE: This study aimed to evaluate the cholinesterase inhibitory potential of propranolol and diltiazem-two widely used cardiovascular drugs-through in silico modelling and in vitro and ex vivo enzyme-inhibition kinetic.

METHODS: Molecular docking was performed using AutoDock Vina to assess the binding affinity of propranolol and diltiazem to AChE and BChE. In vitro screening and inhibition were measured using a modified Ellman's assay with human recombinant AChE and plasma-derived BChE. Ex-vivo IC50 and Ki values were determined through kinetic analyses in pooled plasma samples, and inhibition modes were characterized using nonlinear regression models.

RESULTS: Both propranolol and diltiazem selectively inhibited BChE, with minimal activity against AChE. At 100 μM, BChE inhibition exceeded 80% for both compounds, while AChE inhibition was limited to 18% (propranolol) and 2% (diltiazem). Propranolol exhibited a Ki of 0.19 µM, comparable to the selective BChE inhibitor ethopropazine (Ki = 0.15 µM), and acted as a competitive inhibitor. Diltiazem exhibited a higher Ki of 2.3 µM. These effects were observed at concentrations within or near reported brain levels for propranolol, suggesting potential in vivo relevance.

CONCLUSION: Propranolol and diltiazem demonstrate selective BChE inhibition, with propranolol showing potency comparable to established potent BChE inhibitors. Given their established safety profiles and CNS activity, these compounds represent promising candidates for repurposing in the treatment of AD and other cognitive disorders. Further in vivo studies are warranted to explore their therapeutic potential.},
}

@article {pmid41322203,
year = {2025},
author = {Cody, KA and Langhough, RE and Janelidze, S and Jonaitis, EM and Wilson, RE and Christian, BT and Asthana, S and Johnson, SC and Zetterberg, H and Hansson, O and Betthauser, TJ},
title = {Characterizing the onset and progression of Alzheimer's pathologies using amyloid and tau PET imaging and plasma p-tau217.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf449},
pmid = {41322203},
issn = {2632-1297},
abstract = {Characterizing the onset and progression of Alzheimer's disease pathologies relative to one another is important for biological staging and clinical trial design. Recent advances in blood plasma assays of Alzheimer's disease amyloid and tau pathology have enabled detection of Alzheimer's disease pathophysiology during life, but it remains unclear when plasma biomarker abnormalities are detectable relative to established amyloid and tau PET imaging biomarkers, and the extent to which plasma biomarkers can be used for biological disease staging. This work applies a novel temporal modelling approach to amyloid PET and plasma p-tau217 data from two different assay platforms to characterize when plasma p-tau217 become abnormal relative to amyloid PET, tau PET, and cognitive decline in a predominantly cognitively unimpaired cohort. This study included a subset of 172 Wisconsin Registry for Alzheimer's Prevention participants (mean (standard deviation (SD)) age at baseline plasma = 63.2 (6.3) years; 149 cognitively unimpaired at last cognitive assessment) with available amyloid PET imaging and plasma p-tau217 data assayed on the Lilly Meso Scale Delivery and Quanterix Alzpath platforms. We estimated the within-person onsets of detectable amyloid PET and plasma p-tau217 using sampled iterative local approximation and investigated the impact of this timing on downstream tau PET accumulation and cognitive decline using linear mixed-effects models. Longitudinal modelling revealed that on average, amyloid PET positivity preceded p-tau217 positivity, and both amyloid and p-tau217 preceded detectable changes in brain tau accumulation. Comparisons of 'time from biomarker onset' indicated that time from p-tau217 onset explained more variability in tau PET accumulation and cognitive decline than time from amyloid PET onset for the Lilly assay but did not differ for the Alzpath assay. Overall, the timing between amyloid PET and p-tau217 onset (in a subset positive for both) ranged from -5.5-24.6 years. These results suggest that plasma p-tau217 follows a predictable path once above thresholds thereby enabling estimation of p-tau217 + age and suggesting these assays may be useful for disease staging. Information regarding the timing of abnormal detection of amyloid PET, plasma p-tau217, and tau PET in relation to preclinical cognitive decline suggests that an optimal window for secondary prevention of Alzheimer's disease may be within ten years of amyloid PET positivity and within five years of plasma p-tau217 positivity. Future work is needed to identify sources of observed interindividual heterogeneity in the timing of biomarker abnormalities and cognitive decline and impairment following biomarker positivity.},
}

@article {pmid41321688,
year = {2025},
author = {Carmichael, OT and Harvey, D and Fletcher, E},
title = {Editorial: Neuroimaging of the aging brain.},
journal = {Frontiers in neuroimaging},
volume = {4},
number = {},
pages = {1724972},
pmid = {41321688},
issn = {2813-1193},
}

@article {pmid41321673,
year = {2025},
author = {Soans, JS and Noronha, JA and Mundkur, SC and Nayak, BS and Garg, M and D'Souza, SRB and Jathanna, RD and Kotebagilu, NP and Shenoy, RP and Nagaraja, R and Kamath, P},
title = {Intake of fruits and vegetables (FAVs) on cognitive functions among adolescents and young adults: a scoping review.},
journal = {Journal of nutritional science},
volume = {14},
number = {},
pages = {e82},
pmid = {41321673},
issn = {2048-6790},
mesh = {Humans ; *Vegetables ; Adolescent ; *Fruit ; *Cognition/physiology ; Young Adult ; *Diet ; Child ; Adult ; Male ; Cross-Sectional Studies ; Female ; },
abstract = {This scoping review provides an overview of the impact of fruit and vegetable (FAV) consumption on cognitive function in adolescents and young adults between January 2014 and February 2024. A comprehensive search across six databases, CINAHL, PubMed-MEDLINE, ProQuest, Web of Science, Scopus, and Embase, identified 5,181 articles, of which six met the inclusion criteria after deduplication and screening. This scoping review focused on individuals aged 11-35 years in schools, colleges, universities, and communities. Following a descriptive and narrative synthesis of the data, tables and figures were used to present the findings. Across the six included studies, most consistently demonstrated a positive association between higher fruit and vegetable (FAV) intake and improved cognitive performance among adolescents and young adults. This association was evident in both cross-sectional and longitudinal studies, with stronger effects observed for whole fruits and vegetables high in fibre and polyphenols. Cognitive domains positively impacted included psychomotor speed, memory, attention, and mood. However, findings varied by type of food and cognitive domain; while whole FAVs were generally beneficial, results for fruit juice were mixed-some studies showed acute benefits. Differences in study designs, dietary assessment tools, and cognitive measures contributed to variability. Despite these inconsistencies, the overall trend supports a beneficial role of FAV consumption in promoting cognitive health during adolescence and early adulthood. This review demonstrates that increased fruit and vegetable consumption is consistently linked to improved cognitive function in adolescents and young adults. However, further research is needed to establish its long-term effects on cognitive ageing and disease prevention.},
}

Humans
*Vegetables
Adolescent
*Fruit
*Cognition/physiology
Young Adult
*Diet
Child
Adult
Male
Cross-Sectional Studies
Female

@article {pmid41321280,
year = {2025},
author = {Huang, L and Liu, D and Wei, Q and He, C and Zhang, J and Dong, S},
title = {α-O-Glycosylation at Tyrosine 10 Promotes the Astrocyte Clearance of Amyloid-β Peptide 1-42.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {},
number = {},
pages = {e202500459},
doi = {10.1002/cbic.202500459},
pmid = {41321280},
issn = {1439-7633},
support = {22321005//National Natural Science Foundation of China/ ; 92153301//National Natural Science Foundation of China/ ; //State Key Laboratory of Natural and Biomimetic Drugs./ ; },
abstract = {Therapies targeting amyloid β (Aβ), especially promoting Aβ clearance, have attracted increasing attention in treating Alzheimer's disease (AD). However, the regulatory factors in Aβ metabolism remain poorly understood. Herein, three homogeneously glycosylated Aβ42 peptides are utilized to explore the impacts of Tyr10 O-glycosylation on Aβ clearance in astrocytes. Based on various biochemical and cellular assays, it is shown that the introduced α-O-glycan stabilizes the Aβ oligomers and enhances Aβ42 endocytosis and autophagy in astrocytes, which ultimately promotes the intracellular degradation of Aβ42 and the secretion of Aβ-degrading enzymes. Particularly, a disaccharide, Galβ1-3GalNAc, exhibits the most substantial clearance-enhancing effect. Moreover, experiments with AD-like model mice show protective effects from the disaccharide modification in alleviating Aβ42-induced impairment of spatial cognitive performance. Thus, beyond showing the influences induced by particular O-glycosylation on Aβ42 degradation, the study provides implications of a possible role of Tyr10 O-glycan in regulating Aβ clearance in the brain.},
}

@article {pmid41321279,
year = {2025},
author = {Dulewicz, M and Kac, PR and Ortiz, FG and Karikari, TK and Kulczyńska-Przybik, A and Mroczko, B and Turton, M and Harrison, P and Maler, M and Oberstein, T and Kornhuber, J and Hanrieder, J and Zetterberg, H and Blennow, K and Lewczuk, P},
title = {Clinical Validation of Novel Immunoassays for Plasma Phosphorylated Tau 217, 212, 181, 231, and Brain-Derived Tau Across the Biochemical Spectrum of Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {169},
number = {12},
pages = {e70313},
doi = {10.1111/jnc.70313},
pmid = {41321279},
issn = {1471-4159},
support = {#2023-00356//Swedish Research Council/ ; #2022-01018//Swedish Research Council/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/cerebrospinal fluid ; *tau Proteins/blood ; Female ; Male ; Aged ; Phosphorylation/physiology ; Biomarkers/blood ; Immunoassay/methods/standards ; Aged, 80 and over ; Middle Aged ; *Brain/metabolism ; Cohort Studies ; },
abstract = {Plasma biomarkers have emerged as promising less invasive alternatives for Alzheimer's disease (AD) detection. However, the diagnostic performance of phosphorylated tau (p-tau) isoforms remains incompletely validated. In a cohort of 160 patients from a memory clinic, plasma levels of p-tau217, p-tau212, p-tau181, p-tau231, and BD-tau were measured using Single Molecule Array (Simoa) in-house assays, alongside NFL and GFAP. Subjects were classified using the Erlangen Score into Controls (n = 53), neurochemically possible AD (n = 27), and probable AD (n = 80). Plasma concentrations of all p-tau isoforms were significantly elevated in both Possible AD and Probable AD groups compared to Controls (p < 0.001). Notably, p-tau217 exhibited the highest diagnostic accuracy (AUC = 0.954) and correlated with CSF classical biomarkers. A positive result for p-tau217 increases the probability of AD almost fivefold. Plasma p-tau217 reflects AD neurochemical changes and has high negative predictive value, supporting its use as a screening tool. However, moderate PPV suggests the need for confirmatory testing to ensure an accurate diagnosis.},
}

Humans
*Alzheimer Disease/blood/diagnosis/cerebrospinal fluid
*tau Proteins/blood
Female
Male
Aged
Phosphorylation/physiology
Biomarkers/blood
Immunoassay/methods/standards
Aged, 80 and over
Middle Aged
*Brain/metabolism
Cohort Studies

@article {pmid41321177,
year = {2025},
author = {Sahakian, BJ},
title = {The role of psychopharmacology and cognitive neuroscience in understanding the brain in the treatment of psychiatric disorders and neurological diseases for the benefit of society.},
journal = {Journal of psychopharmacology (Oxford, England)},
volume = {},
number = {},
pages = {2698811251397329},
doi = {10.1177/02698811251397329},
pmid = {41321177},
issn = {1461-7285},
abstract = {This perspectives piece reflects on some of the major scientific contributions in psychopharmacology, cognitive neuroscience, and public policy of Professor Barbara J. Sahakian, Commander of the Most Excellent Order of the British Empire (CBE). Her pioneering research has advanced the understanding of brain mechanisms, including neurotransmitter modulation, and psychological processes involved in cognition, emotion, and motivation, leading to novel treatments for disorders such as Alzheimer's disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and depression. She has also contributed to a better understanding of brain mechanisms underlying and psychological processes involved in these disorders. She has championed early detection of Alzheimer's disease through neuropsychological tools, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning (PAL) test and contributed to identifying cognitive and neural changes in Huntington's disease gene carriers. Beyond clinical research, Sahakian has influenced public health policy through initiatives such as the UK Government Foresight Project on Mental Capital and Wellbeing and the National Institute for Health and Care Excellence guidelines on gambling-related harms. She has also led efforts in neuroethics and public engagement, co-authoring accessible science books and participating in global forums. Recent research emphasises preventative psychiatry, including lifestyle interventions, such as diet, sleep, social connection, and lifelong learning as preventive strategies for cognitive decline and mental health problems. Through interdisciplinary collaborations and mentorship, Sahakian continues to inspire the next generation of scientists to pursue innovative research for societal benefit in neuropsychopharmacology and cognitive neuroscience.},
}

@article {pmid41320930,
year = {2025},
author = {Suthar, T and Maurya, R and Sonwani, A and Upadhayay, P and Datusalia, AK and Naqvi, S and Jain, K},
title = {Nose-to-Brain Delivery of Donepezil Hydrochloride via Oleic Acid-Conjugated PAMAM G4 Dendrimers for the Treatment of Alzheimer's-Like Dementia.},
journal = {Molecular pharmaceutics},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.molpharmaceut.5c00761},
pmid = {41320930},
issn = {1543-8392},
abstract = {Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder characterized by dementia and cognitive impairments. Acetylcholinesterase (AChE) inhibitors are generally prescribed for clinical management of AD symptoms. Donepezil hydrochloride (DPZ) is a reversible, selective, and noncompetitive inhibitor of AChE recommended for the treatment of mild-to-moderate AD. However, a higher dose of this drug must be administered to achieve adequate therapeutic concentrations in the brain, leading to peripheral side effects. In the present research work, oleic acid (OA) conjugated PAMAM G4 dendrimers (OA-G4) are explored for delivering DPZ to the brain. OA was conjugated to PAMAM G4 dendrimers using EDC conjugation chemistry, and the conjugation was confirmed by nuclear magnetic resonance (NMR) and Fourier-transform infrared (FTIR) spectroscopy. DPZ was successfully loaded on the OA-G4 conjugate, and the loading and entrapment efficiency were found to be 78.59% ± 5.52% and 62.12% ± 0.67%, respectively. The drug release studies showed a faster release of DPZ from the DPZ-OA-G4 conjugate for the initial 6 h, followed by a sustained release, with 68.44% ± 1.88% of the drug released in 24 h. Cytotoxicity studies in SH-SY5Y cells demonstrated the safety and cytocompatibility of the conjugate at a wide range of concentrations. Cell internalization study revealed deep localization of the dendrimeric nanoconjugate in SH-SY5Y cells. Biodistribution studies of the OA-G4 conjugate through the intranasal route, using an IVIS whole-body live imaging system, demonstrated abundant fluorescence in the brain, indicating efficient brain targeting via nose-to-brain delivery. Neurobehavior studies in male SD rats suggested significant attenuation of AlCl3-induced cognitive decline in DPZ-OA-G4 treated animals, which was further confirmed with biochemical and histological evaluations. In conclusion, this study provides proof of concept that DPZ can be successfully targeted to the brain using ligand-conjugated dendrimeric systems via intranasal administration, a noninvasive route that enables direct nose-to-brain delivery, bypasses the blood-brain barrier, and minimizes systemic side effects.},
}

@article {pmid41320876,
year = {2025},
author = {Tang, YB and Zhang, J and Liu, Q},
title = {tRNA-derived small noncoding RNAs: Roles in brain aging and neurodegenerative disorders.},
journal = {Zoological research},
volume = {46},
number = {6},
pages = {1575-1587},
doi = {10.24272/j.issn.2095-8137.2025.349},
pmid = {41320876},
issn = {2095-8137},
mesh = {*Aging/physiology ; *Neurodegenerative Diseases/genetics/metabolism ; Animals ; *Brain/physiology/metabolism ; *RNA, Transfer/metabolism/genetics ; *RNA, Small Untranslated/metabolism/genetics ; Humans ; },
abstract = {Transfer ribonucleic acid-derived small ribonucleic acids (tsRNAs) are an emerging class of regulatory noncoding RNAs produced through the precise cleavage of mature or precursor tRNAs (pre-tRNAs). Once considered degradation byproducts, tsRNAs are now recognized as key modulators of gene expression, epigenetic regulation, and cellular stress responses. In recent years, growing evidence has implicated tsRNAs in the aging process of the brain and in the pathogenesis of age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). These small RNAs are involved in modulating synaptic function, neuronal survival, and neuroinflammation, and their expression profiles are dynamically altered in response to aging and disease-associated stressors. This review summarizes the biogenesis, classification, and molecular and cellular mechanisms of tsRNAs, with an emphasis on their subcellular locations and associated biological functions. We further explore their roles in brain aging and age-related neurodegenerative diseases and the emerging potential of tsRNAs as biomarkers and therapeutic targets for age-related neurological disorders while highlighting current challenges and future directions in this rapidly advancing field.},
}

*Aging/physiology
*Neurodegenerative Diseases/genetics/metabolism
Animals
*Brain/physiology/metabolism
*RNA, Transfer/metabolism/genetics
*RNA, Small Untranslated/metabolism/genetics
Humans

@article {pmid41320758,
year = {2025},
author = {Burade, A and Lakhani, DA and Dagher, R and Anosh, J and Sair, HI and Luna, LP},
title = {Beyond Parkinson's Disease: A Narrative Review of Neuromelanin MRI in Neurodegenerative Diseases.},
journal = {Journal of neuroimaging : official journal of the American Society of Neuroimaging},
volume = {35},
number = {6},
pages = {e70113},
doi = {10.1111/jon.70113},
pmid = {41320758},
issn = {1552-6569},
mesh = {Humans ; *Melanins/metabolism ; *Magnetic Resonance Imaging/methods ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; Parkinson Disease/diagnostic imaging ; Biomarkers/metabolism ; Sensitivity and Specificity ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND AND PURPOSE: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) is an emerging noninvasive biomarker of catecholaminergic neurons. It assesses neuromelanin-rich regions such as the substantia nigra pars compacta (SNc) and locus coeruleus (LC). Although initially developed for Parkinson's disease (PD), evidence supports broader utility. This narrative review highlights the diagnostic and prognostic applications of NM-MRI in PD, atypical parkinsonian syndromes, spinocerebellar ataxias (SCA), and Alzheimer's disease (AD), while evaluating methodological heterogeneity, diagnostic performance across diseases, and directions for clinical implementation.

RESULTS: In PD, reduced SNc volume and contrast-to-noise ratio (CNR) correlate with motor symptom severity. Early-stage PD shows lateral SNc signal attenuation progressing ventromedially with disease advancement. NM-MRI sensitivity and specificity range from 70%-92% to 65%-89%, respectively, with higher accuracy at 7T. In progressive supranuclear palsy (PSP), SNc degeneration is more pronounced medially; LC contrast ratio (CR) is elevated compared to PD. In multiple system atrophy (MSA), LC signal attenuation is particularly marked in the parkinsonian subtype (MSA-P). NM-MRI findings in SCA (notably SCA2 and SCA7) vary by genotype; AD is characterized by reduction in the middle and caudal segments of LC, reflecting early tau pathology. NM-MRI LC signal reduction variably correlates with cognitive scores and Braak staging, suggesting potential as a preclinical biomarker.

CONCLUSION: NM-MRI holds promise for early diagnosis and monitoring of neurodegenerative diseases. While its role in PD is well established, emerging data in PSP, MSA, SCA, and AD suggest wider applicability. Standardization, multimodal imaging integration, and machine learning are critical for clinical translation.},
}

Humans
*Melanins/metabolism
*Magnetic Resonance Imaging/methods
*Neurodegenerative Diseases/diagnostic imaging/metabolism
Parkinson Disease/diagnostic imaging
Biomarkers/metabolism
Sensitivity and Specificity
Brain/diagnostic imaging

@article {pmid41320113,
year = {2025},
author = {Su, X and Pu, J and Liao, J and Tang, Y and Feng, L and Wu, Z},
title = {Assessment of Ultrasonic Vocalization-Mediated Communication Deficits in AD Rats: A Social Learning Paradigm Using Conspecific Drinking Behavior.},
journal = {Behavioural processes},
volume = {},
number = {},
pages = {105311},
doi = {10.1016/j.beproc.2025.105311},
pmid = {41320113},
issn = {1872-8308},
abstract = {OBJECTIVE: This study aimed to explore the effect of Alzheimer's disease (AD) rats on the drinking behavior of Sprague-Dawley (SD) rats and observe the ultrasonic vocalizations (USVs) of AD rats and SD rats.

METHODS: The 12 AD rats were equally divided into two groups (6 rats per group), and the 36SD rats were divided into 6 groups (6 rats per group), with no rat reused across different experimental groups. Two independent experimental tasks were conducted: 1) A test field with a sugar area (containing 10% sucrose solution) and a chili area (containing 0.02% capsaicin solution) was constructed. The drinking behavior of SD rats (placed in the middle area of the test field) was recorded in the presence of different "guiding rats" (placed in the side area of the test field). The experiment was divided into 5 groups: unguided group (UG, no guiding rats in the side area), normal SD rats guiding group (NG), AD rats guiding group (ADG), AD rats guiding group with memantine administration (ADMG), and the Ultrasonic Vocalizations Guiding Group (USVsG, an animal ultrasonic sound player was used to broadcast the USVs). Additionally, the escape latency results of the Morris water maze test, a commonly used cognitive evaluation task in AD rats, were compared and correlated with the drinking behavior results - the core hypothesis here was to verify whether the drinking behavior method established in this study could serve as a valid tool for assessing AD behavioral phenotypes, consistent with the evaluation effect of the traditional Morris water maze. 2) USV characteristics of SD rats, AD rats, and memantine-administered AD rats were recorded and analyzed separately.

RESULTS: Compared with the UG, the NG had more drinking bouts in the sugar area and fewer in the chili area. In contrast, the ADG showed the opposite trend vs. NG, indicating impaired social information transmission in AD rats. For USVs, normal SD rats had environment-specific frequency differentiation: dominant high-frequency USVs in sugar-water and low-frequency ones in chili-water, while AD rats had disorganized USV frequency bands. After memantine intervention, ADMG had enhanced sugar preference, shortened Morris water maze escape latency, and USV frequencies gradually approaching normal SD rats. Moreover, USVsG had no obvious difference in drinking behavior vs. NG, confirming USVs as the core medium of social guidance.

CONCLUSION: This study reveals AD rats' abnormal USV characteristics, preliminarily lays an experimental basis for an evaluation method combining USVs and drinking behavior, provides a new non-invasive, low-cost perspective for assessing AD rats' behavioral phenotypes, and verifies this method correlates with traditional cognitive evaluation (Morris water maze) and can effectively reflect the improvement of AD behavioral phenotypes after memantine intervention.},
}

@article {pmid41319834,
year = {2025},
author = {Matsumoto, K and Maeda, S},
title = {The Application of Directly Induced Neurons into Neurodegenerative Disease Modeling.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {104993},
doi = {10.1016/j.neures.2025.104993},
pmid = {41319834},
issn = {1872-8111},
abstract = {The advent of directly induced neurons (iNs) from human somatic cells has revolutionized disease modeling in neurodegeneration. This approach bypasses pluripotent stage during the neuronal cell inducing steps and preserves donor age-related signatures. This review explores the trajectory of iNs, including multiple induction methods, their applications in modeling neurodegenerative diseases, recent innovations such as three-dimensional (3D) culture platforms, and their potential to advance personalized medicine.},
}

@article {pmid41319778,
year = {2025},
author = {Wang, J and Geng, A and Yan, Z and Lin, X and Li, Y and Xu, J and Meng, Y and Zhang, Z and Wei, L and Zou, Q and Cui, F},
title = {FA-Amy: An amyloid protein prediction model based on protein pre-trained large models and an attention-fusion strategy.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {149267},
doi = {10.1016/j.ijbiomac.2025.149267},
pmid = {41319778},
issn = {1879-0003},
abstract = {Amyloid proteins are misfolded proteins that aggregate into insoluble fibrils under specific conditions. Their abnormal accumulation is closely linked to neurodegenerative diseases like Alzheimer's. Accurate prediction of amyloidogenic proteins is thus essential for understanding disease mechanisms and guiding therapeutic development. However, current methods for amyloid protein prediction still face several challenges, such as insufficient feature extraction and the reliance on relatively outdated traditional machine learning techniques. In this study, we present FA-Amy, a novel amyloid protein prediction model based on the ESM C protein language model and an attention fusion mechanism. To overcome the limitations of previous methods that relied on handcrafted features and insufficient utilization of sequence information, we employ the ESM C model to generate deep, comprehensive representations of protein sequences. Additionally, we design a fusion mechanism that integrates global and local attention, enhancing the model's ability to identify crucial regions associated with amyloid aggregation. Results from five-fold cross-validation confirm the complementarity and effectiveness of our multi- attention fusion strategy. FA-Amy demonstrates excellent stability and robustness, and is particularly effective in handling highly imbalanced classification tasks. Notably, the attention mechanism successfully focuses on sequence segments likely to contribute to β-sheet stacking. On an independent test set, FA-Amy consistently outperforms the current state-of-the-art model, achieving an 8.1 % improvement in Matthews Correlation Coefficient. To enhance accessibility, we have built a user-friendly online server for the model, which can be accessed at: http://www.bioai-lab.com/FA-Amy.},
}

@article {pmid41319675,
year = {2025},
author = {Langbaum, JB and Bradbury, AR and Egleston, BL and McCarty Wood, E and Langlois, CM and Largent, EA and Harkins, K and Erickson, CM and Stites, SD and Oyen, E and Riviere, ME and Liu, F and Graf, A and Kim, SYH and Grill, JD and Reiman, EM and Tariot, PN and Roberts, JS and Karlawish, J},
title = {Impact of learning APOE genotype on cognitively unimpaired adults: a pre-screening cohort study of the Alzheimer's Prevention Initiative Generation Study 1.},
journal = {The lancet. Healthy longevity},
volume = {},
number = {},
pages = {100778},
doi = {10.1016/j.lanhl.2025.100778},
pmid = {41319675},
issn = {2666-7568},
abstract = {BACKGROUND: The apolipoprotein E (APOE) gene is the best established genetic risk factor for Alzheimer's disease in later life, with the ε4 allele conferring higher risk. APOE disclosure is becoming increasingly common in the clinical care of people with Alzheimer's disease and in cognitively unimpaired adults. In this study, we aimed to describe changes in measures of genetic disease knowledge and psychiatric symptoms following APOE disclosure to cognitively unimpaired adults.

METHODS: Data were collected as part of the screening phase of the global, multicentre, Alzheimer's Prevention Initiative Generation Study 1 (NCT02565511). Eligible individuals were cognitively unimpaired (Mini-Mental State Exam total score ≥24), aged 60-75 years, and psychologically pre-screened for readiness (by measures of depressive symptoms and anxiety) to receive their APOE genotype from a health-care provider. Participants were assessed before disclosure, and 2-7 days, 6 weeks, 6 months, and 12 months after disclosure. Multivariable linear and ordinal logistic regressions were used to compare changes in genetic disease knowledge, anxiety, depression, and distress by APOE4 genotype status, adjusting for key covariates, with a focus on 2-7 days after disclosure. Multiple imputation by chained equations methods was used to account for missing outcome data.

FINDINGS: The trial took place between Nov 30, 2015, and Sept 23, 2019. In total, 9496 participants (including 790 APOE4 homozygotes, 4869 heterozygotes, and 3837 non-carriers) learned their APOE genotype from a health-care provider as part of Generation Study 1 screening. 4038 (42·5%) participants were in the 65-69-year age group, 5790 (61·0%) were female, 3706 (39·0%) were male, and 8862 (93·3%) self-identified as White. Increase in genetic disease knowledge 2-7 days after disclosure was greater in APOE4 homozygotes (mean 1·19 [SD 3·95]) than in heterozygotes (0·78 [3·95], p=0·042) and non-carriers (0·29 [3·96], p=0·0002). Disease-specific distress 2-7 days after disclosure increased more in homozygotes (2·25 [6·42]) than in heterozygotes (0·53 [5·08], p<0·0001) and non-carriers (0·79 [4·95], p<0·0001). Levels of anxiety 2-7 days after disclosure increased in homozygotes (0·17 [2·95]) but decreased in heterozygotes (-0·67 [2·68], p<0·0001) and non-carriers (-0·66 [2·67], p<0·0001). There were no significant changes in depressive symptoms following disclosure for any APOE4 group. Notably, for all APOE4 groups, increases in distress and anxiety were small and did not reach predefined levels of clinical concern.

INTERPRETATION: In cognitively unimpaired, psychologically pre-screened adults, APOE disclosure by a trained health-care provider was generally safe and well tolerated, consistent with results from previous studies. To our knowledge, this is the largest study experience of APOE disclosure to date, especially for homozygotes, and is notable for the older age of participants compared with previous research. These results are timely and important given anticipated increases in APOE disclosure to guide clinical decision making once an Alzheimer's disease prevention treatment is approved for cognitively unimpaired adults or if patients' family members are interested in genetic testing. Scalable approaches for returning Alzheimer's disease risk information are critical to meeting anticipated demand. Results from this study may be useful to bolster clinical translatability of disclosure programmes.

FUNDING: The National Institute on Aging, Alzheimer's Association, Banner Alzheimer's Foundation, GHR Foundation, F-Prime Biomedical Research Initiative (FBRI), and Novartis Pharma.},
}

@article {pmid41319481,
year = {2025},
author = {Svobodová Burianová, J and Černotová, D and Klausová, T and Profant, O and Fuksa, J and Syka, J and Svoboda, J},
title = {Impaired prepulse inhibition in APP/PS1 mice is accompanied by substantial morphological changes in neurons of the central auditory system and hippocampus.},
journal = {Hearing research},
volume = {469},
number = {},
pages = {109484},
doi = {10.1016/j.heares.2025.109484},
pmid = {41319481},
issn = {1878-5891},
abstract = {Auditory dysfunction is increasingly recognized as a non-cognitive feature of Alzheimer's disease (AD). We examined auditory processing and neuronal morphology in APPswe/PSEN1dE9 (APP/PS1) transgenic mice, a model of AD. Ten-month-old male APP/PS1 and wild-type (WT) littermates were tested for auditory thresholds using auditory brainstem responses (ABR) and for sensorimotor gating using prepulse inhibition (PPI) of the acoustic startle reflex. ABR thresholds did not differ between groups across tested frequencies (2-16 kHz), indicating preserved peripheral hearing. In contrast, APP/PS1 mice showed significantly impaired PPI at 4, 12, and 20 kHz prepulses and displayed exaggerated startle responses to high-intensity stimuli. Exploratory and anxiety-like behavior, assessed in the open field and elevated plus maze, did not differ between groups. Morphological analysis of Golgi-Cox-stained neurons revealed widespread dendritic pathology in the inferior colliculus, medial geniculate body and auditory cortex, as well as in hippocampal CA1. Compared with WT, APP/PS1 neurons exhibited shorter dendrites, reduced branching, and lower spine density, accompanied by markedly decreased dendritic complexity in Sholl analyses. These findings demonstrate that sensorimotor gating deficits in APP/PS1 mice are accompanied by degeneration in central auditory and hippocampal circuits; however, a contribution of peripheral degeneration cannot be excluded. The data highlights the vulnerability of auditory midbrain and thalamic structures in this model of AD and suggests that dendritic alterations along the auditory pathway may contribute to central auditory dysfunction and serve as potential early biomarkers of disease.},
}

@article {pmid41319459,
year = {2025},
author = {Lin, J and Li, J and Liang, Z and Yu, H and Liu, S and Zheng, Q and Yu, J and Du, Z and Luo, K and Yang, X and Yang, L and Deng, P and Pi, H and Yu, Z and Zhou, Z and Yuan, W and Hong, H},
title = {Aflatoxin B1-induced lipid disturbance and neuroinflammation contribute to Alzheimer's disease-like neuropathology in C57BL/6J mice.},
journal = {Ecotoxicology and environmental safety},
volume = {308},
number = {},
pages = {119495},
doi = {10.1016/j.ecoenv.2025.119495},
pmid = {41319459},
issn = {1090-2414},
abstract = {Aflatoxin B1 (AFB1) is a ubiquitous foodborne mycotoxin that has been associated with cognitive decline. In this study, we investigated the neuropathology linked to Alzheimer's disease (AD) caused by AFB1 and revealed the underlying mechanism. Here, C57BL/6 J mice received AFB1 (1.5 mg/L in drinking water) for 8 weeks. Behavioral tests, including Morris water maze and Y-maze, were conducted alongside hippocampal histology and immunostaining to detect cognitive deficits and hippocampal neuronal impairment. Non-targeted lipidomics was also employed to dissect alterations in the hippocampal lipid profile. Furthermore, dysregulation of the lipid-driven inflammatory response was confirmed by gene and protein assays for lipid metabolism and inflammatory signaling, as well as serum cytokine measurements. Results showed that AFB1 impaired spatial learning and memory, caused hippocampal neuronal loss and increased App and phosphorylated Tau. Non-targeted lipidomics revealed that the AFB1 exposure led to derangements in glycerophospholipid metabolism and increased the abundance of pro-inflammatory phosphatidylcholine (PC) species. Concurrently, the Tlr4/NF-κB cascade contributed to the enhanced systemic and hippocampal pro-inflammatory cytokine responses. Taken together, these results indicate that exposure to a low dose of AFB1 results in an increase in pro-inflammatory PC species and hippocampal neuroinflammation via the Tlr4/NF-κB axis and hence contribute to the development of AD-like neuropathology. This highlights the therapeutic significance of targeting dysregulated lipid metabolism to counteract AFB1-induced neurotoxicity in relation to AD.},
}

@article {pmid41319367,
year = {2025},
author = {Ji, S and Wang, W and Ma, S and Zhang, P and Xiang, Z and Liu, G and Wu, J and Wang, K and Pan, J},
title = {A novel enzyme-activated tandem fluorescent probe for dual detection of BChE and A β plaques in Alzheimer's disease.},
journal = {Talanta},
volume = {300},
number = {},
pages = {129169},
doi = {10.1016/j.talanta.2025.129169},
pmid = {41319367},
issn = {1873-3573},
abstract = {Alzheimer's disease (AD) has early symptoms that are subtle and easily confused with other brain disorders, necessitating the development of precise diagnostic technologies for AD. This study reported novel tandem detection molecular probes (HCys) for two key pathological markers in the AD process, namely butyrylcholinesterase (BChE) and β-amyloid (A β). The probe undergoes BChE-specific esterase hydrolysis, resulting in a 48-fold enhancement of fluorescence. After hydrolysis, the probe formed could further bind to A β aggregates and triggered a 6-7-fold fluorescence enhancement, establishing an "enzyme-activated" cascade detection mechanism. In ex vivo brain tissue experiments, the probe successfully visualized the spatial distribution of BChE in the brains of AD mice, and the hydrolyzed probe specifically labeled A β plaques in the brains of AD mice. The low molecular weight of the probes HCys enable it to rapidly cross the blood-brain barrier (BBB) and identify both early and late-stage AD models. This study is the first time to report near-infrared fluorescent probes targeting BChE and A β aggregates, providing a new tool for the early diagnosis of AD.},
}

@article {pmid41319341,
year = {2025},
author = {Bonin, L and Hedouin, M and Furman, C and Not, O and Lancel, S and Bensalah, M and Coadou, G and Boulanger, E and Shova, S and Oulyadi, H and Ghinet, A},
title = {Development of New Benzo[b]Thiophene-2-Carboxamide Derivatives as Advanced Glycation End-Products Receptor (RAGE) Antagonists.},
journal = {ChemMedChem},
volume = {},
number = {},
pages = {e202500503},
doi = {10.1002/cmdc.202500503},
pmid = {41319341},
issn = {1860-7187},
support = {ANR-23-CE14-0063//Agence Nationale de la Recherche/ ; },
abstract = {The activation of the receptor for advanced glycation end-products (RAGE) induces a chronic, low-noise inflammation responsible for the aging process, known as inflammaging. Associated with numerous pathologies such as Alzheimer's, insulin-resistant diabetes, cardiovascular diseases, and certain cancers, RAGE has become an interesting therapeutic target in the context of aging well. To this end, we identified new benzo[b]thiophene-2-carboxamide derivatives as potential RAGE ligands. Herein, we developed an alternative approach to easily synthesize benzo[b]thiophene-2-carboxamide analogs from 5-arylidene-2,4-thiazolidinedione intermediates based on the Ullmann-Goldberg coupling conditions. In light of LCMS, NMR, X-ray, and DFT studies, a mechanism for this reaction was proposed. This novel strategy enabled us to synthesize analogs whose best molecule 3t', with an IC50 of 13.2 µM, shows similar interactions with RAGE as the reference molecule Azeliragon (13.0 µM).},
}

@article {pmid41319336,
year = {2025},
author = {Piano, M and Nguyen, B and Conrick, J and Joubert, L and McKendrick, AM},
title = {Breaking down barriers to accessing dementia-friendly eyecare.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251395222},
doi = {10.1177/13872877251395222},
pmid = {41319336},
issn = {1875-8908},
abstract = {BackgroundPeople living with Alzheimer's disease and related dementias experience barriers to accessing routine primary eyecare, increasing risk of preventable sight loss. One barrier is a negative experience with previous eye tests (defined as a comprehensive eye examination involving multiple tests to assess visual function and eye health). We explored eye test experiences for people with dementia and identified improvements. Supporting people with dementia to keep up regular eye tests may reduce risk of preventable sight loss, thereby supporting wellbeing and independence.ObjectiveFrom the perspectives of people living with dementia, family carers and optometrists: 1) Identify ways to improve experiences of having an eye test, and self-managing eye problems at home; and 2) Determine if/how optometrists change their testing and management approach to accommodate dementia.MethodsSemi-structured interviews were conducted with people living with dementia at home, past/current family carers and practicing optometrists. Framework analysis produced an integrated perspective. People with dementia and carers guided the research.ResultsIdentified themes were: 1) Good eyesight matters to people with dementia; 2) Varied impacts of dementia upon the eye test and following eyecare advice at home; 3) Adapting the eye test and eyecare advice to accommodate dementia; 4) What makes a good eye test experience for people living with dementia; and 5) Unmet training and education needs in dementia-friendly eyecare.ConclusionsDementia education/training to support optometrists to accommodate dementia, and encouraging people with dementia and carers to declare a dementia diagnosis before the eye test, could help break down barriers to accessing dementia-friendly eyecare.},
}

@article {pmid41319164,
year = {2025},
author = {Miners, JS and Roy, G and Love, S and , },
title = {CSF markers of vascular injury correlate with tau and cognitive decline in early Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70957},
pmid = {41319164},
issn = {1552-5279},
support = {U01 AG024904/NH/NIH HHS/United States ; ARUK-SRF-2019A-001//Alzheimer's Research UK/ ; APP14626/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/complications ; Male ; Female ; *tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid/blood ; *Cognitive Dysfunction/cerebrospinal fluid ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; Positron-Emission Tomography ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Cerebrovascular injury is common in Alzheimer's disease (AD), but its timing in relation to Aβ and tau pathology and cognitive decline remains unclear.

METHODS: We measured baseline vascular marker levels in cerebrospinal fluid (CSF) and serum from 75 Alzheimer's Disease Neuroimaging Initiative (ADNI) study participants, stratified into cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD groups (n = 25/group) and investigated associations with disease pathology (CSF and positron emission tomography [PET] amyloid beta [Aβ] and tau) and cognition (Clinical Dementia Rating scale [CDR], Montreal Cognitive Assessment, Mini-Mental State Examination, and Alzheimer's Disease Assessment Scale).

RESULTS: CSF markers of endothelial (placental growth factor, angiopoietin 2, angiotensin-converting enzyme-1 [ACE-1]) and pericyte (soluble platelet-derived growth factor receptor beta [sPDGFRβ]) injury were elevated in AD. Most were also higher in CDR 0.5 than CDR 0 and correlated with CSF tau and cognitive impairment in CU and MCI groups, particularly in PET Aβ-positive (Aβ+) participants. Serum sPDGFRβ, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains-2 (TIE-2), and ACE-1 correlated with CSF measurements.

DISCUSSION: Cerebrovascular injury precedes the development of dementia and, particularly in PET Aβ+ individuals, progresses in close association with CSF tau and cognitive decline.

HIGHLIGHTS: We measured the levels of multiple markers of neurovascular injury in serum and CSF taken at baseline from CU, MCI, and AD participants in the ADNI study and investigated associations with CSF and PET markers of disease pathology and with cognitive decline. CSF markers of neurovascular injury, particularly PlGF, are elevated in very early stages of AD, including in MCI and in PET Aβ+ CU individuals. The levels are closely related to CSF t-tau and p-tau and to cognitive decline Levels of only a few neurovascular markers in serum correlate with those in CSF: sPDGFRβ, TIE-2, and ACE-1.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/complications
Male
Female
*tau Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid/blood
*Cognitive Dysfunction/cerebrospinal fluid
Aged
Amyloid beta-Peptides/cerebrospinal fluid
Positron-Emission Tomography
Aged, 80 and over

@article {pmid41319161,
year = {2025},
author = {Patsyuk, Y and Van Egroo, M and Beckers, E and Koops, EA and Ashton, NJ and Janelidze, S and Blennow, K and Hansson, O and Zetterberg, H and Poser, BA and Jacobs, HIL},
title = {Locus coeruleus-entorhinal cortex tract integrity is linked to plasma tau and glial fibrillary acidic protein.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70915},
pmid = {41319161},
issn = {1552-5279},
support = {88587//H2020 FET-Open AROMA/ ; UKDRI-1003//UK Dementia Research Institute/ ; //UCLH Biomedical Research Centre/ ; JPND2021-00694//EU Joint Programme - Neurodegenerative Disease Research/ ; //Stiftelsen för Gamla Tjänarinnor/ ; //Familjen Erling-Perssons Stiftelse/ ; //Olav Thon Stiftelsen/ ; //Bluefield Project/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; ALFGBG-715986//Swedish federal government under the ALF agreement/ ; ALFGBG-965240//Swedish federal government under the ALF agreement/ ; 2018-Projekt0279//Swedish federal government under the ALF agreement/ ; 2020-0314//Regionalt Forskningsstöd/ ; 2020-O000028//Skånes universitetssjukhus/ ; //Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; //Cure Alzheimer's Fund/ ; 1280/20//Parkinson foundation of Sweden/ ; 2015.0125//Marianne and Marcus Wallenberg Foundation/ ; 2017-0383//Knut och Alice Wallenbergs Stiftelse/ ; R01AG062559//National Institutes of Health (NIH)/ ; R01AG06806//National Institutes of Health (NIH)/ ; R01AG082006//National Institutes of Health (NIH)/ ; R21AG074220//National Institutes of Health (NIH)/ ; 1R01AG068398-01//National Institutes of Health (NIH)/ ; JPND2019-466-236//European Union Joint Program for Neurodegenerative Disorders/ ; ALFGBG-715986//Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement/ ; ALFGBG-965240//Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement/ ; ALFGBG-71320//Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement/ ; FO2021-0293//Hjärnfonden/ ; FO2022-0270//Hjärnfonden/ ; FO2017-0243//Hjärnfonden/ ; ALZ2022-0006//Hjärnfonden/ ; AF-939932//Swedish Alzheimer Foundation/ ; AF-930351//Swedish Alzheimer Foundation/ ; AF-939721//Swedish Alzheimer Foundation/ ; AF-968270//Swedish Alzheimer Foundation/ ; 201809-2016862//Alzheimer's Drug Discovery Foundation/ ; 201809-2016615//Alzheimer's Drug Discovery Foundation/ ; 2016-00906//Vetenskapsrådet/ ; 2017-00915//Vetenskapsrådet/ ; 2019-02397//Vetenskapsrådet/ ; 2022-01018//Vetenskapsrådet/ ; 2023-00356//Vetenskapsrådet/ ; 860197//HORIZON EUROPE Marie Sklodowska-Curie Actions/ ; 101109451-ADEEPSLEEP//HORIZON EUROPE Marie Sklodowska-Curie Actions/ ; A20211016F//BrightFocus Foundation/ ; 23AARF-1026796/ALZ/Alzheimer's Association/United States ; AARG-22-920434/ALZ/Alzheimer's Association/United States ; ZEN-21-848495/ALZ/Alzheimer's Association/United States ; WE.03-2019-02//Alzheimer Nederland/ ; ADSF-21-831376-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831381-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831377-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-24-1284328-C//AD Strategic Fund and the Alzheimer's Association/ ; },
mesh = {Humans ; *tau Proteins/blood ; *Locus Coeruleus/diagnostic imaging/pathology ; Male ; Female ; *Glial Fibrillary Acidic Protein/blood ; *Entorhinal Cortex/diagnostic imaging/pathology ; Aged ; Biomarkers/blood ; Middle Aged ; *Alzheimer Disease/blood/pathology ; Diffusion Magnetic Resonance Imaging ; Neural Pathways/diagnostic imaging/pathology ; },
abstract = {INTRODUCTION: Pretangle tau inclusions from the locus coeruleus (LC) are hypothesized to propagate to the entorhinal cortex (EC) via neuron-to-neuron transmission along its projections. The lower integrity of the LC-EC pathway accompanying Alzheimer's disease (AD) pathology is supported by post mortem studies, but in vivo evidence remains limited.

METHODS: We associated diffusion-weighted 7T magnetic resonance imaging (MRI) metrics of microstructural integrity within the LC-EC tract to plasma AD-related biomarkers in a cohort of 47 cognitively unimpaired adults.

RESULTS: Worse overall and local LC-EC integrity, indicated by lower fractional anisotropy (FA) and higher mean diffusivity (MD), was related to elevated concentrations of plasma phosphorylated tau 181 (p-tau181), p-tau217, and glial fibrillary acidic protein (GFAP). A higher orientation dispersion index (ODI) within the LC-EC tract was linked to elevated plasma p-tau181 and p-tau231 levels.

DISCUSSION: The lower integrity of the LC-EC pathway may serve as a key indicator of the earliest AD-related pathophysiological processes to improve detection of at-risk individuals.

HIGHLIGHTS: Standard DTI model metrics in the LC- EC tract are linked to elevated plasma p-tau and GFAP. A higher ODI in the voxels containing the LC-EC tract is related to elevated plasma p-tau. LC-EC integrity links to AD-related biomarkers show topographic specificity. Lower LC-EC integrity may be a key indicator of the earliest AD-related pathology.},
}

Humans
*tau Proteins/blood
*Locus Coeruleus/diagnostic imaging/pathology
Male
Female
*Glial Fibrillary Acidic Protein/blood
*Entorhinal Cortex/diagnostic imaging/pathology
Aged
Biomarkers/blood
Middle Aged
*Alzheimer Disease/blood/pathology
Diffusion Magnetic Resonance Imaging
Neural Pathways/diagnostic imaging/pathology

@article {pmid41319155,
year = {2025},
author = {Nichols, E and Bindas, A and Atshan, S and Chang, H and Chiang, YY and Claus Henn, B and Hayes-Larson, E and Keller, KP and Kezios, KL and Shih, RA and Szpiro, AA and Weiss, J and Adar, SD and Knapp, DM and Lee, J and Weuve, J},
title = {Modeling approaches for estimating the effects of risk factors using longitudinal lifecourse exposure data in dementia research.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70971},
pmid = {41319155},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; /NH/NIH HHS/United States ; U24AG088894/AG/NIA NIH HHS/United States ; R00AG084769/AG/NIA NIH HHS/United States ; R13AG064971/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Risk Factors ; *Dementia/epidemiology/etiology ; Longitudinal Studies ; },
abstract = {Longitudinal data on risk factors at different ages across the lifecourse are essential for gaining important insights into how the timing and accumulation of exposure to risk factors influence the risk of Alzheimer's disease and related dementias (dementia). With increased interest in the exposome and lifecourse research questions, there have been commensurate increases in data sources and methodological approaches for answering these questions using empirical data. Methodological approaches developed within specific disciplines have largely remained within disciplinary silos, despite their potential for broader applications. By enumerating these approaches in a single place, we aim to expand discovery in lifecourse dementia research and help investigators align their research questions with appropriate analytic methods. In doing so, we seek to guide methodological decision-making and ensure that researchers use appropriate statistical tools to answer important questions about the exposome and lifecourse risk factors for dementia. HIGHLIGHTS: Longitudinal exposure data are valuable for exposome and lifecourse research on dementia. Multiple methodological approaches exist to analyze such data, with different assumptions, advantages, and disadvantages. Some methodological approaches have been used predominantly in specific disciplines but may have wider utility. Additional research is needed to integrate added complexity from the co-occurrence of multiple exposures into existing methods. Comparisons between methods help researchers make informed decisions on the appropriate method for a specific research question.},
}

Humans
Risk Factors
*Dementia/epidemiology/etiology
Longitudinal Studies

@article {pmid41319153,
year = {2025},
author = {Wu, CY and Chen, L and Fatima, H and Gatchel, J and Das, S and Kivisäkk, P and Arnold, SE and Dodge, HH},
title = {Combined use of plasma p-tau217, NfL, and GFAP predicts domain-specific cognitive decline in cognitively unimpaired and MCI individuals.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70934},
pmid = {41319153},
issn = {1552-5279},
support = {P30AG062421/GF/NIH HHS/United States ; R01AG051628/GF/NIH HHS/United States ; R01AG056102/GF/NIH HHS/United States ; K01AG088184/GF/NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/blood ; Male ; Female ; *Cognitive Dysfunction/blood/diagnosis ; *Glial Fibrillary Acidic Protein/blood ; *Neurofilament Proteins/blood ; Biomarkers/blood ; Aged ; Phosphorylation ; Neuropsychological Tests ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Accurate identification of individuals at risk for cognitive decline is critical for treatment planning and trial enrichment strategies. We evaluated the combined utility of plasma phosphorylated tau at threonine 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in predicting domain-specific cognitive decline.

METHODS: Participants (n = 523; 40.9% cognitively unimpaired [CU]; 59.1% mild cognitive impairment [MCI]) were from the Massachusetts Alzheimer's Disease Research Center. Cognition was assessed using the National Alzheimer's Coordinating Center Uniform Data Set. Participants were classified as high(+)/low(-) for each biomarker using Gaussian mixture models.

RESULTS: Among all participants, high p-tau217 alone [p-tau217(+)NfL(-)GFAP(-)] was associated with a steeper decline in episodic/semantic memory and processing speed compared to the all-low group (p ≤ 0.02). With the addition of high GFAP [p-tau217(+)NfL(-)GFAP(+)], steeper decline extended to most cognitive domains, including global cognition and executive function, compared to the all-low group. In CU, faster decline in global cognition and executive function was seen when all biomarkers were elevated ([p-tau217(+)NfL(+)GFAP(+)]; p ≤ 0.04).

DISCUSSION: Combined plasma biomarkers predict decline in cognitive domains vulnerable to early disease.

HIGHLIGHTS: High phosphorylated tau at threonine 217 (p-tau217) alone was associated with declines in semantic/episodic memory, whereas its combination with elevated glial fibrillary acidic protein (GFAP) predicted declines in a wider range of cognitive domains. Elevated neurofilament light chain (NfL) amplifies the cognitive decline already driven by p-tau217 and GFAP. In cognitively unimpaired individuals, subtle domain-specific cognitive declines can be detected when both core and non-core Alzheimer's disease biomarkers are used. Our finding highlights the importance of focusing on vulnerable cognitive domains during early disease where global cognition may appear stable but specific impairments can be masked within composite scores.},
}

Humans
*tau Proteins/blood
Male
Female
*Cognitive Dysfunction/blood/diagnosis
*Glial Fibrillary Acidic Protein/blood
*Neurofilament Proteins/blood
Biomarkers/blood
Aged
Phosphorylation
Neuropsychological Tests
Aged, 80 and over

@article {pmid41319123,
year = {2025},
author = {Dachet, F and Loeb, JA},
title = {Non-Protein-Coding RNA Instability in the Human Postmortem Brain.},
journal = {Toxicologic pathology},
volume = {},
number = {},
pages = {1926233251395687},
doi = {10.1177/01926233251395687},
pmid = {41319123},
issn = {1533-1601},
abstract = {A majority of the human genome codes for genes that do not produce proteins. Many of these long non-coding RNA (lncRNA) transcripts have evolved at a faster rate than genes that code for proteins, have critical regulatory and structural roles, and have important roles in higher-level brain functioning and diseases. We have shown selective time and cell-type stability of RNA transcripts in human brain during the postmortem interval. Here, we have extended these studies to examine the stability of lncRNAs in a simulated human postmortem interval. We found that lncRNA stability is variable and cell-type specific. While some lncRNAs are stable for up to 24 hours, those expressed in neurons decline rapidly and those expressed in glial cells such as astrocytes and microglia increase dramatically during this same time interval. The lncRNAs are less stable than protein-coding RNAs, and microRNAs were highly unstable in the simulated postmortem interval. Knowing the stability of human brain protein-coding and non-coding genes in the postmortem interval is critical to interpret studies of all human brain disorders ranging from Alzheimer's disease to schizophrenia.},
}

@article {pmid41319103,
year = {2025},
author = {Milner, O and Fisher, RA and Asby, DJ and Cross, S and Boche, D and Miners, JS},
title = {Vessel-associated microglia are differentially activated and distributed in relation to systemic infection and Alzheimer's disease.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70052},
doi = {10.1111/bpa.70052},
pmid = {41319103},
issn = {1750-3639},
support = {ARUK-SRF-2019A-001//Alzheimer's Research UK/ ; },
abstract = {Vessel-associated microglia (VAM) are an integral part of the neurovascular unit and have recently been implicated in the pathophysiology of cerebrovascular injury and blood-brain barrier (BBB) leakiness in Alzheimer's disease (AD). In this neuropathological study, we explored the hypothesis that the distribution and activation of VAM are altered in AD in the presence of systemic infection, associated with cerebrovascular dysfunction. We studied VAM density in the temporal cortex and underlying white matter from AD and age-matched controls with and without terminal systemic infection (SI) (n = 15 per group). The area of VAM labelled with microglial markers (Iba1, HLA-DR, CD68) was quantified in proximity to CD31-labelled microvessels within three predefined regions: contact VAM, proximity <15 μm, and parenchymal >15 μm. The relationships between VAM and previously measured brain cytokine levels and biochemical markers of cerebral perfusion (MAG:PLP1, endothelin-1) and BBB leakiness (VEGF-A and fibrinogen), were explored in a subset of cases. Compared to controls, the relative area of Iba1+ VAM was higher in SI and in AD. The area of HLA-DR+ VAM was higher in AD only. The area of Iba1+ VAM that expressed CD68, a marker of phagocytosis, was higher in both AD and AD + SI. Iba1+ and HLA-DR+ VAM correlated inversely with anti-inflammatory cytokines (IL-10, IL-23) in AD and positively with pro-inflammatory cytokines (IL-6, IL-23, GM-CSF, IL-17) in AD + SI. Iba1+ VAM density correlated positively with endothelin-1, VEGF-A and fibrinogen in controls. HLA-DR+ VAM density correlated positively with Aβ1-42 in both controls and AD, and inversely with PDGFRβ and VCAM-1 in AD. Our data reveal the distribution of VAM is elevated in AD, and altered in the presence of systemic infection, which together are likely to be independent and synergistic contributors to cerebrovascular dysfunction in AD.},
}

@article {pmid41319102,
year = {2025},
author = {Ichimata, S and Yoshida, K and Tanaka, R},
title = {Alzheimer's disease and mixed pathologies as a hidden contributor to fatal hypothermia: A large-scale forensic autopsy-based study.},
journal = {Brain pathology (Zurich, Switzerland)},
volume = {},
number = {},
pages = {e70051},
doi = {10.1111/bpa.70051},
pmid = {41319102},
issn = {1750-3639},
support = {//FIRSTBANK OF TOYAMA SCHOLARSHIP FOUNDATION RESEARCH GRANT/ ; },
abstract = {There is a paucity of autopsy-based studies providing detailed neuropathological characteristics of fatal hypothermia cases, particularly in trauma-associated cases. Hence, this study investigated 2054 serial autopsy cases in which histopathological examination of all organs, including the brain, could be performed. We identified 168 cases (75 female and 93 male patients) of fatal hypothermia and examined the clinical and neuropathological characteristics in these cases. Patients aged ≥65 years constituted 80% of the cohort (135 cases). Cognitive impairment (CI) was identified in 39% of cases with available clinical histories, and approximately half of these cases were presumed to have developed hypothermia while wandering, based on clinical history and the circumstances of discovery. Alzheimer's disease was the most commonly identified pathology, affecting 40% of the total and approximately two-thirds of patients aged ≥80 years. CI caused by multiple pathologies, especially two, was more frequently observed than by a single pathology. The most common manner of exposure to cold temperatures was accidents (120 cases), including 35 cases with multiple traumatic injuries, most likely resulting from falls. In these cases, the trauma was considered the primary cause of immobility, leading to subsequent exposure to cold environments. Importantly, 30 (86%) of these trauma-associated cases showed one or more neuropathological conditions, and CI was documented in 13, with four presumed to have fallen while wandering. Notable neuropathological manifestations were also observed in eight of the 33 cases of patients aged less than 65 years. Our results demonstrate that neurodegenerative diseases, especially Alzheimer's disease, are underlying conditions in fatal hypothermia in the elderly and in relatively younger individuals, suggesting that they may contribute to its onset. These findings highlight the necessity for comprehensive neuropathological examination in all forensic autopsy cases of hypothermia.},
}

@article {pmid41319088,
year = {2025},
author = {TomHon, P and Gyesi, J and Abdurraheem, A and McBride, S and Samoilenko, A and Oladun, C and Curran, E and Pike, M and Welch, SD and Scofield, S and Goodson, BM and Sadagurski, M and Theis, T and Chekmenev, EY},
title = {Biocompatible SABRE Hyperpolarization of [1-[13]C]Ketoleucine for Cellular Metabolic Flux Sensing.},
journal = {Chemistry (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e02734},
doi = {10.1002/chem.202502734},
pmid = {41319088},
issn = {1521-3765},
support = {R01ES033171/ES/NIEHS NIH HHS/United States ; P42ES030991/ES/NIEHS NIH HHS/United States ; P30ES020957/ES/NIEHS NIH HHS/United States ; T32ES036169/ES/NIEHS NIH HHS/United States ; R01AG078170//National Institute of Aging/ ; DE-SC0023334,DE-SC0025315//Biological and Environmental Research/ ; CHE-2404387,CHE-2404388//National Science Foundation/ ; R01EB034197/EB/NIBIB NIH HHS/United States ; R21EB033872/EB/NIBIB NIH HHS/United States ; },
abstract = {Ketoleucine (α-ketoisocaproate) is a novel hyperpolarized substrate for noninvasive metabolic imaging, enabling rapid, high-sensitivity detection of branched-chain amino acid flux, a pathway that is aberrant in many diseases including cancer and Alzheimer's disease. Utilizing NMR Signal Amplification by Reversible Exchange (SABRE) with an 80:20 acetone:water solvent system, we achieved >11% polarization of [1-[13]C]ketoleucine (corresponding to signal enhancement over 230,000-fold at 0.55 T) at 70 mM within 2 min, using parahydrogen as a cheap and fast source of hyperpolarization. A two-stage liquid-liquid extraction and gas stripping protocol removes excess excipients, yielding a biocompatible aqueous solution of [1-[13]C]ketoleucine (79 ± 10 mM). When mixed with Saccharomyces cerevisiae (Baker's yeast), hyperpolarized [1-[13]C]ketoleucine produced strong, long-lasting signals, where downstream metabolites are observed for >200 s, allowing first-order kinetic modeling of CO2 and bicarbonate. These cell experiments demonstrate both the biocompatibility and signal strength of SABRE-hyperpolarized KL, establishing KL as a versatile hyperpolarized agent and opening avenues for real-time investigation of metabolic dysregulation in cancer, neurodegenerative disorders, and beyond.},
}

@article {pmid41318982,
year = {2025},
author = {Huang, Y and Guo, Y and Zhang, H and Deng, J and Huang, Z and Chen, A and Wu, X and Lin, D and Ye, P and Chen, X and Zheng, X},
title = {Repeated Exposure to Lidocaine Induces Alzheimer's-Like Cognitive Impairment Neuropathology in Aged Mice Through BDNF-Regulated Autophagy.},
journal = {Journal of cellular and molecular medicine},
volume = {29},
number = {23},
pages = {e70970},
pmid = {41318982},
issn = {1582-4934},
support = {82171186//National Natural Science Foundation of China/ ; 82471278//National Natural Science Foundation of China/ ; 2023Y9282//The Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; 2023Y9315//The Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; 2021QH1307//Startup Fund for scientific research, Fujian Medical University/ ; },
mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; *Autophagy/drug effects ; Mice ; *Lidocaine/adverse effects ; *Cognitive Dysfunction/pathology/metabolism/chemically induced ; *Alzheimer Disease/pathology/metabolism/chemically induced ; Hippocampus/pathology/metabolism/drug effects ; Male ; Signal Transduction/drug effects ; Receptor, trkB/metabolism ; Astrocytes/metabolism/drug effects/pathology ; Disease Models, Animal ; TOR Serine-Threonine Kinases/metabolism ; *Aging/pathology ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; },
abstract = {Lidocaine is widely used for perioperative pain management, but repeated exposure may cause neurotoxicity, including neurological deficits. This study investigates mechanisms underlying cognitive decline induced by repeated lidocaine exposure. Eighteen-month-old mice received repeated clinically relevant lidocaine infusions over 3 days. Cognitive function was assessed by Morris water maze, Y-maze and open field tests. Hippocampal pathology was examined via TEM, Nissl staining, immunofluorescence for astrocyte polarisation and Aβ deposition, and western blot for tau, BDNF, TrkB, mTOR and autophagy proteins. The TrkB agonist 7,8-DHF was used to modulate BDNF/TrkB/mTOR signalling. Repeated lidocaine exposure impaired cognition and induced Alzheimer's-like hippocampal pathology, as evidenced by increased accumulation of Aβ and tau toxic proteins, along with neuronal death. It reduced BDNF expression, inhibited TrkB phosphorylation, and activated mTOR signalling, leading to autophagy inhibition and pathological protein accumulation. Lidocaine shifted astrocytes towards the neurotoxic A1 phenotype, decreasing neuroprotective A2 astrocytes and BDNF synthesis. TrkB agonist treatment restored signalling, enhanced autophagy and improved cognitive deficits and pathology. Repeated lidocaine exposure promotes A1 astrocyte increase and A2 decrease, inhibiting autophagy via the BDNF/TrkB/mTOR pathway, resulting in toxic protein deposition and Alzheimer's-like cognitive impairment.},
}

Animals
*Brain-Derived Neurotrophic Factor/metabolism
*Autophagy/drug effects
Mice
*Lidocaine/adverse effects
*Cognitive Dysfunction/pathology/metabolism/chemically induced
*Alzheimer Disease/pathology/metabolism/chemically induced
Hippocampus/pathology/metabolism/drug effects
Male
Signal Transduction/drug effects
Receptor, trkB/metabolism
Astrocytes/metabolism/drug effects/pathology
Disease Models, Animal
TOR Serine-Threonine Kinases/metabolism
*Aging/pathology
Amyloid beta-Peptides/metabolism
Mice, Inbred C57BL

@article {pmid41318807,
year = {2025},
author = {Wang, B and Ding, H and Qi, D and Tisminetzky, MS and Murabito, JM and Lin, H},
title = {Plasma-based brain age as a potential biomarker for cognitive health and risk of brain-related disorders.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-025-01268-w},
pmid = {41318807},
issn = {2730-664X},
support = {R01AG083735//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R21HL175584//U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; },
abstract = {BACKGROUND: Understanding brain aging is essential for identifying early markers of cognitive decline. This study aimed to develop plasma-based biomarkers of brain aging and examine their associations with cognitive function.

METHODS: We used data from 53,005 UK Biobank participants (2006-2010) with available Olink proteomics data (mean age 57 ± 8 years, 54% women). Protein levels were used to estimate brain age, organismal age, and conventional proteomic age using Least Absolute Shrinkage and Selection Operator (LASSO) regression. We assessed the relationships between these biological ages and cognitive function using multivariable-adjusted linear regression models, and their association with incident Alzheimer's disease (AD) and stroke using Cox proportional hazards models. Findings were validated in 2066 participants from the Framingham Heart Study (FHS) Offspring cohort (Exam 8, 2002-2005, mean age 67 ± 9 years, 55% women), also using the Olink platform.

RESULTS: Accelerated brain aging is significantly associated with poorer cognitive performance, whereas organismal and conventional proteomic ages are not. All three biological age measures are linked to increased risk of AD and stroke, but brain aging shows the strongest association (hazard ratio (HR) for AD: 1.79 [95% confidence interval (CI): 1.66-1.93]; HR for stroke: 1.25 [95% CI: 1.17-1.33]). In the FHS validation, brain aging is associated with lower performance in cognitive domains such as attention and visual memory, and with increased risk of AD (HR: 1.64 [95% CI: 1.37-1.97]).

CONCLUSIONS: Plasma-based biomarkers of brain aging may offer a promising tool for monitoring cognitive health and identifying individuals at risk for age-related diseases.},
}

@article {pmid41318546,
year = {2025},
author = {Bayaraa, O and Aksu, M and DeBose-Scarlett, E and Hocke, E and Jain, V and Wang, SJ and Cruz, DA and Gregory, SG},
title = {Multi-region spatial transcriptomics reveals region specific differences in response to amyloid beta (Aβ) plaque induced changes in Alzheimer's disease (AD).},
journal = {Human genomics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40246-025-00875-x},
pmid = {41318546},
issn = {1479-7364},
support = {P30AG072958//National Institute on Aging (NIA)/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia affecting 55 million people worldwide. The pathological hallmarks of AD, beta-amyloid (Aβ) plaques and neurofibrillary tangles (NFT), follow distinct stereotypical patterns of progression across brain regions and trigger a multicellular response that ultimately leads to neuronal loss and cognitive decline. Despite the uniform spread of Aβ plaque across the cortex during AD progression, different regions demonstrate varying levels of vulnerability and resilience to temporal Aβ plaque induced changes, such as NFT accumulation. There is a critical gap in our understanding of the cell types and molecular mechanisms that underlie these region-specific differences in resilience to Aβ plaque induced changes. In this study, we hypothesized that brain region and cell type specific transcriptional responses within the Aβ microenvironment, and more broadly within the grey matter, may contribute to this variation.

RESULTS: We carried out matched multi-region spatial transcriptomics and Aβ immunofluorescence staining from the entorhinal, occipito-temporal, dorsolateral prefrontal, and striate cortices from two individuals with Braak III and Thal 4 AD. Spatiotemporal comparisons of cell type proportions, gene expression, and cell-cell communication revealed differences in the vulnerability of somatostatin and somatostatin chondrolectin inhibitory neurons and the expression of endosomal and lysosomal trafficking and metallothionein genes within the Aβ plaque microenvironment. We also observed variations in blood-brain-barrier dysfunction, fibroblast growth factor signaling, and vascular impairment and repair related cell-cell communication networks within the grey matter across the four regions.

CONCLUSIONS: Our results demonstrate the value of simultaneously profiling AD-omic and spatial modalities in multiple regions to elucidate how cortical region-specific differences contribute to selective vulnerability and resilience during neurodegeneration. These cortical region and Aβ microenvironment-specific transcriptional changes during AD neurodegeneration highlight the potential for spatially targeted therapeutic approaches.},
}

@article {pmid41318530,
year = {2025},
author = {Sung, S and Kim, HJ and Cha, SJ and Nahm, M and Kim, SH and Kwon, MS},
title = {Microglial lipid droplets as therapeutic targets in age-related neurodegenerative diseases.},
journal = {npj aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41514-025-00295-0},
pmid = {41318530},
issn = {2731-6068},
support = {2023R1A2C1006622//National Research Foundation of Korea/ ; },
abstract = {Monoclonal antibodies approved for Alzheimer's disease (AD), such as lecanemab and aducanumab, have been shown to enhance microglial phagocytic function, underscoring the therapeutic relevance of microglia in neurodegenerative diseases (NDDs). Emerging evidence implicates lipid droplets (LDs) in brain aging and NDDs, particularly through LDs-laden microglia known as lipid droplet-accumulating microglia (LDAM), which exhibit impaired phagocytosis, elevated oxidative stress, and dysregulated lipid metabolism. Among microglial subtypes identified through transcriptomic and functional profiling-including disease-associated microglia (DAM), microglia in neurodegenerative disease (MGnD), white matter-associated microglia (WAM), and dark microglia-LDs-laden microglia have clear metabolic signatures defined by excessive LDs accumulation and disrupted lipid turnover. Here, we discuss the biogenesis of LDs, their pathological accumulation in microglia, and the therapeutic potential of targeting LDs. We further propose a hypothetical mechanism by which LDs clearance restore energy metabolism, nuclear transport, facilitate DNA repair, suppress inflammation, and phagocytosis in microglia. Thus, elucidating LDs dynamics in microglia may provide novel therapeutic avenues for modifying the course of NDDs.},
}

@article {pmid41318503,
year = {2025},
author = {Le Bars, S and Soudy, M and Nickels, SL and Schwamborn, JC and Glaab, E},
title = {Single-cell analysis reveals shared and distinct molecular signatures in brain organoid models of neurodegeneration and neuroinflammation.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01926-0},
pmid = {41318503},
issn = {1758-9193},
support = {INTER/JPND23/17999421/AD-PLCG2//Fonds National de la Recherche Luxembourg/ ; },
}

@article {pmid41318453,
year = {2025},
author = {Zhang, S and Guo, D and Zhao, C and Shi, Y and Zou, J and Shi, H and Cheng, J and Sun, J and Zhang, X},
title = {Integrating serum pharmacochemistry with network pharmacology and pharmacological validation to elucidate the mechanism of KaiXinSan in treating insomnia.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-025-05196-z},
pmid = {41318453},
issn = {2662-7671},
support = {KF202303//Shaanxi University of Traditional Chinese Medicine Shaanxi Provincial Key Laboratory of Basic and New Drug Research Open Project/ ; 2021YFD1601004, 2023YFD1600402, 2023YFD1600403//National Key Research and Development Program of China/ ; 2024CY-JJQ-36//Shaanxi Provincial Key Research and Development Program Project/ ; DJK-2023-004//Science and Technology Programme of Xixian New Area/ ; TZKN-CXTD-03//Shaanxi Provincial Traditional Chinese Medicine Science and Technology Innovation Team/ ; 2024ZC-YYDP-110//haanxi Provincial Department of Science and Technology Project/ ; L2024-QCY-ZYYJJQ-X28//Shaanxi Province Xianyang City Science and Technology Bureau Project/ ; ZYJXG-Y23005//Shaanxi Provincial Administration of Traditional Chinese Medicine/ ; },
abstract = {BACKGROUND: KaiXinSan (KXS) is a classic Chinese herbal compound used for treating insomnia and related mental disorders. Modern medical studies have shown that KXS can treat depression, Alzheimer's disease, memory loss, and other conditions. In addition, the effect of KXS in treating insomnia has been confirmed in clinical applications and animal experiments. However, the mechanism by which KXS treats insomnia remains unclear. The purpose of this study is to evaluate the impact of KXS on insomnia and explore its mechanism.

METHODS: A rat insomnia model was established using p-chlorophenylalanine (PCPA). Pharmacodynamic evaluation was performed via animal behavioral assessments, ELISA detection of biochemical indicators, and pathological tissue observation. The key mechanisms of KXS in treating insomnia were clarified through an integrated approach combining serum pharmacochemistry, network pharmacology, transcriptomics, and metabolomics. These mechanisms were further validated by molecular docking, in vivo, and in vitro experiments.

RESULTS: KXS improved motor activity and sleep status in insomniac rats and alleviated hippocampal neuronal damage. ELISA analysis showed that KXS increased levels of 5-HT and GABA while reducing DA and NE levels in rats. Additionally, KXS decreased levels of TNF-α, IL-6, IL-1β, and ROS. Using UPLC-Q-Orbitrap MS/MS technology, 169 chemical components and 39 blood- enterable components of KXS were identified. Results from network pharmacology and transcriptomics indicated that KXS treats insomnia by regulating serotonin synapse and TNF signaling pathways. Furthermore, KXS reversed abnormal arachidonic acid and tryptophan metabolism in insomniac rats. Molecular docking, immunohistochemistry, and Western blotting showed that active components of KXS exhibited strong binding affinity to relevant proteins, upregulating 5-HTR1A and GABAA protein expression while inhibiting TNF-α and IL-6 protein expression. Cell experiments confirmed that KXS medicated serum reduced LPS induced neuronal damage and inflammatory responses in neural cells.

CONCLUSIONS: KXS treats insomnia by regulating serotonin synapse signaling pathways and inflammatory responses, and influencing arachidonic acid and tryptophan metabolism.},
}

@article {pmid41318200,
year = {2025},
author = {Albahttiti, A and Bodhiseela, N and Abdelnabi, M and Wettasinghe, M and Danaf, N},
title = {Cognitive stimulation enhancing memory and mental function.},
journal = {Progress in brain research},
volume = {298},
number = {},
pages = {73-85},
doi = {10.1016/bs.pbr.2025.08.024},
pmid = {41318200},
issn = {1875-7855},
mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Cognitive Behavioral Therapy/methods ; *Memory/physiology ; Parkinson Disease/therapy ; },
abstract = {Cognitive Stimulation Therapy (CST) is one of the best non-drug treatments for dementia patients that is based on evidence and can help them improve their cognitive and emotional performance. CST developed from reality orientation and social interaction models into a prevalent intervention that employs themed activities to stimulate memory, language, and attention functions, thereby improving participant engagement and quality of life. This paper elucidates the theoretical framework, session organisation, and therapeutic methodologies of CST. The research examines the broader implications of CST by assessing its efficacy for patients with Mild Cognitive Impairment (MCI), vascular dementia, and Parkinson's disease. This section assesses the enduring efficacy of CST and examines its correlation with pharmacological interventions, while also exploring contemporary adaptations of CST, including individualised CST (iCST), maintenance CST (MCST), and virtual or technology-enhanced delivery methods. The chapter evaluates global implementation practices, cultural adaptation strategies, and clinical implementation challenges, particularly in resource-limited settings. The chapter illustrates the synergistic benefits of integrating Cognitive Stimulation Therapy (CST) with pharmacological interventions and physical exercise regimens, while emphasising the necessity for research to attain universal and sustainable access for global populations.},
}

Humans
*Cognitive Dysfunction/therapy
*Cognitive Behavioral Therapy/methods
*Memory/physiology
Parkinson Disease/therapy

@article {pmid41318068,
year = {2025},
author = {Ning, XY and Liu, WJ and Zhou, LJ and Wang, N and Li, XZ and Wu, LM and Li, ZS and Yang, AZ and Liu, SY and Xu, ZH and Xun, FH and Xu, ZH and Zhao, QC},
title = {A novel GSK3β inhibitor ameliorates tau aggregation and neuroinflammation in Alzheimer's disease.},
journal = {Neurochemistry international},
volume = {192},
number = {},
pages = {106090},
doi = {10.1016/j.neuint.2025.106090},
pmid = {41318068},
issn = {1872-9754},
abstract = {In Alzheimer's disease, increased GSK3β activity drives tau phosphorylation and directly or indirectly triggers neuroinflammation, neuronal damage and cognitive decline. We previously developed a novel GSK3β inhibitor, ZLWH-60, which demonstrated inhibitory activity with an IC50 of 11.5 nM. Here, we comprehensively evaluated the therapeutic potential of ZLWH-60 in suppressing tau pathology and neuroinflammation using multiple chemically-induced AD models. Our results demonstrate that ZLWH-60 could reduce the phosphorylation of multiple tau epitopes by inhibiting the activity of GSK3β, thereby ameliorating cognitive impairments in OKA-induced mouse model. In the LPS-induced mouse model, ZLWH-60 also reduced the secretion of inflammatory factors in the brain, exerting a neuroprotective effect. Our data highlight that ZLWH-60, as a GSK3β inhibitor, has a powerful ability to reduce the phosphorylation of tau protein and shift the balance of the inflammatory response from pro-inflammatory to anti-inflammatory, demonstrating the potential for therapeutic use of this drug to control AD.},
}

@article {pmid41318029,
year = {2025},
author = {Juanes, AM and Vogels, T and Hertog, SK and Loos, M and Lütjohann, D and Giera, M and van der Kant, R},
title = {Characterization of the brain lipidome associated with frontotemporal lobar degeneration MAPT P301S mutation.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {100952},
doi = {10.1016/j.jlr.2025.100952},
pmid = {41318029},
issn = {1539-7262},
abstract = {Mutations in microtubule-associated protein Tau (MAPT), the gene that codes for the protein Tau, cause frontotemporal lobar degeneration (FTLD) with phenotypes ranging from behavioral changes to cognitive impairment and parkinsonism. Recently, lipid changes have been heavily implicated in synucleinopathies and secondary tauopathies such as Alzheimer's Disease (AD). Whether mutations in MAPT or accumulation of hyperphosphorylated Tau (pTau) can contribute to lipid changes in primary tauopathies is unknown. Here, we examine the effect of the FTLD-associated mutation MAPT P301S on brain lipid metabolism in a Tau transgenic mouse model. We find that the MAPT P301S mutation drives increased levels of diglycerides and hexosyl- and lactosylceramides while reducing triglycerides, specifically those triglyceride species containing monounsaturated fatty acids, but does not affect cholesterol metabolism prior to pTau accumulation. Strikingly, with increasing accumulation of pTau, neutral lipids such as cholesteryl esters and triglycerides start to accumulate in the brain of mutant mice, as also reported in the AD and FTLD brain. Furthermore, with increasing buildup of pTau, we observe a decrease in cholesterol synthesis and turnover to 24S-hydroxycholesterol. Overall our data indicates that Tau mutations strongly affect brain lipid metabolism.},
}

@article {pmid41318027,
year = {2025},
author = {Martins-Pais, IMN and Suemoto, CK and Marchioni, DML and Cacau, LT and Gonçalves, NG and Ferreira, NV},
title = {Racial differences in the association between Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) Diet scores and cognitive performance.},
journal = {Clinical nutrition ESPEN},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.clnesp.2025.11.152},
pmid = {41318027},
issn = {2405-4577},
abstract = {BACKGROUND & AIMS: The Mediterranean-DASH (Dietary Approaches to Stop Hypertension) Diet Intervention for Neurodegenerative Delay (MIND) diet has been associated with cognitive performance, but little is known about factors related to the social determinants of health, such as race, influence this association. The aim of this study was to investigate racial differences in the association between MIND diet scores and cognitive performance.

METHODS: In this cross-sectional analysis of older adults from the National Health and Nutrition Examination Survey (NHANES) 2011-2014, MIND diet scores (0-15) were calculated based on the intake of 15 food groups assessed using a 24-hour dietary recall. Cognitive performance was assessed using a word list from the Consortium to Establish a Registry for Alzheimer's Disease, the Animal Fluency, and the Digit Symbol Substitution Test. We conducted linear regression models to assess the association of MIND diet scores with cognition, as well as interaction and stratified analysis using sociodemographic variables.

RESULTS: We included 2,354 participants (mean age 68.9±6.6, 54% female). The median MIND diet score was 4.5 (IQR 3.5-6). Higher MIND diet scores were associated with better memory (β=0.034, 95% CI= 0.010; 0.057, p=0.008) and global cognitive performances (β=0.031, 95% CI= 0.004; 0.059, p=0.023). Race was a modifier in the association between MIND diet scores and cognitive performance (p<0.001). In stratified analysis, higher MIND diet scores were associated with better global cognitive performance in White participants (β=0.048, 95% CI= 0.012; 0.083, p= 0.010) and worse global cognitive performance in Black participants (β=-0.046, 95% CI= -0.086; -0.007, p= 0.024). Socioeconomic and MIND diet component intakes differed between Black and White participants.

CONCLUSIONS: Higher MIND diet scores were associated with better global and domain-specific cognitive performance, particularly in White participants, but with worse global performance in Black participants. Future studies with multiple dietary assessments focusing on the components of the MIND diet, differences in socioeconomic status (SES), and other risk factors between Black and White individuals, in order to gain a deeper understanding of the racial differences observed in this study.},
}

@article {pmid41318018,
year = {2025},
author = {de Souza, PC and Bezerra, TPW and de Melo Rêgo, MJB and da Rosa, MM},
title = {Advances in Neurological Therapies: A Review of Clinical Trials in Alzheimer's, Parkinson's, and Multiple Sclerosis.},
journal = {The American journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.amjmed.2025.11.025},
pmid = {41318018},
issn = {1555-7162},
abstract = {The period from 2020 to 2025 marked a pivotal juncture in the treatment of major neurological diseases, with Phase II-IV trials delivering the first compelling evidence for disease-modifying interventions in Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This narrative review provides a critical analysis of this evolving therapeutic landscape, focusing on efficacy, safety, and practical implications. Our analysis reveals unprecedented yet heterogeneous progress. In Alzheimer's disease, anti-amyloid monoclonal antibodies (donanemab, lecanemab) achieved regulatory approval, establishing a new treatment paradigm despite modest efficacy and risks of amyloid-related imaging abnormalities (ARIA). In Parkinson's disease, GLP-1 receptor agonists (lixisenatide) demonstrated the first convincing disease modification signals in Phase II trials. For multiple sclerosis, the failure of Bruton's tyrosine kinase (BTK) inhibitors contrasted with the consolidation of anti-CD20 therapies as the therapeutic standard, refined by innovations in dosing and delivery. Collectively, these findings herald a new era of disease-modifying therapy in neurology, though current gains remain limited and dependent on biomarker stratification and safety monitoring. The challenge ahead is translating these successes into accessible, sustainable clinical benefits.},
}

@article {pmid41317483,
year = {2025},
author = {Huang, T and Yu, JS and Keum, GC and Yang, HO},
title = {Dihydrotricetin from Euonymus hamiltonianus ameliorates neuroinflammation and exhibits neuroprotective effect in LPS-induced microglia.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118810},
doi = {10.1016/j.biopha.2025.118810},
pmid = {41317483},
issn = {1950-6007},
abstract = {Microglia cells are the initial immune cells regulating neuroinflammation response. Under neuro-degenerative conditions, microglia exhibit as an over-activated phenotype, which generate large amounts of cytokines and inflammatory mediators. Euonymus hamiltonianus Wall. (E. hamiltonianus) showed an effect of enhanced memory and cognitive abilities in Alzheimer Disease (AD) model in our previous research. However, it is remained unknown about the anti-inflammation effect of E. hamiltonianus behind the neurodegenerative situation. The aims of the research are clarifying the possible therapeutic effects and its active compound of E. hamiltonianus on neuro-inflammation on the central nervous system. By the activity guided isolation, dihydrotricetin (compound 1) was identified as an active compound with BV-2 microglia and NMR Spectroscopy. In BV-2 LPS-induced microglial cells, compound 1 inhibited the pro-inflammatory factors, including Prostaglandin E2 (PGE2), interleukin (IL)-6, tumor necrosis factor (TNF)-α, and nitrite oxide (NO) production. This suppressed the activation of microglia in LPS-injected mouse cortex. Besides, the research indicated that compound 1 inhibited PI3K/AKT/IκB/NF-κB and MAPK pathways, and further promoted the inhibition of NLRP3 signaling activation. This research determined that compound 1 is involved in the NRF2/HO-1 signaling and anti-oxidative activity. These data suggest that compound 1 can be a key regulator of microglial activation in LPS-induced neuro-inflammation in vivo and in vitro.},
}

@article {pmid41317273,
year = {2025},
author = {Li, HT and Zhang, JW and Li, BW and Wu, HY and Ge, JW and Wu, DH and Zhao, QL and Wang, YH},
title = {Screening and In Vivo Validation of Key Genes Involved in Myelin Damage in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {213},
pmid = {41317273},
issn = {1559-1182},
support = {82205064//Natural Science Foundation of China/ ; ZR2021QH110//Natural Science Foundation of Shandong Province/ ; },
mesh = {*Alzheimer Disease/genetics/pathology ; Animals ; *Myelin Sheath/pathology/metabolism/ultrastructure/genetics ; Signal Transduction/genetics ; Humans ; Glycogen Synthase Kinase 3 beta/metabolism ; Amyloid beta-Peptides/metabolism ; Insulin Receptor Substrate Proteins/metabolism/genetics ; Mice ; Male ; Proto-Oncogene Proteins c-akt/metabolism ; Reproducibility of Results ; Disease Models, Animal ; Mice, Inbred C57BL ; tau Proteins/metabolism ; Synapses/metabolism ; },
abstract = {Myelin sheath damage exacerbates cognitive deterioration in Alzheimer's disease (AD). This study identified 11 key genes related to myelin sheath damage between AD and control samples based on the GSE118553 dataset, and their expression was verified in the AD mouse model. Furthermore, the damage to myelin and synapses as well as the expression of the insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK3β) signaling pathway proteins were observed by transmission electron microscopy and molecular biology techniques. The results confirmed that the expression of 8 out of 11 key genes was downregulated in mice with AD, which showed amyloid β-protein (Aβ) deposition, tau hyperphosphorylation, myelin and synaptic damage, and an abnormal expression of IRS-1/PI3K/Akt/GSK3β signaling and glucose transporter1/3 (GLUT1/3). This study provides a basis for the in-depth exploration of the gene regulatory mechanisms of myelin sheath injury in AD.},
}

*Alzheimer Disease/genetics/pathology
Animals
*Myelin Sheath/pathology/metabolism/ultrastructure/genetics
Signal Transduction/genetics
Humans
Glycogen Synthase Kinase 3 beta/metabolism
Amyloid beta-Peptides/metabolism
Insulin Receptor Substrate Proteins/metabolism/genetics
Mice
Male
Proto-Oncogene Proteins c-akt/metabolism
Reproducibility of Results
Disease Models, Animal
Mice, Inbred C57BL
tau Proteins/metabolism
Synapses/metabolism

@article {pmid41317260,
year = {2025},
author = {Ebrahimi, R and Hatami, S and Hashempoor, A and Oraee, S and Salarvandian, S and Faramarzi, A and Esmaeilpour, K},
title = {Role of Mitochondrial Calcium Dysregulation in Alzheimer's Disease Pathogenesis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {214},
pmid = {41317260},
issn = {1559-1182},
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Mitochondria/metabolism/pathology ; *Calcium/metabolism ; Animals ; Calcium Signaling ; Amyloid beta-Peptides/metabolism ; },
abstract = {Mitochondrial calcium has emerged as a critical player in Alzheimer's disease (AD), closely linked to neuronal dysfunction and cognitive decline seen in patients. Intracellular calcium signaling is essential for processes like synaptic plasticity, neuronal survival, and differentiation. When this balance is disturbed, it can trigger early pathological changes in AD, including the accumulation of amyloid-β (Aβ) peptides and the development of neurofibrillary tangles (NFTs), the hallmark features of the disease. Calcium imbalance in mitochondria disrupts their function, leading to reduced adenosine triphosphate (ATP) production, increased reactive oxygen species (ROS), and ultimately neuronal death. Aβ and tau act synergistically to further disturb calcium regulation, intensifying neurodegeneration. Excess mitochondrial calcium is also linked to altered activity of key calcium transporters, such as the mitochondrial calcium uniporter (MCU) and sodium/calcium/lithium exchanger (NCLX). Moreover, several genetic risk factors for AD, including ApoE4, PS1, PS2, and CALHM1, are known to influence intracellular calcium homeostasis. Building on this, the present study investigates how calcium dysregulation impairs mitochondrial function in AD. Understanding the mechanisms of calcium-induced mitochondrial dysfunction and identifying potential targets to control mitochondrial calcium levels could provide valuable insights for developing therapies against AD and other neurodegenerative diseases.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Mitochondria/metabolism/pathology
*Calcium/metabolism
Animals
Calcium Signaling
Amyloid beta-Peptides/metabolism

@article {pmid41317215,
year = {2025},
author = {Mishra, J and Singh, C and Bhatti, JS},
title = {Neuroprotective Role of Piperine-Encapsulated Casein Micelles in Mitigating Intracellular Dyshomeostasis in Alzheimer's Disease Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {218},
pmid = {41317215},
issn = {1559-1182},
support = {IF4190498//DST-INSPIRE Fellowship/ ; EEQ/ 2020/000188//Science and Engineering Research Board/ ; },
mesh = {*Polyunsaturated Alkamides/pharmacology/administration & dosage/chemistry ; *Benzodioxoles/pharmacology/administration & dosage ; *Piperidines/pharmacology/administration & dosage ; *Alkaloids/pharmacology/administration & dosage/chemistry ; Humans ; *Micelles ; *Alzheimer Disease/pathology/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology ; Cell Line, Tumor ; *Caseins/chemistry ; Amyloid beta-Peptides/toxicity ; *Homeostasis/drug effects ; Oxidative Stress/drug effects ; Mitochondria/drug effects/metabolism ; Peptide Fragments/toxicity ; *Intracellular Space/metabolism/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; },
abstract = {Alzheimer's disease remains a complex neurodegenerative disorder characterized by multifactorial mechanisms that undermine the efficacy of monotherapeutic strategies. Multi-targeted therapies have emerged as promising strategies, particularly those addressing mitochondrial dysfunction, a key contributor to AD pathophysiology. This study explores the neuroprotective efficacy of piperine encapsulated casein micelles (PIP@CMs) against Aβ(1-42)-induced-neurotoxicity in differentiated SH-SY5Y cells, an established in vitro model of Alzheimer's pathology. The formulation was synthesized and characterized using techniques such as FTIR, DSC, PXRD, SEM, and TEM, confirming its physicochemical integrity and optimal surface morphology. Comprehensive physicochemical characterization confirmed the structural integrity and stability of PIP@CMs, which demonstrated a uniform particle size of 196.32 ± 5.70 nm, a negative zeta potential of -11.95 ± 6.08 mV, and a controlled release profile. Functional assays demonstrated that PIP@CMs exhibited superior antioxidant activity, mitigated oxidative stress, and restored mitochondrial homeostasis more effectively than free piperine. Key parameters, including intracellular ROS generation, calcium imbalance, mitochondrial superoxide levels, mitochondrial membrane potential, and expression profile of autophagy and mitophagy markers, were significantly improved in PIP@CMs-treated cells. Additionally, PIP@CMs provided dose-dependent protection against Aβ(1-42)-induced cytotoxicity and apoptosis. The findings suggest that PIP@CMs not only enhance the bioavailability of piperine but also amplify its neuroprotective effects through controlled drug release and targeted action on AD's pathological hallmarks. By combining piperine's neuroprotective properties with the enhanced delivery capabilities of casein micelles, this study provides a promising platform for developing effective AD treatments. However, the present study is limited by its exclusive reliance on in vitro cellular models without in vivo validation, which constrains direct clinical translation. Further investigations in relevant animal models are necessary to establish the pharmacokinetics, blood-brain barrier penetration, safety, and behavioral outcomes associated with PIP@CMs. Future research should also explore combinatorial approaches and extended nanocarrier applications to optimize therapeutic outcomes for neurodegenerative diseases.},
}

*Polyunsaturated Alkamides/pharmacology/administration & dosage/chemistry
*Benzodioxoles/pharmacology/administration & dosage
*Piperidines/pharmacology/administration & dosage
*Alkaloids/pharmacology/administration & dosage/chemistry
Humans
*Micelles
*Alzheimer Disease/pathology/drug therapy/metabolism
*Neuroprotective Agents/pharmacology
Cell Line, Tumor
*Caseins/chemistry
Amyloid beta-Peptides/toxicity
*Homeostasis/drug effects
Oxidative Stress/drug effects
Mitochondria/drug effects/metabolism
Peptide Fragments/toxicity
*Intracellular Space/metabolism/drug effects
Membrane Potential, Mitochondrial/drug effects
Reactive Oxygen Species/metabolism
Cell Survival/drug effects

@article {pmid41317211,
year = {2025},
author = {Zhang, Y and Hao, M and Li, Y and Cheng, K and Zhang, C},
title = {The Role of Thyroid Hormones in Neurodegenerative Disorders: Opportunities and Challenges.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {217},
pmid = {41317211},
issn = {1559-1182},
support = {2024SCZ21//Jilin Province Health Research Talents Special Project/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; *Thyroid Hormones/metabolism ; Animals ; },
abstract = {Thyroid hormone (TH) is crucial to maintaining nervous system's normal function and is essential for formation of dendrites, axons, and myelin sheaths of neurons, which form the basis for transmitting messages between neurons, and the deficiency of TH affects their development, which in turn affects nervous system's normal operation. Recent articles have found that TH deficiency or abnormal levels not only affect mood and cognitive function but are also closely related to the development of a series of neurodegenerative disorders, like Alzheimer's, Parkinson's and Huntington's diseases, along with multiple sclerosis. The pathologic mechanisms of such diseases are complex, and it is difficult to confirm clinical diagnosis, and there exists a shortage of valid therapies, which can greatly reduce patients' life quality once they develop. Therefore, a deep comprehension of TH mechanism in neurodegenerative disorders and exploring factors affecting its relationship with neurodegenerative disorders are of great clinical and research value. This article reviews the research progress in this field so far, analyzes the functional changes of TH in neurological pathological states, and explores its potential in clinical applications, aiming to provide new orientation for neurodegenerative disorders' future diagnosis and therapy, and thus for developing more valid therapeutic strategies.},
}

Humans
*Neurodegenerative Diseases/metabolism/pathology
*Thyroid Hormones/metabolism
Animals

@article {pmid41317176,
year = {2025},
author = {Pour, FT and Saadatpour, F and Salari, A},
title = {Comprehensive and In-Depth Molecular and Pathway Studies of the Hippocampus in Alzheimer's Disease.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {110},
pmid = {41317176},
issn = {1573-6830},
support = {CSBI14011102//Cognitive Science and Biology Institute (CSBI)/ ; SBNGC14011101//Systems Biology and Next Generation Company (SBNGC)/ ; },
mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; Humans ; *Hippocampus/metabolism/pathology ; Protein Interaction Maps/genetics ; *Signal Transduction/genetics ; Gene Regulatory Networks ; Gene Expression Profiling ; Male ; Gene Expression Regulation ; Female ; },
abstract = {Alzheimer's disease (AD) still lacks a conclusive treatment, largely due to an incomplete understanding of the molecular mechanisms involved. To enhance our knowledge of AD pathogenesis and identify potential therapeutic targets, this study integrates differential gene expression analysis, pathway enrichment, hub gene discovery, protein-protein interaction (PPI) clustering, and transcription factor/protein kinase regulation into a single, cohesive pipeline. This comprehensive systems-level approach moves beyond single-gene analyses to offer a broader, mechanistically focused insight into AD biology. Using RNA-seq data from the CA1 region of the hippocampus-a subregion selectively affected in early AD-we identified 1,104 differentially expressed genes (DEGs). Among the enriched pathways, "7-alpha-hydroxycholesterol" was upregulated, while "vacuolar organization" was downregulated in AD samples. Furthermore, five novel hub genes (MRPS7, RPL5, GFM1, RAD51, and ASPM) were identified within the PPI network. The first three-MRPS7, RPL5, and GFM1-along with ACO2 and MT-ATP6, are potentially linked to hereditary forms of AD due to their roles in mitochondrial function. We also discovered four collaborative clusters within the network that notably associated with the "inflammatory response", "7-alpha-hydroxycholesterol", "Mitochondrial dysfunction" and "Oxidative phosphorylation" pathways, making them promising candidates for therapeutic and diagnostic investigation due their behavioral information members. Additionally, we identified ten transcription factors (GATA2, CHD1, THRA, IRF7, ZBTB48, POLE4, ZNF219, SLC2A4RG, NR1D1, and RXRA) and one protein kinase (PRKCZ) as potential regulatory elements in AD. This study broadens our understanding of Alzheimer's disease by identifying five candidate hub genes, two functional PPI clusters, two signaling pathways, and eleven regulatory proteins, thereby laying the groundwork for future therapeutic and diagnostic developments in molecular AD research.},
}

*Alzheimer Disease/genetics/metabolism/pathology
Humans
*Hippocampus/metabolism/pathology
Protein Interaction Maps/genetics
*Signal Transduction/genetics
Gene Regulatory Networks
Gene Expression Profiling
Male
Gene Expression Regulation
Female

@article {pmid41317171,
year = {2025},
author = {Wang, CH and Chou, YC and Li, HY and Tseng, YT and Sun, YL and Jen, PC and Wang, SC and Chau, LK and Lu, CL and Chen, YL},
title = {Development of surface-enhanced Raman scattering nanoprobes for the simultaneous multiplex detection of characteristic DNA sequences: case studies of pathogenic Vibrio parahaemolyticus and Apolipoprotein E gene polymorphisms.},
journal = {Mikrochimica acta},
volume = {192},
number = {12},
pages = {865},
pmid = {41317171},
issn = {1436-5073},
support = {MOST 109-2123-M-194-001//National Science and Technology Council of Taiwan/ ; },
mesh = {*Vibrio parahaemolyticus/genetics/isolation & purification ; *Spectrum Analysis, Raman/methods ; *Apolipoproteins E/genetics ; Humans ; Limit of Detection ; Polymorphism, Single Nucleotide ; },
abstract = {Relying on a single biomarker in biomedical analysis is often insufficient for accurate disease or pathogen determination. A recent trend is using simultaneous multiplex detection of multiple biomarkers to improve diagnostic accuracy and throughput. To enable multiplex detection, we developed a series of surface-enhanced Raman scattering (SERS) nanoprobes, referred to as nanoaggregate-embedded beads (NAEBs). These NAEBs were synthesized using three distinct Raman reporter molecules: Safranin O, ethyl violet, and cresyl violet acetate. By integrating the NAEBs with magnetic nanoparticles and a simple capillary magnetofluidic device, we developed a rapid and simultaneous multiplex detection platform for genetic analysis of an aquacultural pathogen Vibrio parahaemolyticus (VP) for pirA, pirB, and ompA and genotyping of Alzheimer's disease's risk factor biomarker Apoliproprotein E (ApoE). For VP detection, a limit of detection (LOD) as low as ~ 10[-16] M and a broad dynamic range of six orders were found . For ApoE genotyping, the platform was capable of detecting single nucleotide polymorphisms (SNPs) of rs429358 and rs7412 in the ApoE gene with a LOD of approximately 10[-13] M. These results highlight the potential of this SERS-based simultaneous multiplex detection platform for sensitive and quantitative determination of multiple DNA biomarkers as well as SNPs in complex biological matrices.},
}

*Vibrio parahaemolyticus/genetics/isolation & purification
*Spectrum Analysis, Raman/methods
*Apolipoproteins E/genetics
Humans
Limit of Detection
Polymorphism, Single Nucleotide

@article {pmid41316897,
year = {2025},
author = {Sebastiani, P and Reed, E and Chandler, KB and Lopez, P and Lords, H and Bae, H and Costello, CE and Au, M and Deng, LL and Li, M and Xiang, Q and Noh, H and Pflieger, L and Funk, C and Rappaport, N and Nygaard, M and Short, MI and Brent, M and Monti, S and Andersen, SL and Perls, TT},
title = {A Robust Serum Proteomic Signature of the E2 Allele of Apolipoprotein E.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e09764},
doi = {10.1002/advs.202509764},
pmid = {41316897},
issn = {2198-3844},
support = {U19-AG023122//National Institutes of Health, NIA/ ; U19-AG063893//National Institutes of Health, NIA/ ; UH2-AG064704//National Institutes of Health, NIA/ ; R24-GM134210//National Institutes of Health, NIA/ ; S10-OD021728//National Institutes of Health, NIA/ ; R01-AG061844//National Institutes of Health, NIA/ ; },
abstract = {A signature of 16 serum proteins that were previously profiled using the aptamer-based Somascan technology highlighted the roles of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE) and in inflammation. Here, the serum protein signature of APOE is validated and expanded using a combination of mass-spectrometry, ELISA, Luminex, blood transcriptomics, and antibody-based Olink serum proteomics. Some of the findings were replicated in the UK Biobank using antibody-based Olink serum proteomics. This analysis replicated the association between APOB and the e2 allele of APOE, detected a new, robust pattern of association between APOE genotypes and the serum level of APOE, and discovered new associations between APOE genotypes and the complex of apolipoproteins APOC1, APOC2, APOC3, APOC4, APOE, APOF, and APOL1. In addition, 13 new proteins correlated with APOE genotypes. This extended signature includes granule proteins CAMP, CTSG, DEFA3, and MPO secreted from neutrophils and points to olfactomedin 4 (OLFM4) as a new target for the prevention of Alzheimer's disease.},
}

@article {pmid41316489,
year = {2025},
author = {Tkach, VV and Bager, NS and Michaelsen, SR and Litman, T and Josefsen, K and Kristensen, BW and Lund, EL and Areškevičiūtė, A},
title = {Combined neocortical protein and morphological profiling of reactive microglia across Alzheimer's and Creutzfeldt-Jakob disease.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {244},
pmid = {41316489},
issn = {2051-5960},
mesh = {Humans ; *Creutzfeldt-Jakob Syndrome/pathology/metabolism ; *Microglia/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; *Neocortex/pathology/metabolism ; Male ; Female ; Aged ; Aged, 80 and over ; Middle Aged ; Calcium-Binding Proteins ; Microfilament Proteins ; },
abstract = {Recent RNA-sequencing studies have established a reactive molecular signature and highlighted substantial regional diversity of microglia, underscoring their involvement in neurodegenerative proteinopathies. However, the implications of these findings have not been fully elucidated at the protein expression level in neuropathological settings, especially when comparing different proteinopathies. Using FFPE tissue from postmortem human brains with neuropathologically confirmed sporadic Creutzfeldt-Jakob disease, subtype MM1 (n = 5, formic acid-treated tissue), Alzheimer's disease, Braak stage VI (n = 5), and control brains with no noteworthy pathological changes (n = 2), we (1) verify the reactive microglial signature at the protein expression level utilizing spatial protein profiling, (2) detect a disease-specific amoeboid IBA1+ cell subtype identified with digital morphological profiling, and (3) determine the correlation between identified microglia protein expression profiles and morphology within each and across all brain sample groups. As proof-of-concept, the protein expression and morphology profiling modalities can be bioinformatically integrated to quantify the reactivity of analyzed IBA1+ cells when comparing different neocortical layers (superficial grey matter, deep grey matter, and white matter) and frontal and occipital neocortex across the different diseases. We observed greater microglial reactivity in Creutzfeldt-Jakob disease compared to Alzheimer's disease, and more remarkably, greater reactivity in occipital cortex compared to frontal cortex across both diseases. Both profiling modalities additionally revealed consistent molecular and morphological differences between grey matter and white matter IBA1+ cells, with similar distributional changes observed in the layers across both diseases. This study refines the understanding of canonical, disease-specific, and brain regional features of reactive microglia in two different neurodegenerative proteinopathies and demonstrates the successful application of spatial probe-based protein profiling together with digital morphological profiling on long-term fixed FFPE and even formic acid-treated human brain tissue.},
}

Humans
*Creutzfeldt-Jakob Syndrome/pathology/metabolism
*Microglia/pathology/metabolism
*Alzheimer Disease/pathology/metabolism
*Neocortex/pathology/metabolism
Male
Female
Aged
Aged, 80 and over
Middle Aged
Calcium-Binding Proteins
Microfilament Proteins

@article {pmid41316313,
year = {2025},
author = {Li, K and Qian, W and Wang, S and Sun, Z and Zeng, Q and Hong, H and Ge, Y and Luo, X and Wang, C and , },
title = {Characterizing choroid plexus cyst burden across the Alzheimer's disease continuum.},
journal = {Fluids and barriers of the CNS},
volume = {22},
number = {1},
pages = {122},
pmid = {41316313},
issn = {2045-8118},
abstract = {BACKGROUND: Choroid plexus (ChP) is responsible for producing cerebrospinal fluid, which is increasingly recognized as important in the context of aging and Alzheimer’ disease (AD). However, structural alteration (especially cystic alteration) of ChP across the pathologically confirmed AD continuum remains unclear.

MATERIALS AND METHODS: All data used in this study were drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Aβ and Tau PET were utilized to define the pathologically confirmed AD continuum. The number of ChP cysts on each side were counted and the largest cyst was delineated by experienced neuroradiologist using 3D T2-FLAIR images. The number of ChP cysts was further divided into four grades on each side according to the number of cysts (grade 0 = none, grade 1 = 1–5, grade 2 = 6–10, grade 3 > 10). Then, the ChP cysts rating and the largest cyst volume were compared among subjects across the pathologically confirmed AD continuum. Moreover, correlation analyses were conducted to assess the associations of cystic alteration of ChP with pathological biomarkers, and cognitive performance.

RESULTS: This study included 615 individuals (mean age, 73 years ± 7.7 [SD]; 349 [57%] female), including 259 CU cognitively unimpaired controls with negative Aβ and tau (CU A-T-), 126 CU with positive Aβ, 166 mild cognitive impairment with positive Aβ (MCI A+), and 64 AD with positive Aβ. We found that ChP cyst burden exhibited a stage-specific distribution across the AD continuum (p = 0.004), with MCI A + individuals showing prominent enrichment in Grade 2, while AD A + individuals were significantly overrepresented in Grade 1. The ChP cysts rating were positively associated with age (p < 0.001). Both the ChP cysts rating and largest ChP cyst volume were associated with enlarged perivascular spaces ratings (p < 0.05). The ChP cyst indices were significantly associated with amyloid (p < 0.05).

DISCUSSION: In addition to volume change, cystic alteration of the ChP may serve as a valuable neuroimaging biomarker for early diagnosing and disease progression monitoring on AD continuum.

CLINICAL TRIAL REGISTRATION: Not applicable.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12987-025-00729-7.},
}

@article {pmid41316284,
year = {2025},
author = {Chen, C and Mo, M and Åkerman, M and Garcia-Ptacek, S and Xu, H and Eriksdotter, M},
title = {Dynamic associations of cholinesterase inhibitors and memantine with cognitive trajectories in individuals with Alzheimer's or mixed dementia: a real-world analysis using the quality registry SveDem.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01918-0},
pmid = {41316284},
issn = {1758-9193},
}

@article {pmid41315874,
year = {2025},
author = {Butovsky, O and Rosenzweig, N and Kleemann, KL and Jorfi, M and Kuchroo, VK and Tanzi, RE and Weiner, HL},
title = {Immune dysfunction in Alzheimer disease.},
journal = {Nature reviews. Neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41315874},
issn = {1471-0048},
abstract = {Emerging evidence highlights the crucial role of peripheral immune cells in maintaining brain homeostasis and their influence on the pathology of Alzheimer disease (AD). Genome-wide association studies have identified numerous AD risk variants in genes expressed by immune cells, implicating innate and adaptive immune pathways in disease progression. Advances in neuroimmunology have revealed that immune cell crosstalk involving T cells, B cells, monocytes and/or macrophages and neutrophils can modulate the hallmark features of AD, including amyloid plaque accumulation, tau pathology and chronic neuroinflammation. Mechanistic insights suggest that chronic peripheral inflammation, immune exhaustion, metabolic dysfunction and epigenetic reprogramming exacerbate neurodegeneration in AD by promoting toxic inflammation and impairing protein clearance in the brain. These findings may catalyse the development of novel immunomodulatory strategies, such as immune checkpoint inhibition and cytokine targeting, among others, for AD. This Review examines peripheral immune alterations in AD, evaluates related therapeutic opportunities and highlights key knowledge gaps, particularly the need for human-derived data to advance translational progress. Future research should prioritize personalized approaches that integrate genetic risk, immune profiling and ageing to inform next-generation therapies for AD.},
}

@article {pmid41315858,
year = {2025},
author = {Brown, GC and St George-Hyslop, P and Paolicelli, RC and Lemke, G},
title = {Microglial phagocytosis in Alzheimer disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {41315858},
issn = {1759-4766},
abstract = {Accumulating evidence indicates that Alzheimer disease (AD) is caused by dysregulated microglial phagocytosis. The main risk factor for AD is age, and ageing reduces microglial phagocytosis of amyloid-β (Aβ) plaques, while increasing microglial phagocytosis of synapses and neurons. Most of the known genetic risk for AD can be linked to microglial phagocytosis, including ABCA1, ABI3, ACE, ADAM17, APOE, APP, BIN1, BLNK, CD2AP, CD33, CLU, CR1, CTSB, CTSH, EED, GRN, INPP5D, LILRB2, PICALM, PLCG2, PSEN1, PTK2B, SIGLEC11, SORL1, SPI1, TMEM106B and TREM2. Moreover, the only disease-modifying treatments for AD - anti-Aβ antibodies - work by increasing microglial phagocytosis of Aβ aggregates. Microglial phagocytosis of Aβ via TREM2, LRP1, CD33, TAM receptors and anti-Aβ antibodies appears to reduce AD pathology by pruning and compacting plaques, restricting subsequent tau pathology, whereas microglial phagocytosis of synapses and neurons seems detrimental in the later stages of AD, via complement, P2Y6 receptor and TREM2. However, the roles of microglial phagocytosis in AD are complex and multifaceted, and improved treatments are likely to require a deeper understanding of these roles.},
}

@article {pmid41315790,
year = {2025},
author = {Dong, D and Ahmed, W and Sagar, R and Boyd, RJ and Mahairaki, V},
title = {Mapping key mitochondrial genes in Alzheimer's disease through human tissue and iPSC derived neurons.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {42766},
pmid = {41315790},
issn = {2045-2322},
support = {RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Neurons/metabolism/pathology ; *Mitochondria/genetics/metabolism ; *Genes, Mitochondrial ; Oxidative Stress/genetics ; Gene Expression Profiling ; Gene Ontology ; Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition that has become a global health challenge due to an aging world population and no available effective treatment. Mitochondrial dysfunction plays a crucial role in the development of AD due to its critical role in neuronal survival and function. However, the specific mitochondrial genes and pathways involved in AD pathogenesis remain poorly defined. In this study, we incorporated seven AD human postmortem and three AD iPSC-derived neurons (iNs) gene expression datasets to identify mitochondria-related Differentially Expressed Genes (mitoDEGs) between AD and control. The Gene Ontology (GO) analysis is conducted to investigate the AD biological mechanisms, and a random forest model is developed to assess how well the key mitoDEGs differentiate AD and control groups. Through our analysis, we identified fourteen key mitochondria related genes that show significant dysregulation in both postmortem brain tissues and iNs derived from AD patients. These genes have strong connections to oxidative stress, indicating mitochondrial dysfunction plays a crucial role in Alzheimer's disease pathology. Our study identified the key genes and pathways as promising targets for future research and therapeutic interventions, highlighting the importance of mitigating oxidative stress and restoring mitochondrial function in AD.},
}

Humans
*Alzheimer Disease/genetics/pathology/metabolism
*Induced Pluripotent Stem Cells/metabolism/cytology
*Neurons/metabolism/pathology
*Mitochondria/genetics/metabolism
*Genes, Mitochondrial
Oxidative Stress/genetics
Gene Expression Profiling
Gene Ontology
Brain/metabolism/pathology

@article {pmid41315611,
year = {2025},
author = {Wang, G and Liu, S and Liu, G and Fan, N and Zhang, W and Dong, W and Yin, J},
title = {Abnormal glycosylation changes in brain tissue of kainic acid-induced epileptic rats.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-29690-z},
pmid = {41315611},
issn = {2045-2322},
support = {2024-BS-179//Doctoral research Foundation of Liaoning Province/ ; 32171280//National Nature Science Foundation of China Research Grant/ ; JCHZ2023013//Dalian Medical University Interdisciplinary Research Cooperation Project Team/ ; },
abstract = {Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. Despite significant progress in epilepsy research, about 30% of patients continue to experience uncontrolled seizures and clear diagnostic criteria remain elusive. Abnormal glycosylation contributes to various neurological disorders, including Alzheimer's and Parkinson's diseases. However, it is unclear whether protein glycosylation is altered in epilepsy. Herein, we established a chronic epilepsy rat model by injecting kainic acid solution into the right lateral ventricle and examined the changes in protein N-glycosylation and O-GlcNAcylation in rat brain tissues using mass spectrometry and lectin blotting. We found a significant reduction in complex N-glycan abundance in the hippocampal tissue of epileptic rats, which may be related to decreased MGAT1 expression. Additionally, we observed a marked decrease in protein O-GlcNAcylation, which may be associated with reduced levels of GFPT1, the rate-limiting enzyme in the hexosamine biosynthesis pathway. This research offers new insight into potential therapeutic strategies for epilepsy.},
}

@article {pmid41315531,
year = {2025},
author = {George, JC and Tipton, AE and Bonfa, NVS and Farb, DH and Russek, SJ},
title = {Age-dependent increases in dorsal hippocampal postsynaptic α5GABA-a receptors may be lost in a rat model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-28973-9},
pmid = {41315531},
issn = {2045-2322},
support = {NIGMS T32 GM008541, NIA R21AG056947, NIA R21AF061553-01//National Institutes of Health, United States/ ; NIA R21AG056947 NIH/NIA R21AF061553-01/NH/NIH HHS/United States ; },
}

@article {pmid41315482,
year = {2025},
author = {Park, S and Kim, K and Lim, KY and Na, DL and Kim, HJ and Jang, H and Kim, JP and Kang, SH and Yun, J and Chun, MY and Seo, SW and Kwak, K},
title = {Computed tomography-based nnU-Net for region-specific brain structural changes across the alzheimer's continuum and frontotemporal dementia subtypes.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {42597},
pmid = {41315482},
issn = {2045-2322},
support = {HU20C0111//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; NRF-2019R1A5A2027340//National Research Foundation of Korea/ ; 2021-ER1006-00//Research of Korea Disease Control and Prevention Agency/ ; },
mesh = {Humans ; *Frontotemporal Dementia/diagnostic imaging/pathology/cerebrospinal fluid ; *Alzheimer Disease/diagnostic imaging/pathology/cerebrospinal fluid ; Male ; Female ; Aged ; *Tomography, X-Ray Computed/methods ; *Brain/diagnostic imaging/pathology ; Middle Aged ; Magnetic Resonance Imaging ; Deep Learning ; Cognitive Dysfunction/diagnostic imaging/pathology ; Aged, 80 and over ; },
abstract = {Quantifying structural brain changes is critical for diagnosing and monitoring neurodegenerative diseases. Although magnetic resonance imaging (MRI) is the silver standard, limited accessibility and cost hamper routine use. We developed a deep learning-based framework using the nnU-Net for brain segmentation using computed tomography (CT) to assess cerebrospinal fluid (CSF) volume changes, as an indirect marker of tissue loss, and evaluated its utility across Alzheimer's disease (AD) stages and frontotemporal dementia (FTD) subtypes. We included 2357 participants: cognitively unimpaired (CU, n = 595), mild cognitive impairment (MCI, n = 954), dementia of Alzheimer's type (DAT, n = 663), and FTD subtypes (FTD, n = 145, behavioral variant FTD (bvFTD, n = 66), nonfluent variant primary progressive aphasia (nfvPPA, n = 29), and semantic variant PPA (svPPA, n = 50). CT-based segmentation was trained and validated using 3D T1-weighted MRI as reference. We assessed (1) segmentation accuracy via Dice similarity coefficients (DSCs), (2) reliability and precision using correlation and Bland-Altman analyses, and (3) clinical utility by identifying stage- and region-specific changes in CSF volumes. Key regions, including anterior and posterior lateral ventricles, showed DSCs above 0.93 and correlations ranging from 0.822 to 0.996. CT-based measurements revealed increasing CSF volumes from CU to DAT and distinct patterns of CSF volume enlargement across FTD subtypes. This framework enables accurate, reliable assessment of CSF volume changes as an indirect marker of atrophy, and supports early detection and differential diagnosis.},
}

Humans
*Frontotemporal Dementia/diagnostic imaging/pathology/cerebrospinal fluid
*Alzheimer Disease/diagnostic imaging/pathology/cerebrospinal fluid
Male
Female
Aged
*Tomography, X-Ray Computed/methods
*Brain/diagnostic imaging/pathology
Middle Aged
Magnetic Resonance Imaging
Deep Learning
Cognitive Dysfunction/diagnostic imaging/pathology
Aged, 80 and over

@article {pmid41315191,
year = {2025},
author = {Gao, R and Rao, S and Cheng, S and Gong, Z and Bu, B and Ba, L and Sun, X and Zhang, M},
title = {Assessing outer retinal and choroidal changes in scd: potential for high-risk screening using SS-OCTA.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-025-03781-x},
pmid = {41315191},
issn = {2158-3188},
abstract = {Subjective cognitive decline (SCD) serves as an initial symptom of preclinical Alzheimer's disease (AD). The accumulation of amyloid-beta (Aβ) is acknowledged as a critical risk factor for the eventual progression to mild cognitive impairment or dementia in individuals with SCD, highlighting the necessity for early detection and intervention. Previous studies have identified the retina and choriocapillaris as potential biomarkers for AD; however, these investigations have not thoroughly examined large and medium-sized choroidal vessels. Ultra-wide swept-source optical coherence tomography angiography (SS-OCTA), an innovative noninvasive imaging modality, facilitates rapid and precise quantitative assessment of retinal and choroidal boundaries and vasculature through dynamic scanning, encompassing large and medium-sized choroidal vessels. This study aims to characterize the outer retinal and choroidal vasculature and structure in individuals with SCD, examine the correlation between altered choroidal vasculature parameters and amyloid burden, and the presence of the apolipoprotein E (APOE) ε4 allele in SCD participants, to identify potential ocular biomarkers for high-risk SCD screening. In this study, 57 individuals with SCD and 45 matched normal controls were enrolled. Ultra-wide SS-OCTA was employed to assess the thickness of the outer retina and choroid and the blood flow within the choriocapillaris and large, medium-sized choroidal vessels. [18]F-Florbetapir positron emission tomography scans were performed to classify amyloid-positive-SCD (Aβ + SCD) and amyloid-negative-SCD (Aβ-SCD) groups. Plasma Aβ42/40 and APOE ε4 genotypes were also measured. Compared with normal controls, individuals with SCD exhibited a significant increase in the choroidal vessel index and a reduction in outer retinal thickness. The Aβ + SCD group demonstrated an elevated choriocapillaris flow area relative to the Aβ- SCD group. Moreover, a negative correlation was observed between the choriocapillaris flow area and plasma Aβ42/40 levels in the SCD cohort. Among SCD participants, APOE ε4 carriers displayed increased choriocapillaris flow area and choroidal vessel volume compared to APOE ε4 non-carriers. Our findings provide intriguing insights into the relationship between amyloid pathology and changes in the choriocapillaris flow area. The choroid may serve as a potential biomarker for screening Aβ + SCD.},
}

@article {pmid41315136,
year = {2025},
author = {Buzinova, VA and Johnson, CE and Turton, SM and Barth, SE and Padgett, S and Maisel, MT and Kohler, K and Whitlock, HR and Bachstetter, AD and Sunderam, S and O'Hara, BF and Duncan, MJ and Murphy, MP},
title = {Circadian rhythm of amyloid-β in the olfactory bulb and cerebellum of wild-type and APPxPS1 knock-in mice indicates a loss of rhythmicity in regions more vulnerable to amyloid pathology.},
journal = {Biogerontology},
volume = {27},
number = {1},
pages = {11},
pmid = {41315136},
issn = {1573-6768},
support = {AG078110//T32/ ; AG068215/NH/NIH HHS/United States ; },
mesh = {Animals ; *Circadian Rhythm/physiology ; *Olfactory Bulb/metabolism/pathology ; Male ; *Amyloid beta-Peptides/metabolism ; Female ; Mice, Transgenic ; Mice ; Gene Knock-In Techniques ; *Amyloid beta-Protein Precursor/genetics/metabolism ; *Cerebellum/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology/genetics ; Disease Models, Animal ; *Presenilin-1/genetics/metabolism ; Mice, Inbred C57BL ; },
abstract = {Amyloid-β (Aβ) plaques are one of the primary biomarkers of Alzheimer's Disease (AD). Other publications have reported various mechanisms regarding the clearance of Aβ, and recent studies have also investigated the relationship between daily rhythms of Aβ and AD. The intent of this study was to determine if the circadian rhythm of Aβ differed between a region that was more vulnerable to AD-related pathology (the olfactory bulbs; OB) compared to a region that is less vulnerable (the cerebellum; CER). We chose to utilize an APPxPS1 knock-in (KI) mouse strain as this strain expresses amyloid precursor protein (APP) and Aβ under control of its normal promoter as opposed to AD transgenic models that overexpress APP and, as a consequence, Aβ. Mice (N = 128, equally divided between male and female, wild type and KI) were acclimated to a 12:12 light cycle for two weeks, and tissue was collected over a 24-h period in constant darkness. Using a unique immunoassay designed to measure human or rodent Aβ side-by-side, we confirmed a robust circadian Aβ rhythm in the mouse brain and that the OB contains more overall Aβ accumulation than the CER. The circadian Aβ rhythm was not present in the OB of the KI as compared to the WT mice. In contrast, the Aβ rhythm in the CER did not differ between genotypes. These results suggest that the loss of Aβ rhythm in disease-affected brain regions may be associated with the development of AD pathology and could have important implications for therapy.},
}

Animals
*Circadian Rhythm/physiology
*Olfactory Bulb/metabolism/pathology
Male
*Amyloid beta-Peptides/metabolism
Female
Mice, Transgenic
Mice
Gene Knock-In Techniques
*Amyloid beta-Protein Precursor/genetics/metabolism
*Cerebellum/metabolism/pathology
*Alzheimer Disease/metabolism/pathology/genetics
Disease Models, Animal
*Presenilin-1/genetics/metabolism
Mice, Inbred C57BL

@article {pmid41315132,
year = {2025},
author = {Lumsden, AL and Mulugeta, A and Hyppönen, E},
title = {Dementia risk across distinct metabolic profiles in the UK Biobank.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41315132},
issn = {2509-2723},
support = {GNT1157281//National Health and Medical Research Council/ ; MRF2007431//Medical Research Future Fund (AU)/ ; },
abstract = {Sub-optimal metabolism is linked to dementia risk, yet metabolic traits rarely occur in isolation. Using data from 308,019 UK Biobank participants, we examined associations of six diverse metabolic subgroups (I-VI) - previously derived via a self-organising map (SOM) that captures patterns of co-occurring metabolic biomarker traits in the population - and 39 individual biomarkers, with incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD). Biomarker associations were assessed using both linear and nonlinear (restricted cubic spline) models. After adjusting for age, sex, socioeconomic, and lifestyle factors, subgroup analyses showed that participants in the two leanest and two most adipose subgroups had higher risk of dementia outcomes compared to others. Subgroups with high adiposity exhibited elevated VaD risk, which was linked to hypertension, hyperglycaemia, and liver stress (Subgroup II); inflammation, microalbuminuria, and low apolipoprotein A1 (III). For AD, the risk was elevated in the lean subgroups (IV, V), characterised by low body mass index (BMI), triglycerides, and urate, and high sex-hormone binding globulin; as well as for adipose Subgroup II. APOE-ε4 allele count had limited influence on dementia associations with metabolic subgroups and biomarkers. This marked metabolic heterogeneity in dementia risk suggests that metabolic profiling could inform targeted prevention strategies. Interpretation of these findings is supported by previously reported MRI profiles of the metabolic subgroups, providing biological context.},
}

@article {pmid41315049,
year = {2025},
author = {Bolton, CJ and Zhang, P and Wilhoite, SR and Moore, EE and Houston, ML and Pechman, KR and Dumitrescu, L and Peterson, A and Khan, OA and Liu, D and Gifford, KA and Blennow, K and Hohman, TJ and Zetterberg, H and Jefferson, AL},
title = {Increased neuroplastic activity in the pathogenesis of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70897},
doi = {10.1002/alz.70897},
pmid = {41315049},
issn = {1552-5279},
support = {IIRG-08-88733/ALZ/Alzheimer's Association/United States ; P20-AG068082/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/genetics/physiopathology/pathology ; Female ; Male ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; *GAP-43 Protein/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; *Neuronal Plasticity/physiology ; Biomarkers/cerebrospinal fluid ; Cross-Sectional Studies ; Longitudinal Studies ; Peptide Fragments/cerebrospinal fluid ; Aged, 80 and over ; Risk Factors ; Middle Aged ; Cognitive Dysfunction/cerebrospinal fluid ; Apolipoprotein E4/genetics ; },
abstract = {INTRODUCTION: We test the hypothesis that high levels of neuroplasticity in the context of Alzheimer's disease (AD) risk factors are involved in AD pathogenesis by investigating interactions between cerebrospinal fluid (CSF) levels of growth-associated protein-43 (GAP-43) and AD risk factors (female sex, cerebrovascular risk, mild cognitive impairment, apolipoprotein E [APOE] ε4 genotype, amyloid positivity) on CSF biomarkers of AD pathology (amyloid beta 42/40[Aβ42/40], phosphorylated tau (p-tau)) and neurodegeneration (tau).

METHODS: Baseline GAP-43 levels in 161 non-demented older adults were related to cross-sectional and longitudinal (mean follow-up = 4 years) CSF biomarkers of AD, adjusting for covariates, with GAP-43 x AD risk factor interaction terms.

RESULTS: Higher GAP-43 was cross-sectionally related to all AD biomarkers (p-values < 0.0001) and predicted longitudinal reductions in Aβ42 (p < 0.0001). Associations were stronger in AD risk groups.

DISCUSSION: We found strong support linking increased levels of neuroplasticity in the context of AD risk factors to the pathological cascade of AD over a 4-year mean follow-up period.

HIGHLIGHTS: Cerebrospinal fluid growth-associated protein-43 (GAP-43) is associated with Alzheimer's disease (AD) biomarkers cross-sectionally and longitudinally. GAP-43 interacts with AD risk factors to predict AD biomarkers. Increased neuroplastic activity may play a role in AD pathogenesis.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/genetics/physiopathology/pathology
Female
Male
Aged
Amyloid beta-Peptides/cerebrospinal fluid
*GAP-43 Protein/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
*Neuronal Plasticity/physiology
Biomarkers/cerebrospinal fluid
Cross-Sectional Studies
Longitudinal Studies
Peptide Fragments/cerebrospinal fluid
Aged, 80 and over
Risk Factors
Middle Aged
Cognitive Dysfunction/cerebrospinal fluid
Apolipoprotein E4/genetics

@article {pmid41314835,
year = {2025},
author = {Murad-Kassam, S and O'Rourke, HM and Hunter, K and Tate, K and Salma, J},
title = {Exploring the hospitalisation experience of racialised older adults and caregivers living with dementia: a scoping review protocol.},
journal = {BMJ open},
volume = {15},
number = {11},
pages = {e096069},
doi = {10.1136/bmjopen-2024-096069},
pmid = {41314835},
issn = {2044-6055},
mesh = {Humans ; Scoping Review as Topic ; *Dementia/therapy/psychology/ethnology ; *Caregivers/psychology ; *Hospitalization/statistics & numerical data ; Aged ; Research Design ; Quality of Life ; *Racism ; },
abstract = {INTRODUCTION: Racialised older adults living with dementia face various challenges and barriers in receiving culturally sensitive care in hospital settings. Stigma, discrimination and healthcare provider bias toward racialised older adults living with dementia infringe on their right to access quality care services in acute hospital settings and can negatively affect their quality of life. Despite the growing need to integrate culturally sensitive dementia care into acute hospital care, little research has been done in this area. Therefore, the aim of this scoping review is to summarise and map what is known about the hospitalisation experience of racialised older adults with dementia in receiving care and identify research gaps.

METHOD AND ANALYSIS: We will use Arksey and O'Malley's framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist to conduct and write the review. The search strategy will use keywords and index terms across selected databases: Google Scholar, PubMed, Scopus, Medline, PsycINFO and Cumulative Index for Nursing and Allied Health Literature, and hand-searching the reference lists from chosen literature. Grey literature will be searched using Google and the Alzheimer Society websites to find further evidence and literature. Two researchers will screen the titles and abstracts independently by referring to the inclusion criteria. Data from the extracted studies will be reported in tabular and narrative form that answer the scoping review's questions. Research gaps and recommendations for future research will be identified and summarised. The review's results will be shared with stakeholders, policymakers, healthcare professionals and community organisations working with the racialised community and dementia care.

ETHICS AND DISSEMINATION: This scoping review does not require ethics approval because it collects data from publicly available resources. The results will be disseminated through peer-reviewed scientific journals, professional conferences and with community organisations and healthcare providers.

REGISTRATION DETAILS: This review is registered in the Open Science Framework registration link: osf.io/7rfje.},
}

Humans
Scoping Review as Topic
*Dementia/therapy/psychology/ethnology
*Caregivers/psychology
*Hospitalization/statistics & numerical data
Aged
Research Design
Quality of Life
*Racism

@article {pmid41314755,
year = {2025},
author = {Roy, K and Syed, M and Narad, P and Sengupta, A},
title = {Genetic and epigenetic drivers of neurodegenerative disorders.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {53-130},
doi = {10.1016/bs.pbr.2025.08.002},
pmid = {41314755},
issn = {1875-7855},
mesh = {Humans ; *Neurodegenerative Diseases/genetics ; *Epigenesis, Genetic/genetics ; Animals ; },
abstract = {Neurodegenerative illnesses such as Alzheimer's disease, Parkinson's disease, and Huntington's disease present with increasing neurodegeneration and derangement. Genomic mutations and epigenetic changes are known to be part of their causation. This particular chapter discusses the key genetic factors like APP, SNCA, HTT, and C9orf72 mutations that influence the development and course of the disease. Furthermore, we examine epigenetic mechanisms-DNA methylation, histone modification, and non-coding RNAs-that regulate gene expression and contribute to neuronal susceptibility. The discussion also focuses on environmental and behavioral factors that affect the epigenome, highlighting gene-environment interactions. Advancements in omics technology and integrative studies have enhanced comprehension of biological pathways and uncovered novel biomarkers and therapeutic targets. The chapter therefore integrates epigenetic and genetic viewpoints to elucidate the intricate regulatory processes responsible for neurodegeneration and highlights potential avenues for early diagnosis, precision medicine, and therapeutic interventions aimed at remodeling disease pathways.},
}

Humans
*Neurodegenerative Diseases/genetics
*Epigenesis, Genetic/genetics
Animals

@article {pmid41314754,
year = {2025},
author = {Jana, MK and Swarup, V and Tripathy, S and Gupta, NM and Chatla, SS and Joshi, D and Mandal, S and Giri, A and Jana, S and Narayan, M and Maiti, SB and Das, S},
title = {Future horizons: Innovation, aging, and equity.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {427-468},
doi = {10.1016/bs.pbr.2025.08.010},
pmid = {41314754},
issn = {1875-7855},
mesh = {Humans ; *Aging ; *Precision Medicine/trends/methods ; *Neurodegenerative Diseases/therapy/diagnosis ; Artificial Intelligence ; },
abstract = {Precision medicine is on the verge of transforming the treatment of neurodegenerative diseases (NDDs) like Alzheimer's disease (AD) and Parkinson's disease (PD), in response to the intricate interactions of genetic, epigenetic, environmental, and lifestyle factors underlying disease heterogeneity. As the world's aging populations grow, with dementia cases expected to double by 2040 and the costs amounting to over €130 billion a year in Europe alone, there is an urgent need for novel strategies to stem the socioeconomic costs of NDDs. Conventional "one-drug-fits-all" strategies that depend on late-stage symptom treatment are progressively insufficient for disorders that are marked by heterogeneous molecular pathways and unpredictable clinical courses. Recent improvements in artificial intelligence (AI), multi-omics integration, and biomarker research now allow patients to be stratified into subpopulations following their genetic risk profiles, neuroimaging signatures, and fluid biomarkers (e.g., amyloid-beta, tau, α-synuclein), enabling early diagnosis and focused treatments. For example, artificial intelligence platforms such as the IHI-PROMINENT project are creating forecasting algorithms to chart disease progression and tailor treatment outcomes, and gene therapy and antisense oligonucleotides (ASOs) address precise mutations in familial AD and PD. These advances are supported by pharmacogenomics, which individualizes drug regimens according to metabolic profiles to reduce side effects and maximize efficacy. Still, translating these advances into practice has major barriers to overcome, such as large-scale biomarker validation, multi-omics standardization, and incorporating real-world evidence from digital health technologies. Aging populations only add complexity to this environment, as comorbidities like diabetes and cardiovascular diseases interact with neurodegenerative pathways, requiring system-based, holistic approaches to care. Equity is still a key challenge: differences in access to sophisticated diagnostics (e.g., PET scans, CSF examination) and expensive therapies (e.g., monoclonal antibodies, CAR-T cell therapy) threaten to worsen global health disparities. In retaliation, initiatives such as the JPND research paradigm advance remote clinical trials and telemedicine platforms for the diverse community in decentralized settings, and policies target reducing financial disincentives through risk-sharing strategies and public-private partnerships. Precision medicine in the treatment of NDDs depends on an integrated network among academia, clinics, and industry, by taking advantage of communal biobanks and AI-enabled big data analysis, for refining the drug development process and validating new targets, e.g., neuroinflammatory signaling and gut-brain axis dysfunction. Innovations, like CRISPR-mediated editing and ambient neuroimaging, have innate or potential power to personalize treatment by identifying early-stage and even pre-symptomatic patients and modulating one's lifestyle in light of genetic risk. However ethical considerations around data privacy, algorithmic bias, and informed consent for Sustained therapeutic interventions over a lifetime should guide, not lag, the transformation. With the drive toward preventive rather than delayed care, precision medicine represents a revolutionary paradigm shift in health care, and a possibility to convert NDDs from devastatingly fatal diagnoses to easily managed chronic diseases and render equitable access to innovations possible for the masses. Success will require consistent investment in translational studies, interdisciplinary training, and global regulatory harmonization to translate the promise of precision medicine into tangible improvements in the quality of life for the millions of individuals afflicted with neurodegenerative disorders.},
}

Humans
*Aging
*Precision Medicine/trends/methods
*Neurodegenerative Diseases/therapy/diagnosis
Artificial Intelligence

@article {pmid41314753,
year = {2025},
author = {Jana, MK and Mukherjee, P and Chatla, SS and Sharma, P and Mistry, J and Swarup, V and Srivastava, AK and Das, S and Gupta, NM and Ahuja, A and Samanta, S and Narayan, M},
title = {Global case studies and collaborative frameworks.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {377-426},
doi = {10.1016/bs.pbr.2025.08.013},
pmid = {41314753},
issn = {1875-7855},
mesh = {Humans ; *Neurodegenerative Diseases/therapy/diagnosis ; *Biomedical Research ; *International Cooperation ; },
abstract = {As neurodegenerative diseases (NDDs) like Alzheimer's and Parkinson's continue to rise globally, the need for cross-border collaboration in research and treatment has never been more critical. This chapter explores prominent global case studies and collaborative frameworks that exemplify how united efforts are transforming the landscape of NDD research. By pooling expertise, data, and resources, international initiatives are accelerating discoveries in early diagnosis, biomarker identification, and personalized therapies. Highlighting landmark consortia such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n.d.), Parkinson's Progression Markers Initiative (PPMI), and emerging multi-omics collaborations, the chapter illustrates how these partnerships overcome the complexity and heterogeneity of NDDs. It delves into technological innovations like artificial intelligence, blockchain data sharing, and real-time patient monitoring, which empower researchers and clinicians to connect genetic, environmental, and lifestyle factors in a holistic manner. Ethical considerations and data privacy frameworks are underscored as pivotal to fostering trust among participants and bridging disparities between regions with varying access to precision medicine. The chapter also sheds light on successful public-private partnerships and patient-focused global networks that place individuals at the center of discovery and care. Challenges such as standardizing protocols across countries, navigating legal frameworks, and securing sustainable funding are discussed alongside future directions for expanding collaborative reach. Ultimately, this comprehensive overview conveys the unprecedented promise held by global cooperation in combating neurodegenerative diseases-offering hope for improved diagnostics, innovative treatments, and enhanced quality of life for millions worldwide.},
}

Humans
*Neurodegenerative Diseases/therapy/diagnosis
*Biomedical Research
*International Cooperation

@article {pmid41314749,
year = {2025},
author = {Priyanka, S and Manjari, T and Hemalatha, S and Ambika, S and Yılmaz, B and Aktürk, B and Arısan, ED and Kumari, A and Manojkumar, Y},
title = {Precision therapeutics for Alzheimer's disease.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {247-276},
doi = {10.1016/bs.pbr.2025.08.011},
pmid = {41314749},
issn = {1875-7855},
mesh = {Humans ; *Alzheimer Disease/therapy/genetics/drug therapy ; *Precision Medicine/methods ; Animals ; },
abstract = {Despite extensive research, Alzheimer's disease (AD) a progressive neurodegenerative disorder marked by cognitive decline, neuronal loss, and the build-up of amyloid-beta plaques and tau tangles continues to lack effective treatments. Precision medicine presents a promising shift by customizing interventions to an individual's genetic, molecular, and lifestyle profile. This chapter explores key advancements in precision therapeutics for AD, including biomarker-driven therapies, pharmacogenomics, and targeted disease-modifying agents such as monoclonal antibodies. Recent innovations, including RNA-based therapeutics, stem cell approaches, and CRISPR-mediated gene editing, are also discussed. While precision medicine holds immense promise, challenges in clinical translation, patient stratification, and regulatory pathways must be addressed. By bridging cutting-edge research with clinical applications, this chapter provides insights into the evolving landscape of individualized treatment strategies for AD.},
}

Humans
*Alzheimer Disease/therapy/genetics/drug therapy
*Precision Medicine/methods
Animals

@article {pmid41314748,
year = {2025},
author = {Quadri, SN and Tiwari, S and Siddiqi, B and Fatima, S and Khan, MA and Abdin, MZ},
title = {Advanced neuroimaging in precision neurology: Tools, trends, and translational impact.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {221-246},
doi = {10.1016/bs.pbr.2025.08.005},
pmid = {41314748},
issn = {1875-7855},
mesh = {Humans ; *Neuroimaging/methods/trends ; *Neurodegenerative Diseases/diagnostic imaging ; *Precision Medicine/methods/trends ; Translational Research, Biomedical ; *Neurology/methods/trends ; Artificial Intelligence ; Machine Learning ; },
abstract = {Advances in neuroimaging are revolutionizing the landscape of precision neurology by enabling high-resolution, multimodal visualization of brain structure, function, and pathology. As traditional, symptom-based frameworks fall short in capturing the biological complexity of neurodegenerative diseases, imaging modalities such as structural MRI, diffusion tensor imaging, functional MRI, PET, and hybrid PET/MRI have emerged as essential tools for early diagnosis, patient stratification, and therapeutic monitoring. These technologies not only reveal hallmark features like hippocampal atrophy and disrupted neural networks but also uncover molecular signatures such as amyloid and tau deposition, synaptic density, and neuroinflammation. Integration with artificial intelligence (AI) and machine learning (ML) further enhances diagnostic precision by decoding subtle imaging patterns, facilitating subtype classification, and predicting disease progression. Despite transformative progress, disparities in access and implementation remain a critical challenge, particularly in low- and middle-income countries. This chapter provides a comprehensive overview of neuroimaging modalities, their diagnostic and prognostic relevance across major neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, ALS, and frontotemporal dementia and the evolving role of hybrid platforms and AI integration in shaping the future of individualized neurological care.},
}

Humans
*Neuroimaging/methods/trends
*Neurodegenerative Diseases/diagnostic imaging
*Precision Medicine/methods/trends
Translational Research, Biomedical
*Neurology/methods/trends
Artificial Intelligence
Machine Learning

@article {pmid41314746,
year = {2025},
author = {Ceballos, MWG and Sy, FFA and Akbar, A and Taofiq, A},
title = {Multi-omics integration in disease research.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {155-189},
doi = {10.1016/bs.pbr.2025.08.012},
pmid = {41314746},
issn = {1875-7855},
mesh = {Humans ; *Neurodegenerative Diseases/genetics/metabolism ; *Proteomics/methods ; *Genomics/methods ; *Metabolomics/methods ; Animals ; Multiomics ; },
abstract = {Neurodegenerative diseases, marked by complex molecular mechanisms and diverse clinical features, challenge conventional research approaches. This chapter emphasizes the value of multi-omics integration in understanding the biology of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Genomic studies reveal risk variants such as APOE ε4 in Alzheimer's and rare mutations in familial forms. Transcriptomics highlights gene expression changes, including synaptic dysfunction in early Parkinson's and alternative splicing errors in TARDBP-related ALS. Proteomics identifies key protein aggregates like amyloid beta and alpha-synuclein, along with modifications such as hyperphosphorylated tau that correlate with cognitive decline. Metabolomics uncovers metabolic alterations, including mitochondrial dysfunction in Parkinson's and lipid peroxidation in ALS, which contribute to disease progression. By combining these layers with high-throughput tools like single-cell sequencing, spatial transcriptomics, and mass spectrometry, researchers can reconstruct molecular networks linking genetic risk, gene regulation, protein dysfunction, and metabolic imbalance. This approach enables patient stratification into molecular subtypes, such as neuroinflammatory clusters defined by microglial gene signatures and cytokine expression. Biomarkers from blood and cerebrospinal fluid allow for minimally invasive disease monitoring. Despite challenges such as data heterogeneity and limited standardization, multi-omics approaches support biomarker discovery and therapeutic development. Integrating these datasets with neuroimaging and digital tools enhances diagnostic precision and guides targeted interventions, such as antisense therapies for SOD1-linked ALS. Multi-omics integration is thus a critical foundation for advancing personalized strategies in neurodegenerative disease research.},
}

Humans
*Neurodegenerative Diseases/genetics/metabolism
*Proteomics/methods
*Genomics/methods
*Metabolomics/methods
Animals
Multiomics

@article {pmid41314745,
year = {2025},
author = {Fatima, S and Tiwari, S and Siddiqi, B and Quadri, SN and Abdin, MZ},
title = {Biomarkers: From early detection to treatment personalization.},
journal = {Progress in brain research},
volume = {297},
number = {},
pages = {131-153},
doi = {10.1016/bs.pbr.2025.08.008},
pmid = {41314745},
issn = {1875-7855},
mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/therapy/metabolism ; *Precision Medicine/methods ; Early Diagnosis ; },
abstract = {Neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), present increasing issues associated with the unavoidable aging of the world's population. These challenges are further highlighted by the socioeconomic consequences of these diseases. The identification and use of biomarkers for prompt diagnosis, careful observation, and efficient treatment approaches is essential to overcoming these obstacles. The primary methods for diagnosing neurodegenerative illnesses are invasive procedures like lumbar punctures to measure CSF fluid or functional brain imaging methods. Biomarkers for underlying proteinopathy in blood serum and cerebral fluid have been the focus of recent biological research, particularly in vivo. With their ability to provide novel pathways for early detection, illness progression tracking, and individualized treatment plans, biomarkers have become essential instruments in precision medicine. The classification of biomarkers including fluid, digital imaging, and molecular biomarkers is examined in this chapter, with an emphasis on their function in neurodegenerative diseases. In neurodegenerative illnesses and the aging brain, tau, amyloid-β, α-synuclein, and TDP-43 are commonly seen to be deposited together rather than separately. These may be disregarded, and it might be challenging to determine their clinicopathological significance. An overview of illness pathophysiology, diagnostic implications, and the most recent molecular and ultrastructural categories for neurodegenerative disorders are given in this chapter. Addressing these issues through interdisciplinary research and technological advancements will be crucial for the future of biomarker-driven precision medicine. This chapter provides an in-depth overview of the evolving landscape of biomarkers and their transformative impact on the early detection and personalized treatment of neurodegenerative diseases.},
}

Humans
*Biomarkers/metabolism
*Neurodegenerative Diseases/diagnosis/therapy/metabolism
*Precision Medicine/methods
Early Diagnosis