@article {pmid41051912,
year = {2025},
author = {Hickman, LB and Pandey, B and Fish, A and Bandla, M and Husein, A and Allas, C and Kottakota, H and Herzog, L and Vossel, K and Stern, JM},
title = {Late-onset epilepsy of unknown etiology is more treatment-responsive than acquired lesional late-onset epilepsy.},
journal = {Epilepsia open},
volume = {},
number = {},
pages = {},
doi = {10.1002/epi4.70156},
pmid = {41051912},
issn = {2470-9239},
support = {UE5 NS065723-16/NS/NINDS NIH HHS/United States ; R01 NS033310/NS/NINDS NIH HHS/United States ; R01 AG058820/NS/NINDS NIH HHS/United States ; R01 AG075955/NS/NINDS NIH HHS/United States ; R56 AG074473/NS/NINDS NIH HHS/United States ; UH2 AG083254/NS/NINDS NIH HHS/United States ; },
abstract = {OBJECTIVE: Late-onset epilepsy of unknown etiology (LOEU) carries an elevated risk of dementia, suggesting that it may represent an early manifestation of neurodegenerative or cerebrovascular disease. Direct comparisons between LOEU and acquired lesional late-onset epilepsy (LOE) may elucidate clinical features specific to LOEU.

METHODS: We performed a retrospective chart review of patients with LOE, with first documented seizure at age 55 or older, whose evaluation included an epilepsy-protocol brain MRI and/or inpatient video-EEG evaluation. Etiology was determined from neuroimaging lesions and medical history. Patients without an identified etiology were categorized as LOEU. Analyses were performed controlling for sex, age of onset, and epilepsy duration.

RESULTS: We identified 75 LOEU (mean onset: 64.9 years, 38.7% female) and 57 acquired lesional LOE cases with etiologies including cortical stroke, hemorrhage, neoplasm, trauma, or infection (mean onset: 66.5 years, 36.8% female). LOEU was less likely to have a history of status epilepticus (6.7% vs. 21.1%, aOR: 0.28, p < 0.03) or to have undergone inpatient video-EEG monitoring (13.3% vs. 24.6%, aOR: 0.34, p < 0.04). LOEU was prescribed fewer ASMs compared to acquired lesional LOE (aOR: 0.43, p < 0.02), and LOEU patients prescribed multiple ASMs had lower average 12-month seizure frequency than acquired lesional LOE (median: 0.2 vs. 1.0, p < 0.01). LOEU had lower rates of vascular comorbidities than acquired lesional LOE, though rates of subsequent dementia were not significantly different (5-year risk: 16.6% vs. 17.7%). An exploratory cluster analysis demonstrated an LOEU subgroup with older onset, higher prevalence of white matter hyperintensities, cerebral atrophy, epileptiform discharges, and greater epilepsy severity.

SIGNIFICANCE: LOEU was associated with fewer proxies for epilepsy severity, signifying that LOEU is more often treatment-responsive than acquired lesional LOE. LOEU has lower rates of comorbid vascular disease compared to acquired lesional LOE, suggesting that occult cerebrovascular disease is not overrepresented in LOEU relative to other forms of LOE.

PLAIN LANGUAGE SUMMARY: People who develop epilepsy after age 55 without a known cause usually respond well to treatment and need fewer antiseizure medications than people with epilepsy from a known brain injury. In this study, they had fewer hospital stays for seizure monitoring and fewer vascular problems. Dementia risk was high in patients with late-onset epilepsy, both when the cause was known and when it was unknown. Late-onset epilepsy without a known cause is often less severe but still needs regular monitoring for memory and thinking problems.},
}

@article {pmid41051722,
year = {2025},
author = {Mohan Kumar, D and Talwar, P},
title = {Amyloid-β, Tau, and α-Synuclein Protein Interactomes as Therapeutic Targets in Neurodegenerative Diseases.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {84},
pmid = {41051722},
issn = {1573-6830},
support = {SG20240107//Vellore Institute of Technology, Vellore, India/ ; },
mesh = {*tau Proteins/metabolism ; *alpha-Synuclein/metabolism ; Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Amyloid beta-Peptides/metabolism ; Protein Interaction Maps ; },
abstract = {Alzheimer's and Parkinson's disease are the most prevalent neurological diseases. Amyloid-β, tau, and α-synuclein proteins are known to be implicated in neurodegenerative disease (NDD). Elucidation of precise therapeutic targets remains a challenge. Therefore, the identification of interactomes of amyloid-β precursor protein (APP), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) proteins is of great interest, aimed at unraveling novel targets. An integrated analysis was employed to identify direct interactors as therapeutic targets, considering protein-protein interactions and subsequent network analysis. Further, it was proposed to identify hub proteins, intended targets, regulatory factors, disease-gene associations, functional enrichment analyses of the protein interactors interfered with gene ontologies and disease-driving pathways. Protein interactome centered on APP, MAPT, and SNCA identified the top hundred high-confidence protein-protein interactions that revealed BACE1, PSEN1, SORL1, GSK3B, CDK5, SNCAIP, PRKN, and APOE as physical and functional protein interactors. The top ten hub proteins were ranked based on multiple centrality measures and topological algorithms. Further, the integrated network of all three protein interactomes contained distinct nodes with edges. Interestingly, regulatory mechanisms have revealed possible regulatory modules, including cleavage, phosphorylation, and ubiquitination. Top interacting proteins were enriched in several ontology terms, such as regulation of neuronal apoptotic processes, amyloid beta fibril formation, and tau protein binding. Pathway analysis mapped the pathways of neurodegeneration-multiple disease, with a significant level of interacting proteins. Finally, the most comprehensive interactome associated with NDD provides insights into protein interactors, regulating the mechanisms of key proteins that can serve as novel therapeutic targets.},
}

*tau Proteins/metabolism
*alpha-Synuclein/metabolism
Humans
*Neurodegenerative Diseases/metabolism/drug therapy
*Amyloid beta-Peptides/metabolism
Protein Interaction Maps

@article {pmid41051689,
year = {2025},
author = {Azam, HMH and Mumtaz, M and Rödiger, S and Schierack, P and Hussain, N and Aisha, A},
title = {MicroRNAs in neurodegenerative diseases: from molecular mechanisms to clinical biomarkers, detection methods and therapeutic strategies-advances and challenges.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {41051689},
issn = {1590-3478},
abstract = {Neurodegenerative diseases (NDDs) pose significant challenges in early detection and treatment due to their complex pathophysiology and heterogeneous clinical presentations. MicroRNAs (miRNAs), small noncoding RNAs that regulate gene expression, have emerged as promising diagnostic biomarkers and therapeutic targets in NDDs. Pathological examination of affected tissues reveals early synaptic dysfunction, protein misfolding, and neuroinflammation occur prior to overt clinical symptoms, highlighting the importance of sensitive diagnostics approaches in prodromal stages. This review summarizes for researchers on the role of miRNAs in NDDs by examining their diagnostic potential in biofluids such as blood and cerebrospinal fluid, and their therapeutic applicability through inhibition or replacement strategies. Literature from peer-reviewed databases was assessed with a focus on recent advances in molecular detection platforms, computational modeling of miRNA-mRNA interactions, and preclinical/clinical investigations.More than 2600 human miRNAs have been identified, collectively regulating over half of mammalian protein-coding genes. Quantitative methodologies, particularly reverse transcription quantitative PCR (RT-qPCR), enable reliable miRNA profiling, facilitating early diagnosis and prognosis of NDDs. Therapeutic strategies, including antagomirs, mimics, sponges and viral or non-viral delivery systems, show promise in modulating disease pathways. However, significant challenges remain, including variability in miRNA extraction and quantification protocols, off-target effects, delivery barriers across the blood brain barrier and limited reproducibility across studies. MiRNAs represent a class of molecular tools with potential to transform diagnostics and therapeutics in NDDs. Future research should prioritize methodological standardization, validation in large multicenter cohorts, and improved computational approaches to elucidate miRNA-mediated regulatory networks in NDDs. Replication studies and translational research are essential harnessing the the full clinical utility of miRNAs in the management of Alzheimer disease, Parkinson disease and other NDDs. Graphical Abstract.},
}

@article {pmid41051550,
year = {2025},
author = {Yang, T},
title = {Molecular Mechanisms of EDC-Induced Alzheimer's Disease and of Traditional Chinese Medicine Active Substances in Treating AD and Antagonizing EDC-Induced Effects.},
journal = {Neurochemical research},
volume = {50},
number = {5},
pages = {319},
pmid = {41051550},
issn = {1573-6903},
mesh = {*Alzheimer Disease/chemically induced/drug therapy/metabolism ; Molecular Docking Simulation/methods ; *Medicine, Chinese Traditional/methods ; Humans ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Animals ; Network Pharmacology ; Ginsenosides/therapeutic use/pharmacology ; Protein Interaction Maps/drug effects ; },
abstract = {AD, a progressive neurodegenerative disorder, imposes an increasingly heavy burden on global public health, with its pathogenesis remaining incompletely understood. Meanwhile, EDCs-widely present in the environment, food, and consumer products-have emerged as a significant public health concern due to their diverse health risks, including potential contributions to neurodegenerative processes such as AD by disrupting neurohomeostasis. Furthermore, as natural compounds, ginsenosides and other AS have been the focus of numerous studies exploring their role in treating AD, thanks to their advantages of multi-target properties and low side effects. However, the specific molecular pathways through which EDCs induce AD, as well as the mechanisms by which AS may counteract EDC-induced toxicity and intervene in AD, remain unclear. Against this background, this study sought to: (1) explore the molecular pathways through which EDCs may induce AD by disrupting neurohomeostasis; (2) preliminarily investigate the potential of AS in treating AD and antagonizing EDC-induced AD at the molecular level. To achieve these goals, we integrated network toxicology, network pharmacology, and molecular docking to construct a multi-dimensional interaction network among EDCs, AD, and AS. By establishing intersecting target sets for EDCs-AD and AS-AD, core targets were identified via topology analysis of protein-protein interaction (PPI) networks. GO and KEGG enrichment analyses highlighted key pathways, including serotonergic synapse and neuroactive ligand-receptor interaction. Molecular docking further explored interactions between EDCs/AS and core target proteins. The results suggest that EDCs may drive neurodegeneration in AD by impairing synaptic function, while AS may counteract these effects by enhancing synaptic activity, stabilizing membrane microenvironments, inhibiting Aβ aggregation, alleviating neuroinflammation, and restoring metabolic homeostasis. Further analysis indicated that AS exhibit stronger binding ability to core targets compared to EDCs, implying a potential antagonistic effect of AS against EDCs. This study provides insights into the molecular mechanisms underlying EDC-induced AD and establishes a multi-target theoretical framework for AS-mediated antagonism of EDC toxicity, offering a reference for the prevention and treatment of neurodegenerative diseases.},
}

*Alzheimer Disease/chemically induced/drug therapy/metabolism
Molecular Docking Simulation/methods
*Medicine, Chinese Traditional/methods
Humans
*Drugs, Chinese Herbal/therapeutic use/pharmacology
Animals
Network Pharmacology
Ginsenosides/therapeutic use/pharmacology
Protein Interaction Maps/drug effects

@article {pmid41051494,
year = {2025},
author = {Das, M and Debnath, S and Sar, S and Kumar, V and Dey, RK and Meena, AK and Roy, S and Bolleddu, R and Babu, G},
title = {HPTLC, GC-MS profiling, and biological activity comparison of Cinnamomum zeylanicum Blume (stem bark) essential oil between Indian and African varieties.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41051494},
issn = {1432-1912},
abstract = {Cinnamomum zeylanicum Blume, known for its medicinal and culinary value, was analyzed for comparative phytochemical profiling and antioxidant potential between Indian (Shillong, Kolkata) and African (Tanzania) stem bark varieties. Using HPTLC and GC-MS, the essential oils revealed key variations in chemical constituents, notably the exclusive presence of eugenol in the Tanzanian variety and higher cinnamaldehyde dimethyl acetal content. Physicochemical and organoleptic differences reflected geographic influence. Antioxidant studies using DPPH and FRAP assays confirmed superior activity in the Tanzanian sample, with the lowest IC50 (22.05 µg/ml) and highest FRAP value (579 µM). Phytochemical screening confirmed the presence of multiple bioactive compounds in the samples. These results underscore the significance of geographical origin in the quality and efficacy of medicinal plants, supporting the need for standardization protocols. This study provides a robust framework for evaluating regional variations in C. zeylanicum, enhancing its pharmacological validation and ensuring authenticity in herbal formulations. Molecular docking study with eugenol revealed strong binding affinity of eugenol with protein targets PTP1B, PPARγ, PPARδ, and PPARα in diabetes, and with BACE1 in Alzheimer's disease.},
}

@article {pmid41051385,
year = {2025},
author = {Xie, D and Zheng, Q and Lv, J and Zhang, Q and Cui, Z and Huang, S and Yu, W and Chen, B and Que, W and Fu, S and Xi, Y and Chen, J and Ye, X and Chen, S and Zhao, H and Yamamoto, T and Koyama, H and Wang, X and Cheng, J},
title = {Uric Acid Functions as an Endogenous Modulator of Microglial Function and Amyloid Clearance in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e10270},
doi = {10.1002/advs.202510270},
pmid = {41051385},
issn = {2198-3844},
support = {2022Y4007//Fujian Provincial Industry-University-Research Collaborative Innovation Project Plan/ ; U01 AG024904/AG/NIA NIH HHS/United States ; W81XWH-12-2-0012//DOD ADNI/ ; 2020J01018//Natural Science Foundation of Fujian Province/ ; 82260163//National Natural Science Foundation of China/ ; 82370895//National Natural Science Foundation of China/ ; 82271451//National Natural Science Foundation of China/ ; },
abstract = {Epidemiological studies have linked uric acid (UA), the end product of purine metabolism in humans, with reduced Alzheimer's disease (AD) risk. Decreased serum UA levels are observed in AD patients versus age-matched controls, while upstream purine metabolites remained unchanged. In 5×FAD mice, two months of UA supplementation improved cognitive function and reduced amyloid plaque burden. Mechanistically, UA enhances microglial amyloid-β (Aβ) phagocytosis and induces transcriptional reprogramming in AD mouse microglia, characterized by upregulated phagocytic pathways and attenuated inflammatory responses. UA treatment restored the recycling of Aβ receptors CD36 and TREM2 in microglia, enhanced lysosomal biogenesis, and facilitated Aβ degradation. These findings identify UA as a critical endogenous modulator of microglial Aβ processing and suggest exploring UA supplementation as a therapeutic strategy for AD.},
}

@article {pmid41051312,
year = {2025},
author = {Karlsson, L and Janelidze, S and Barthélemy, NR and Horie, K and Therriault, J and Gaetani, L and Bellomo, G and Schindler, SE and Vogel, J and Arvidsson, I and Åström, K and Gordon, BA and Raji, CA and Benzinger, TLS and Morris, JC and Nilsson, J and Brinkmalm, A and Palmqvist, S and Stomrud, E and Salvadó, G and Pichet Binette, A and Di Filippo, M and Parnetti, L and Rosa-Neto, P and Blennow, K and Bateman, RJ and Mattsson-Carlgren, N and Hansson, O},
title = {Reference proteins to improve Core 1 and Core 2 Alzheimer's disease CSF and plasma biomarkers.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf375},
pmid = {41051312},
issn = {1460-2156},
abstract = {Concentration-based fluid biomarkers represent an informative and cost-effective way to detect and monitor Alzheimer's disease (AD) pathology. However, non-AD-related inter-individual variation in biofluids can also affect biomarker concentrations. Here, we investigated whether normalization of cerebrospinal fluid (CSF) and plasma biomarkers to reference proteins, such as amyloid-β40 (Aβ40) and non-phosphorylated mid-region tau (np-tau), improves their robustness and reliability of representing AD pathology load. Using the Swedish BioFINDER-2 cohort (n=1702, 50.7% male, mean [SD] age 68.4 [12.2] years), we compared the associations between tau/Aβ-PET load and fluid biomarkers alone versus in a ratio with a reference protein (Aβ40 or np-tau) in univariate linear regression models. Fluid biomarkers included CSF and plasma measures of p-tau217, p-tau181, p-tau205, np-tau181-190, np-tau195-210, np-tau212-221, Aβ42, Aβ40, and CSF MTBR-tau243, SNAP-25, neurogranin, YKL-40, sTREM2, and plasma eMTBR-tau243. Biomarkers were measured with mass spectrometry assays and/or immunoassays. In addition, we performed validation and extended analyses, comparing for example group-level diagnostic differences and longitudinal biomarker trajectories, in three independent prospective cohorts: BioFINDER-1, Knight Alzheimer Disease Research Center (ADRC), and Translational Biomarkers in Aging and Dementia (TRIAD), as well as in an Italian multiple sclerosis cohort. CSF Aβ40 normalization significantly strengthened the associations of several core CSF AD biomarkers, including CSF MTBR-tau243, p-tau isoforms and synaptic biomarkers, with tau-PET (ΔR[2]=0.064-0.24) and Aβ-PET (ΔR[2] = 0.016-0.28). Normalization to CSF np-tau mainly improved concordance with Aβ-PET (ΔR[2] = -0.0059-0.19). The strongest association with tau-PET was observed for MTBR-tau243/Aβ40 (R[2] = 0.78, compared to 0.65 for non-normalized MTBR-tau243), and with Aβ-PET for p-tau217/np-tau (R[2] = 0.65, compared to 0.46 for non-normalized p-tau217). Plasma biomarker associations with tau-PET improved when using normalization to plasma Aβ40 or np-tau (ΔR[2] = 0.004-0.14), with the strongest effect for eMTBR-tau243/np-tau (R[2] = 0.72 versus 0.60). Associations with Aβ-PET were enhanced with np-tau normalization (ΔR[2] = 0.018-0.16, strongest for p-tau217/np-tau: R[2] = 0.62 versus 0.53). The results were replicated in Knight ADRC and TRIAD. Furthermore, longitudinal analyses showed that Aβ40 normalization typically reduced inter-individual rather than intra-individual variability over time. Normalization did not enhance group-level differences in inflammatory CSF biomarkers in AD, nor did it improve biomarker associations in the multiple sclerosis cohort. In conclusion, normalization of CSF and plasma biomarkers to reference proteins, such as Aβ40 or np-tau, enhances their association with brain tau and Aβ pathology, making already high-performing AD fluid biomarkers even more accurate.},
}

@article {pmid41051231,
year = {2025},
author = {Paul, S and Guruprasad, L},
title = {Hexagonal Boron Nitride Nanoparticles for Inhibition of Small Fragment Tau Aggregation.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.5c04935},
pmid = {41051231},
issn = {1520-5207},
abstract = {The aberrant folding of the Tau protein is correlated with several neurodegenerative diseases, such as Alzheimer's and other tauopathies. Recent studies on the neurotoxic species of Tau have identified some smaller nucleating domains of the full-length protein to initiate Tau aggregation and are shown as potential therapeutic targets in Tau pathology. Two hexapeptides, namely, PHF6 ([306]VQIVYK[311]) and PHF6* ([275]VQIINK[280]), have been recognized as the most important aggregation-prone Tau fragments among all. Currently, low-dimensional nanomaterials have shown a plethora of applications in bionanomedicine, including the treatment of amyloid diseases. Hexagonal boron nitride (h-BN) nanoparticles, analogous to carbon nanomaterials, have become potential candidates in this field due to their lower cytotoxicity compared to carbon nanoparticles and biocompatibility. In this study, we have explored the aggregation pattern of PHF6 and PHF6* and the effects of a two-dimensional (2D) h-BN nanosheet (BNNS) on these peptide oligomerizations. Atomistic simulations reveal that the PHF6-PHF6 homomer aggregation is highly favored due to the aromatic π-π interaction between the Tyr residues; furthermore, the heteromeric interaction between PHF6 and PHF6* is stronger than the self-association of PHF6* homomers. In the presence of BNNS, the peptides get absorbed on the nanosurface through weak hydrophobic interactions and aromatic π-π stacking and remain in their monomeric random coil structure. Also, the h-BN nanosheet can destabilize the preformed oligomers of the hexapeptides, hence providing a new direction toward the use of h-BN and other related nanomaterials as potential antiaggregating agents against amyloid deposition.},
}

@article {pmid41051061,
year = {2025},
author = {Dhillon, A and Fazal, J},
title = {Risk Factors for Dementia in a Sample of Patients From a Quaternary Care Hospital Network in the United Arab Emirates: A Case-control Study.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000691},
pmid = {41051061},
issn = {1546-4156},
abstract = {BACKGROUND: Data on risk factors for dementia in the MENA region and specifically in the UAE are limited.

METHODS: A case-control study of dementia patients and age-matched controls identified over 10 years at a quaternary care hospital network in Abu Dhabi. Historic data on cardiovascular, neurological, psychiatric, and nutritional risk factors were collected for patients and controls.

RESULTS: A total of 281 dementia patients (mean age 74.9 ± 9.2 y, 46.3% females) and 281 age-matched controls (mean age 74.3 ± 4.6 y, 55.9% females) were included. Patients with dementia were more likely to have heart failure, cerebrovascular disease, chronic anemia, chronic kidney disease, Parkinson disease, other neurodegenerative changes, mood disorders, psychotic disorders, and vitamin D deficiency, and less likely to have hyperlipidemia compared with controls. On logistic regression, only cerebrovascular disease (OR: 6.578, 95% CI: 2.163-20.004, P = 0.001) and mood disorders (OR: 10.046, 95% CI: 2.255-44.751, P = 0.002) were significantly and independently associated with dementia, while hyperlipidemia was protective (OR: 0.531, 95% CI: 0.360-0.783, P = 0.001).

CONCLUSION: Cerebrovascular disease and mood disorders are potential risk factors for dementia in the MENA region, while a protective role for hyperlipidemia warrants further investigation.},
}

@article {pmid41051040,
year = {2025},
author = {Agarwal, U and Paliwal, S and Yadav, V and Pannu, A and Tonk, RK and Verma, S},
title = {Pathological Insights into Neurodegenerative and Neurodevelopmental Disorders: Perspectives for the Development of Novel Treatment Approaches.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273402657250905055635},
pmid = {41051040},
issn = {1996-3181},
abstract = {Neurodegenerative and neurodevelopmental disorders represent a significant global health burden, characterized by progressive neuronal dysfunction and loss. Both diseases, despite their diverse etiologies and mechanisms, share a complex interplay of genetic, environmental, and biological factors. Neurodegenerative diseases are caused by multiple factors, including aging, mitochondrial dysfunction, oxidative stress, inflammation, genetic mutations, and protein misfolding. In contrast, neurodevelopmental disorders are primarily influenced by epigenetic alterations, neurotransmitter imbalances, early brain damage, environmental factors, and genetic variations. Despite extensive research, effective treatments remain unavailable due to the complexity of their pathologies and the biochemical pathways involved. A deep understanding of the complexities and individual differences associated with these disorders is crucial for developing effective treatments. In this background, this review provides a comprehensive overview of neurodegenerative and neurodevelopmental disorders, including their clinical symptoms, etiology, pathogenesis, underlying mechanisms, potential drug targets, reported drugs, advanced treatment options, and challenges in the drug discovery process. This comprehensive literature review was conducted using databases such as PubMed and Scopus, focusing on research published up to April 2025. By understanding the complexities of these disorders, researchers can develop novel therapeutic approaches, including potential drugs and advanced treatment methods, to mitigate their devastating impact.},
}

@article {pmid41050965,
year = {2025},
author = {Watson, JA and Knoedler, S and von Reibnitz, D and Zurfluh, CE and Imholz, C and Esposito, G and Schreiner, SJ and Gousopoulos, E and Cai, A and Kollarik, S and Giovanoli, P and Baumann, C and Lindenblatt, N},
title = {Brain Drain for Brain Gain: Potential Applications of Robotic-assisted Lymphatic Microsurgery in the Management of Neurological Disorders.},
journal = {Plastic and reconstructive surgery. Global open},
volume = {13},
number = {10},
pages = {e7191},
pmid = {41050965},
issn = {2169-7574},
abstract = {BACKGROUND: The central nervous system (CNS) was long believed to be devoid of lymphatic drainage. However, the discovery of the glymphatic system and meningeal lymphatics has revolutionized our understanding of cerebrospinal fluid homeostasis and neuroimmune interactions. The glymphatic system facilitates perivascular cerebrospinal fluid-interstitial fluid exchange and promotes neurotoxic waste clearance, whereas meningeal lymphatics serve as conduits between the CNS and peripheral lymphatic circulation. Dysfunction in these lymphatic efflux pathways has been implicated in the pathogenesis of neurological disorders such as Alzheimer disease, Parkinson disease, traumatic brain injury, and intracranial hemorrhage, where impaired waste removal contributes to protein aggregation, neuroinflammation, and hence, disease onset and progression.

METHODS: Recent preliminary evidence suggests that surgical modulation of lymphatic drainage may offer novel therapeutic avenues for these disorders, with lymphatic microsurgery, particularly deep cervical lymphovenous anastomosis (LVA), proposed as an innovative procedure to enhance CNS lymphatic outflow. The first case reports in Alzheimer disease patients demonstrated not only the operative feasibility of LVA but also postoperative cognitive improvements. Despite these promising findings, systematic (pre)clinical studies remain scarce, calling for further research.

RESULTS: This article examined the role of the brain lymphatic system in neurological disorders and discussed the potential of lymphatic microsurgery as a novel therapeutic intervention. We also highlight ongoing clinical trials and potential future innovations, including surgical robotic assistance, and report on 2 cases of deep neck LVA for central lymphatic disorders.

CONCLUSIONS: By combining neurolymphatic research with surgical advances, LVAs have the potential to redefine therapeutic paradigms in CNS disorder management.},
}

@article {pmid41050964,
year = {2025},
author = {Zhou, Z and Chen, X and Kou, W and Meng, F and Yu, L and Wen, J and Boey, J and Shah, V and Malagón, P},
title = {Modified Dynamic Lymphaticovenular Anastomosis for Surgical Management of Alzheimer Disease.},
journal = {Plastic and reconstructive surgery. Global open},
volume = {13},
number = {10},
pages = {e7082},
pmid = {41050964},
issn = {2169-7574},
abstract = {Alzheimer disease (AD) is a neurodegenerative disorder that frequently results in progressive cognitive decline. Despite the extensive research conducted on AD, there is presently no solution available due to its increasing prevalence. Recent research has suggested cervical lymphaticovenular anastomosis (LVA) as a therapeutic strategy to improve lymphatic outflow and potentially reduce AD symptoms. We established an amended LVA protocol to mitigate the risk of venous reflux, a prevalent issue associated with the original LVA methodology. A 64-year-old man of Chinese descent exhibited the typical signs and symptoms of AD. The absence of substantial progress with standard medical treatment led to the consideration of LVA. We used a lower limb vein graft for the LVA, anastomosing it to the cervical lymphatic vessels and external jugular vein. The cognitive function of the patient got better after LVA, as shown by higher Mini Mental State Examination and Montreal Cognitive Assessment scores. Fewer β-amyloid and tau protein deposits were observed on positron emission tomography/computed tomography scans. No adverse occurrences or issues were observed. The success in this case demonstrated the potential role of LVA in the management of AD. However, further thorough research is required to evaluate the efficacy of our technique.},
}

@article {pmid41050948,
year = {2025},
author = {Dogan, C and Miller, CE and Jefferis, T and Saranti, M and Tempesta, AJ and Schofield, AJ and Palaniappan, R and Bowman, H},
title = {Headache-specific hyperexcitation sensitises and habituates on different time scales: An event related potential study of pattern-glare.},
journal = {Neuroimage. Reports},
volume = {5},
number = {3},
pages = {100271},
pmid = {41050948},
issn = {2666-9560},
abstract = {Cortical hyperexcitability is a key pathophysiological feature in several neurological disorders, including migraine, epilepsy, tinnitus, and Alzheimer's disease. We examined the temporal characteristics of Event Related Potentials (ERPs) in a healthy population using the Pattern Glare Test, a diagnostic tool used to assess patients with sensitivity to cortical hyperexcitability. In pre-experiment questionnaires, participants reported their susceptibility to a range of symptoms. A factor analysis over these responses identified three variables, with the one we investigate in this paper loading strongly on headache symptoms, e.g. headache frequency. We investigated two timeframes: habituation over the course of the entire experiment and sensitization over the course of a sequence of stimulus presentations. We found evidence of hyperexcitability at electrodes over visual cortex, for the aggravating stimulus (grating of ∼3 cycles/deg). Participants higher on the headache factor exhibited a higher degree of habituation and sensitization, with evidence that the level of sensitization habituated through the course of the experiment. These findings suggest that the same experimental paradigm and analysis should be performed on a clinically diagnosed population.},
}

@article {pmid41050943,
year = {2025},
author = {Huff, AJ and Park, J and Montero-Hernandez, S and Park, L and Lee, C and Pollonini, L and Ahn, H},
title = {Functional near-infrared spectroscopy (fNIRS) detects brain changes for apathy and pain in patients with Alzheimer's disease and related dementias: An exploratory study.},
journal = {Neuroimage. Reports},
volume = {5},
number = {3},
pages = {100266},
pmid = {41050943},
issn = {2666-9560},
abstract = {Alzheimer's Disease and Related Dementias (ADRD) are degenerative and progressive in nature and are often accompanied by chronic pain and neuropsychiatric symptoms, which can be early signs and aggravators of ADRD. This exploratory study explores the relationship between self-reported pain, neuropsychiatric symptoms, and pain-evoked cortical hemodynamic changes measured using functional near-infrared spectroscopy (fNIRS) in the prefrontal and primary motor and somatosensory brain cortices bilaterally, stratified by high or low cognitive function in individuals with ADRD. This study analyzed baseline data of 40 individuals with mild to moderate ADRD with knee osteoarthritis. Baseline data from 40 individuals with mild to moderate ADRD and knee osteoarthritis were analyzed. Measures included self-reported pain, depression, and apathy, along with fNIRS-derived cerebral hemodynamic responses to sub-threshold thermal pain stimulation across five brain regions. The study revealed significant negative correlations for oxyhemoglobin and apathy in the right prefrontal cortex associated with low cognitive function (p = .04) and significant positive correlations for oxyhemoglobin and apathy in the right somatosensory region (p = .04) and for oxyhemoglobin and pain in the medial prefrontal cortex (p = .04) associated with higher cognitive function. Study findings suggest that fNIRS may provide valuable biomarkers for apathy and depression in individuals with ADRD and chronic osteoarthritic pain, with differential patterns based on cognitive function, suggesting neuropsychiatric symptoms may manifest differently depending on the patient's cognitive status. Future studies should explore its utility in larger, diverse samples and clinical interventions targeting neuropsychiatric symptoms.},
}

@article {pmid41050842,
year = {2025},
author = {Sun, Z and Cao, H},
title = {Regression analysis of multiplicative hazards model with time-dependent coefficient for sparse longitudinal covariates.},
journal = {Journal of nonparametric statistics},
volume = {},
number = {},
pages = {},
pmid = {41050842},
issn = {1048-5252},
abstract = {We study the multiplicative hazards model with intermittently observed longitudinal covariates and time-varying coefficients. For such models, the existing ad hoc approach, such as the last value carried forward, is biased. We propose a kernel weighting approach to get an unbiased estimation of the non-parametric coefficient function and establish asymptotic normality for any fixed time point. Furthermore, we construct the simultaneous confidence band to examine the overall magnitude of the variation. Simulation studies support our theoretical predictions and show favorable performance of the proposed method. A data set from Alzheimer's Disease Neuroimaging Initiative study is used to illustrate our methodology.},
}

@article {pmid41050829,
year = {2025},
author = {Christianson, K and Prabhu, M and Popp, ZT and Rahman, MS and Drane, J and Lee, M and Lathan, C and Lin, H and Au, R and Sunderaraman, P and Hwang, PH},
title = {Adherence timescale impacts completion rates of high-frequency mobile cognitive assessments among older adults.},
journal = {Exploration of medicine},
volume = {6},
number = {},
pages = {},
pmid = {41050829},
issn = {2692-3106},
abstract = {AIM: Mobile technology enables frequent, remote cognitive assessments, introducing new methodological opportunities and challenges. The study evaluated the feasibility of a high-frequency cognitive assessment schedule among older adults, in terms of total assessments and adherence to a prescribed schedule.

METHODS: Thirty-three older adults were recruited from the Boston University Alzheimer's Disease Research Center (mean age = 73.5 years; 27.3% cognitively impaired; 57.6% female; 81.8% White, 18.2% Black). Participants downloaded the DANA Brain Vital mobile application on their own mobile devices during a remote study visit, and were provided a schedule with seventeen assessments to complete over one year at varying frequencies. The first segment contained three subsegments to be completed within one week, the second segment consisted of weekly subsegments spanning three weeks, and the third and fourth segments consisted of monthly subsegments spanning five and six months, respectively. Three adherence types were defined to reflect incrementally broader adherence timescales: subsegment adherence (strict adherence to each prescribed assessment period), segment adherence (completing the required number of assessments within each broader segment), and cumulative adherence (completing the total number of assessments irrespective of timing).

RESULTS: Completion rates differed depending on the adherence timescale and corresponding adherence type. Using the strictest adherence definition (subsegment adherence), completion rates declined (from 93.9% to 72.7%, p = 0.05) during the fourth segment. However, when a broader adherence timescale was applied, completion rates did not decline. Overall completion rates increased as adherence timescale parameters were broadened from subsegment adherence (60.6%) to segment adherence (78.8%), to cumulative adherence (90.9%).

CONCLUSIONS: Older adults, including those with cognitive impairment, are able to complete remote cognitive assessments at a high-frequency, but may not necessarily adhere to prescribed schedules. Future high-frequency studies should consider adherence as a potential behavioral variable to complement cognitive test data, while recognizing the potential influence of adherence timescale on interpreting completion rates.},
}

@article {pmid41050469,
year = {2025},
author = {Wang, Y and Liu, T and He, Y and Tang, Y and Tan, P and Huang, L and Huang, D and Wen, T and Shao, L and Wang, J and Wang, Y and Han, Z},
title = {Identifying Alzheimer's disease-related pathways based on whole-genome sequencing data.},
journal = {Computational and structural biotechnology journal},
volume = {27},
number = {},
pages = {4132-4144},
pmid = {41050469},
issn = {2001-0370},
abstract = {Alzheimer's disease (AD) is a highly inheritable neurodegenerative disorder for which pathway-specific genetic profiling provides insights into its key biological mechanisms and potential treatment targets. Traditional disease-pathway analyses for AD have certain limitations, such as environmental interference and arbitrary sample division. We present a comprehensive framework that starts with genome data, avoiding these drawbacks and offering intrinsic pathway-specific genetic profiling for AD. Whole genome sequencing data from 173 individuals were used to quantify transcriptomes in 14 brain regions, estimate individual-level pathway variant scores, and analyze AD risk for each patient. These results were combined to identify AD-related pathways and quantify their interactions. The predicted expression levels were consistent with previous findings, and the estimated AD risk showed a significant correlation with Braak/Thal scores. A total of 3798 pathways were identified as potentially associated with AD, with about 19.7 % previously reported. The pathways identified as AD risk related primarily address six core biological themes, including: Immunity and inflammation, Metabolism, Protein homeostasis, DNA/RNA and Epigenetics, Synapse and structure, Cell cycle. Specifically, key pathways, such as NF-κB signaling and GSK3β activation, were linked to AD pathogenesis. The interactions among pathways highlighted shared gene functions in AD. In summary, we provided an effective framework for disease-pathway analysis, revealing the interdependence or compensatory effects of pathways in AD.},
}

@article {pmid41050397,
year = {2025},
author = {Liu, W and Zhao, Y and Liu, T and Wang, Y and Yin, D and Zou, S and Zou, C and Zhang, Z and Zhi, H and Wang, Y},
title = {Kaixin San Jiawei granule improves cognitive function and alleviates neuronal damage in Alzheimer's disease via multi-component and multi-target mechanisms.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1650534},
pmid = {41050397},
issn = {1663-9812},
abstract = {BACKGROUND: Kaixin San Jiawei Granule (KSG) is a traditional Chinese medicine formulation derived from classical prescriptions. Although it has shown promise in treating Alzheimer's disease (AD), its precise mechanisms of action remain unclear. This study aimed to systematically investigate the molecular mechanisms underlying KSG's therapeutic effects on AD through an integrative approach combining network pharmacology with experimental validation.

METHODS: An in vivo AD model was established in male KM mice via intraperitoneal injection of scopolamine. Cognitive function was assessed using the Morris water maze, and hippocampal levels of acetylcholine (ACh), acetylcholinesterase (AChE), glutathione peroxidase (GSH-Px), and reactive oxygen species (ROS) were measured using ELISA. In vitro, PC12 cells were exposed to Aβ25-35 to induce apoptosis. Immunofluorescence staining, Western blotting, and qPCR were used to assess the expression of amyloid-beta (Aβ), apoptosis-related protein caspase-3, and inflammatory cytokines (TNF-α, IL-1β). Active components of KSG and their potential targets and pathways were identified using mass spectrometry and network pharmacology, while partial validation was performed using molecular docking and Western blotting.

RESULTS: In vivo, KSG significantly alleviated scopolamine-induced cognitive deficits in mice. Treatment increased hippocampal levels of ACh and GSH-Px while reducing AChE and ROS. In vitro, KSG mitigated Aβ25-35-induced cytotoxicity in PC12 cells, decreased Aβ accumulation, and downregulated the expression of TNF-α and IL-1β. However, KSG had no significant effect on telomerase activity, telomere length, or the expression of the telomere-associated protein POT1. Mass spectrometry and network pharmacology analyses identified genistein, quercetin, and apigenin as key active compounds with TP53, AKT1, PTGS2, and CNR2 identified as core targets. Molecular docking validation confirmed the favorable binding activity between them. The calcium signaling, PI3K-Akt, and MAPK pathways emerged as the primary enriched pathways.

CONCLUSION: KSG improves cognitive function and attenuates Aβ-induced neuronal damage in AD through multi-component, multi-target synergistic mechanisms. These effects appear to be mediated by modulation of the cholinergic system, inhibition of oxidative stress and inflammation, and suppression of neuronal apoptosis. These findings provide a theoretical basis and experimental support for developing novel AD therapies based on traditional Chinese medicine.},
}

@article {pmid41050058,
year = {2025},
author = {Ma, M and Deng, C and Liu, Y and Cao, Q and Liu, F and Zhang, Y},
title = {A hypergraph neural network for prioritizing Alzheimer's disease risk genes.},
journal = {Frontiers in genetics},
volume = {16},
number = {},
pages = {1668200},
pmid = {41050058},
issn = {1664-8021},
abstract = {Identifying the complex genetic architecture of Alzheimer's disease (AD) is critical for understanding its pathophysiology. While network-based computational methods assist in this task, they primarily model simple pairwise gene interactions and fail to capture the higher-order associations of genes that drive complex diseases. To address this limitation, we introduce HyperAD, a novel hypergraph neural network framework designed to predict AD risk genes by explicitly modeling these higher-order associations of genes. HyperAD constructs a hypergraph in which functional gene sets from databases such as MSigDB form hyperedges, and uses a two-stage hypergraph message passing neural network to extract high-order association information from the hypergraph. Comprehensive evaluations demonstrate that HyperAD significantly outperforms state-of-the-art methods. We validate the prediction results of HyperAD through multiple lines of evidence. HyperAD-predicted genes are enriched in AD-related biological processes and have significant associations with known related genes in terms of sequence similarity, protein interaction, and miRNA. In addition, their protein expression levels are significantly altered in the brains of AD patients, and they contain both known risk sites and new, high-confidence candidate genes. HyperAD provides a more accurate and biologically insightful tool for prioritizing genes and unraveling the complex genetic landscape of AD.},
}

@article {pmid41049948,
year = {2025},
author = {Lawongsa, K and Kumjan, S},
title = {Prevalence and Determinants of Dementia Among Older Adults Attending Outpatient Clinics in a Tertiary Care Hospital in Thailand: A Secondary Data Analysis.},
journal = {Cureus},
volume = {17},
number = {9},
pages = {e91454},
pmid = {41049948},
issn = {2168-8184},
abstract = {BACKGROUND: Dementia is an increasing public health concern, particularly in aging societies. While most prevalence estimates in Thailand are derived from community-based studies, less is known about the burden and risk factors of dementia in tertiary care outpatients, who often present with multimorbidity.

METHODS: We conducted a retrospective cross-sectional study using secondary data from patients aged ≥60 years attending internal medicine, neurology, and geriatric outpatient clinics of Phramongkutklao Hospital, a tertiary hospital in Bangkok, Thailand, between January 1 and December 31, 2024. Dementia was identified using a hierarchical algorithm incorporating International Classification of Diseases, Tenth Revision (ICD-10) diagnostic codes, prescriptions for anti-dementia medications, and cognitive test results, with sensitivity analyses using stricter definitions. Independent variables included demographic characteristics, vascular and non-vascular comorbidities, medication use, and laboratory results. Prevalence was calculated with 95% confidence intervals (CI). Poisson regression with robust variance estimation was used to calculate crude and adjusted prevalence ratios (aPR) for associated factors.

RESULTS: Of 4,100 older adults, 512 had dementia (12.5%). Alzheimer's disease was the most frequent subtype, accounting for 278 cases (54.3% of dementia; 6.8% of the total sample). In univariable analysis, dementia was associated with age ≥80 years, female sex, low education, hypertension, diabetes mellitus, stroke/transient ischemic attack (TIA) history, depression, and an Anticholinergic Cognitive Burden (ACB) score ≥3. After adjustment, age ≥80 years remained the strongest determinant (aPR 2.41, 95% CI 1.92-3.01). Female sex (aPR 1.28, 95% CI 1.07-1.53), education ≤6 years (aPR 1.64, 95% CI 1.33-2.01), hypertension (aPR 1.21, 95% CI 1.02-1.43), diabetes mellitus (aPR 1.27, 95% CI 1.07-1.52), stroke/TIA (aPR 1.89, 95% CI 1.52-2.35), depression (aPR 1.48, 95% CI 1.16-1.90), and ACB score ≥3 (aPR 1.36, 95% CI 1.09-1.70) were all independently associated with dementia.

CONCLUSION: Dementia was common among tertiary care outpatients, with prevalence higher than community-based estimates. Advanced age, female sex, low education, vascular comorbidities, depression, and anticholinergic medication burden were significant correlates. These findings highlight the need for routine screening, aggressive vascular risk factor management, and medication review in tertiary care settings to mitigate the burden of dementia.},
}

@article {pmid41049759,
year = {2025},
author = {Meden, A and Žnidaršič, N and Knez, D and Wang, Y and Xu, Z and Yang, H and Zhang, W and Pišlar, A and Perdih, A and Brezar, SK and Grgurevič, N and Pajk, S and Sun, H and Gobec, S},
title = {Pleiotropic prodrugs for both symptomatic and disease-modifying treatment of Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {9},
pages = {4807-4828},
pmid = {41049759},
issn = {2211-3835},
abstract = {The inherent complexity of Alzheimer's disease (AD) and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology. Here we present a focused series of pleiotropic N-carbamoylazole prodrugs with dual mechanism of action. Pseudo-irreversible inhibition of the first therapeutic target, human butyrylcholinesterase (hBChE), enhances cholinergic transmission, and thereby provides symptomatic treatment, same as the standard therapeutics in use for AD. Simultaneously, this step also functions as a metabolic activation that liberates a nanomolar selective α 2-adrenergic antagonist atipamezole, which blocks pathological amyloid β (Aβ)-induced and noradrenaline-dependent activation of GSK3β that ultimately leads to hyperphosphorylation of tau, thus achieving a disease-modifying effect. Lead compound 8 demonstrated long-term pseudo-irreversible hBChE inhibition, metabolic activation in human plasma, blood-brain barrier permeability, and p.o. bioavailability in mice. Multi-day in vivo treatment with 8 in an Aβ-induced AD murine model revealed a significant alleviation of cognitive deficit that was comparable to rivastigmine, the current drug of choice for AD therapy. Furthermore, decreased GSK3β activation and lowered tau phosphorylation were observed in APP/PS1 mice. This surpasses the symptomatic-only treatment with cholinesterase inhibitors, as it directly blocks an essential pathological cascade in AD. Therefore, these multifunctional α 2-adrenergic antagonists-butyrylcholinesterase inhibitors, exemplified by lead compound 8, present an innovative, small molecule-based, disease-modifying approach to treatment of AD.},
}

@article {pmid41049755,
year = {2025},
author = {Yang, Y and Diao, Y and Jiang, L and Li, F and Chen, L and Ni, M and Wang, Z and Fang, H},
title = {A computational medicine framework integrating multi-omics, systems biology, and artificial neural networks for Alzheimer's disease therapeutic discovery.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {9},
pages = {4411-4426},
pmid = {41049755},
issn = {2211-3835},
abstract = {The translation of genetic findings from genome-wide association studies into actionable therapeutics persists as a critical challenge in Alzheimer's disease (AD) research. Here, we present PI4AD, a computational medicine framework that integrates multi-omics data, systems biology, and artificial neural networks for therapeutic discovery. This framework leverages multi-omic and network evidence to deliver three core functionalities: clinical target prioritisation; self-organising prioritisation map construction, distinguishing AD-specific targets from those linked to neuropsychiatric disorders; and pathway crosstalk-informed therapeutic discovery. PI4AD successfully recovers clinically validated targets like APP and ESR1, confirming its prioritisation efficacy. Its artificial neural network component identifies disease-specific molecular signatures, while pathway crosstalk analysis reveals critical nodal genes (e.g., HRAS and MAPK1), drug repurposing candidates, and clinically relevant network modules. By validating targets, elucidating disease-specific therapeutic potentials, and exploring crosstalk mechanisms, PI4AD bridges genetic insights with pathway-level biology, establishing a systems genetics foundation for rational therapeutic development. Importantly, its emphasis on Ras-centred pathways-implicated in synaptic dysfunction and neuroinflammation-provides a strategy to disrupt AD progression, complementing conventional amyloid/tau-focused paradigms, with the future potential to redefine treatment strategies in conjunction with mRNA therapeutics and thereby advance translational medicine in neurodegeneration.},
}

@article {pmid41049748,
year = {2025},
author = {Abdelhameed, A and Feng, J and Hu, X and Li, F and Lundin, S and Schulz, PE and Tao, C},
title = {AI-powered model for accurate prediction of MCI-to-AD progression.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {9},
pages = {4427-4437},
pmid = {41049748},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD) remains a formidable challenge in modern healthcare, necessitating innovative approaches for its early detection and intervention. This study aimed to enhance the identification of individuals with mild cognitive impairment (MCI) at risk of developing AD. Leveraging advances in computational power and the extensive availability of healthcare data, we explored the potential of deep learning models for early prediction using medical claims data. We employed a bidirectional gated recurrent unit (BiGRU) deep learning model for predictive modeling of MCI progression across various prediction intervals, extending up to five years post-initial MCI diagnosis. The performance of the BiGRU model was rigorously compared with several machine-learning model baselines to evaluate its efficacy. Using a robust cross-validation methodology, the BiGRU emerged as the top-performing model, achieving an Area Under the Receiver Operating Characteristic Curve (AUC-ROC) of 0.833 (95% CI: 0.822, 0.843), an Area Under the Precision-Recall Curve (AUC-PR) of 0.856 (95% CI: 0.845, 0.867), and an F1-Score of 0.71 (95% CI: 0.694, 0.724) for a five-year prediction interval. The results indicate that BiGRU, utilizing longitudinal claims data, reliably predicts MCI-to-AD progression over a lengthy interval following the initial MCI diagnosis, offering clinicians a valuable tool for targeted risk identification and stratification.},
}

@article {pmid41049735,
year = {2025},
author = {Ai, R and Xiao, X and Deng, S and Yang, N and Xing, X and Watne, LO and Selbæk, G and Wedatilake, Y and Xie, C and Rubinsztein, DC and Palmer, JE and Neerland, BE and Chen, H and Niu, Z and Yang, G and Fang, EF},
title = {Artificial intelligence in drug development for delirium and Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {9},
pages = {4386-4410},
pmid = {41049735},
issn = {2211-3835},
abstract = {Delirium is a common cause and complication of hospitalization in the elderly and is associated with higher risk of future dementia and progression of existing dementia, of which 70% is Alzheimer's disease (AD). AD and delirium, which are known to be aggravated by one another, represent significant societal challenges, especially in light of the absence of effective treatments. The intricate biological mechanisms have led to numerous clinical trial setbacks and likely contribute to the limited efficacy of existing therapeutics. Artificial intelligence (AI) presents a promising avenue for overcoming these hurdles by deploying algorithms to uncover hidden patterns across diverse data types. This review explores the pivotal role of AI in revolutionizing drug discovery for AD and delirium from target identification to the development of small molecule and protein-based therapies. Recent advances in deep learning, particularly in accurate protein structure prediction, are facilitating novel approaches to drug design and expediting the discovery pipeline for biological and small molecule therapeutics. This review concludes with an appraisal of current achievements and limitations, and touches on prospects for the use of AI in advancing drug discovery in AD and delirium, emphasizing its transformative potential in addressing these two and possibly other neurodegenerative conditions.},
}

@article {pmid41049729,
year = {2025},
author = {Ren, F and Wei, J and Chen, Q and Hu, M and Yu, L and Mi, J and Zhou, X and Qin, D and Wu, J and Wu, A},
title = {Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {9},
pages = {4327-4385},
pmid = {41049729},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, with few effective treatments currently available. The multifactorial nature of AD, shaped by genetic, environmental, and biological factors, complicates both research and clinical management. Recent advances in artificial intelligence (AI) and multi-omics technologies provide new opportunities to elucidate the molecular mechanisms of AD and identify early biomarkers for diagnosis and prognosis. AI-driven approaches such as machine learning, deep learning, and network-based models have enabled the integration of large-scale genomic, transcriptomic, proteomic, metabolomic, and microbiomic datasets. These efforts have facilitated the discovery of novel molecular signatures and therapeutic targets. Methods including deep belief networks and joint deep semi-non-negative matrix factorization have contributed to improvements in disease classification and patient stratification. However, ongoing challenges remain. These include data heterogeneity, limited interpretability of complex models, a lack of large and diverse datasets, and insufficient clinical validation. The absence of standardized multi-omics data processing methods further restricts progress. This review systematically summarizes recent advances in AI-driven multi-omics research in AD, highlighting achievements in early diagnosis and biomarker discovery while discussing limitations and future directions needed to advance these approaches toward clinical application.},
}

@article {pmid41049611,
year = {2025},
author = {Huang, J and Zhang, C and Huang, C and Deng, K and Xiao, Y and Gao, W and Wu, M and Lei, M},
title = {Mitochondria Metabolism Regulates Glucose-Lipid Homeostasis in Neurodegenerative Diseases.},
journal = {Research (Washington, D.C.)},
volume = {8},
number = {},
pages = {0912},
pmid = {41049611},
issn = {2639-5274},
abstract = {Neurodegenerative diseases represent a major health threat, with dysfunction in energy metabolism and imbalance in glucose-lipid homeostasis constituting key pathogenic factors. As the cell's energy hub, mitochondria are closely associated with neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. However, the precise mechanism by which mitochondrial energy metabolism affects glucose-lipid homeostasis remains unclear. This review summarizes currents insights into the role of mitochondrial function in energy metabolism and glucose-lipid regulation in neurodegenerative diseases. We examined how mitochondrial dynamics, oxidative phosphorylation, calcium homeostasis, and key signaling pathways-AMP-activated protein kinase/mammalian target of rapamycin, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and Sirtuin 1-contribute to neuronal energy balance and metabolic regulation. We further explored the impact of other organelles on mitochondria and how the dynamic switching of mitochondrial morphology and function disrupts the critical glucose-lipid homeostasis. By focusing on mitochondrial dysfunction, metabolic disorders, and their interactions, we introduce the mitochondria-centered multi-organelle-energy metabolic-glucose-lipid homeostasis (MMH) network as a unifying theoretical framework that positions the progressive loss of metabolic flexibility as the fundamental essence of neurodegenerative disorders. The MMH network furnishes a novel lens through which the shared mechanistic underpinnings of neurodegenerative diseases can be deciphered, and thereby enable earlier diagnosis and precision therapeutics.},
}

@article {pmid41049573,
year = {2025},
author = {Perales-Puchalt, J and Checa, I and Espejo, B and de la C Martín Carbonell, M and Fracachán-Cabrera, M and Baker, C and Ramírez-Mantilla, M and Mendez-Asaro, P and Zimmer, M and Williams, K and Greiner, KA and Zaudke, J and Arreaza, H and Velez-Uribe, I and Moore, HP and Sepulveda-Rivera, V and Meyer, K and Benton, D and Kittle, K and Gillen, L and Burns, JM},
title = {Validation of wellbeing scales among informal caregivers of Latinos with Alzheimer's disease and related dementias.},
journal = {Hispanic journal of behavioral sciences},
volume = {47},
number = {1},
pages = {},
pmid = {41049573},
issn = {0739-9863},
abstract = {OBJECTIVES: To examine the psychometric properties of several wellbeing scales among Latinos in the US, most of which have never been validated in a US-Latino population.

DESIGN: We leveraged secondary baseline data from a one-arm mHealth trial on dementia caregiver support. We included 100 responses for caregiver-focused scales and 88 responses for care recipient-focused scales. Scales included the Neuropsychiatric Inventory Questionnaire Severity and Distress scales, Six-item Zarit Burden Inventory, Ten-item Center for Epidemiologic Studies Depression Scale, 15-item Geriatric Depression Scale, Quality of Life in Alzheimer's Disease, and Single-item Satisfaction With Life Scale. We calculated concurrent validity using Pearson and Spearman correlations and expected correlations amongst all variables in line with the Stress Process Framework. We calculated internal consistency reliability using Cronbach's alpha.

RESULTS: All concurrent validity correlations followed the expected directionality, with 19/21 inter-scale correlations in the total sample reaching statistical significance (p<0.05), and 17/21 reaching at least a low correlation (0.3). Cronbach's alpha ranged from 0.832 to 0.879 in all scales in the total sample.

CONCLUSION: The English and Spanish caregiver-administered scales tested in this manuscript have good psychometric properties among Latinos. These are now appropriately available for use among US Latinos in research and clinical contexts.},
}

@article {pmid41049544,
year = {2025},
author = {Wang, A and Richardson, A and Emmett, I and Friedmann, D and Bakker, S and Richardson, M and Hill, E and Wall, M},
title = {Incubation with tau aggregates increases hippocampal circuit excitability and enhances long-term depression in acute mouse hippocampal slices.},
journal = {Frontiers in neural circuits},
volume = {19},
number = {},
pages = {1596989},
pmid = {41049544},
issn = {1662-5110},
mesh = {Animals ; *tau Proteins/metabolism/pharmacology ; *Hippocampus/drug effects/metabolism ; Mice ; *Long-Term Synaptic Depression/physiology/drug effects ; Long-Term Potentiation/physiology/drug effects ; Mice, Inbred C57BL ; Male ; Excitatory Postsynaptic Potentials/physiology/drug effects ; Pyramidal Cells/drug effects/physiology ; },
abstract = {Aggregation of the protein tau is a key pathological hallmark of tauopathies such as Alzheimer's Disease. Tau dissociates from microtubules and diffuses from the axon into the soma-dendritic compartment, where it aggregates firstly into oligomers and ultimately into neurofibrillary tangles. There is gathering evidence that it is the soluble tau aggregates that are the major active species and that their effects on neuronal electrophysiological properties, synaptic transmission and plasticity could contribute to early cognitive decline. Here we have investigated the effects of incubating acute mouse hippocampal slices with recombinant tau aggregates. We observed interictal events and an increase in excitability of CA3 pyramidal cells. Tau aggregates had little effect on basal synaptic transmission but antagonism of GABAA receptors revealed significant effects of tau aggregates, enhancing the firing of population spikes and the occurrence of bursts following fEPSPs. Tau aggregates produced a concentration-dependent impairment of long-term potentiation (LTP), which could not be overcome by repeated LTP induction stimuli, demonstrating the effects were not just through an elevation of LTP threshold. In contrast to the impairment of LTP, tau aggregates increased G1-mGluR-dependent LTD. Thus, tau aggregates increase hippocampal circuit excitability and shift synaptic plasticity towards depression.},
}

Animals
*tau Proteins/metabolism/pharmacology
*Hippocampus/drug effects/metabolism
Mice
*Long-Term Synaptic Depression/physiology/drug effects
Long-Term Potentiation/physiology/drug effects
Mice, Inbred C57BL
Male
Excitatory Postsynaptic Potentials/physiology/drug effects
Pyramidal Cells/drug effects/physiology

@article {pmid41049537,
year = {2025},
author = {Ottaviani, S and Tagliafico, L and Peruzzo, S and Ponzano, M and Signori, A and Nencioni, A and Monacelli, F},
title = {Beyond traditional proxies: the contribution of leisure to cognitive reserve and dementia.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1600798},
pmid = {41049537},
issn = {1663-4365},
abstract = {INTRODUCTION: Cognitive reserve (CR) is a multidimensional construct based on lifelong engagement in cognitively stimulating domains, including education, occupation and leisure activities, that plays a crucial role in mitigating the presentation of dementia. To date, the contribution of each CR subdomain in the development of dementia is under-investigated. This study is aimed at assessing the association of CR subdomains with cognitive status, accounting for sex and age in an old-age population.

METHODS: 317 older adults were recruited with a diagnosis of subjective cognitive impairment, mild cognitive impairment, and dementia due to Alzheimer's disease or mixed-type dementia. Cognitive Reserve Index questionnaire (CRIq) was used to assess CR. Patients were stratified based on sex and dementia staging (CDR). Significant variables from univariate analysis entered a multivariate ordinal regression model, using CDR as the dependent variable.

RESULTS: The results showed that the leisure activities subdomain was the main determinant of cognitive status (OR 0.90, 95%CI 0.82-1.00, p = 0.003); CR and sex did not show any interaction.

DISCUSSION: Unlike education and occupation, leisure activities may be considered a lifelong, dynamic contributor to CR. These findings highlight the importance of refining CR assessment, with particular attention to leisure activities as a potentially modifiable target for dementia prevention.},
}

@article {pmid41049534,
year = {2025},
author = {Fu, H and Huang, H and Liao, S and Dai, Z},
title = {Global burden of Alzheimer's disease and other dementias (1990-2021): inequality, frontier, and decomposition analysis.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1637029},
pmid = {41049534},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease and other dementias (ADOD) represent a growing global health crisis driven by the rapid aging of the population. Using data from the 2021 Global Burden of Disease (GBD) study, we provide updated global and national estimates of the ADOD burden from 1990 to 2021, quantify key risk factors, and offer evidence to guide resource allocation and prevention strategies.

METHODS: We analyzed age-standardized incidence, prevalence, mortality, and disability-adjusted life years (DALYs) rates, along with the burden attributable to ADOD-related risk factors. Health disparities were assessed using the slope index of inequality and concentration index. We used frontier analysis to evaluate outcomes relative to development levels. Decomposition analysis identified the drivers of burden changes.

RESULTS: Globally, ADOD incidence, prevalence, and mortality increased significantly between 1990 and 2021 (156.54%, 160.81%, and 194.39%, respectively). High fasting blood glucose was the leading modifiable risk factor, contributing to 14.70% of global ADOD mortality, followed by elevated BMI and tobacco use. Burden trends varied across Socio-Demographic Index (SDI) regions, with high-middle SDI regions showing the highest prevalence. Gender-specific risk factor rankings showed high BMI as the second most significant factor in females, while tobacco use ranked second in males but declined over time. Decomposition analysis revealed the greatest increases in DALYs occurred in middle-SDI regions.

DISCUSSION: This study reveals a considerable potential to reduce the ADOD burden in many countries. Although some metrics have stabilized or slowed in growth, significant inequalities remain, particularly in lower-SDI nations. Tailored strategies focusing on strengthening healthcare systems, targeting high-risk populations, and improving health education are essential to narrow these gaps. Greater international collaboration and open data sharing are also key to building a life-course management model for ADOD prevention and care, ultimately improving global health.},
}

@article {pmid41049392,
year = {2025},
author = {Ito, T and Ono, M and Yamaki, S and Hori, Y and Muramoto, S and Yamamoto, R and Furuyama, T and Kato, N},
title = {Disorganized hippocampal excitatory and inhibitory connectivity in a mouse model of Alzheimer's disease.},
journal = {IBRO neuroscience reports},
volume = {19},
number = {},
pages = {646-654},
pmid = {41049392},
issn = {2667-2421},
abstract = {Cortical hyperexcitability is regarded to accompany Alzheimer's disease (AD) and its rodent models, and often claimed to be even causative of AD. To seek its morphological backgrounds, spatial learning was assessed with the Morris water maze test (MWM) in male 3xTg Alzheimer's model mice of 5-6 months old, then their hippocampal tissue was examined by electron microscopy (EM). By assigning EM-based asymmetric and symmetric synapses to excitatory (E) and inhibitory (I) synapses, respectively, and by attributing synapses on spines to those onto excitatory (E) postsynaptic neurons, we defined 2 different types of synapses: E-to-E and I-to-E synapses. In addition, synapses onto non-spinous structures (N) of postsynaptic neurons were designated as E-to-N or I-to-N. We thus categorized hippocampal synapses into 4 classes. I-to-E synapses were 7-fold denser in 3xTg than in wild-type mice, whereas the other types did not differ in density. In MWM, there was a non-significant tendency that AD mice perform worse than WT mice. We found a non-significant tendency for the E-to-E synapse density to correlate inversely with MWM performance in AD mice, though the correlation was significant with AD and WT mice pooled together. When E-to-E and E-to-N synapses are combined as the asymmetric synapse class, the density was significantly correlated in AD mice isolated. The I-to-E synapse density in AD mice exhibited the tendency to inverse correlation with MWM performance. Overall, categorizing hippocampal synapses into 4 classes, we confirmed from a new angle the received view that a higher hippocampal excitability could deteriorate cognition.},
}

@article {pmid41048559,
year = {2025},
author = {Ma, X and Wang, F and Wang, G and Zhao, M and Zheng, Y and Guo, Y and Wu, J and Liu, Y and Liu, Y and He, G and Ren, L and Gong, Z and Wang, J and Chen, L and Hu, S and Chu, Q and Li, Z and Wu, J and Li, R and Zhang, X and Shi, Q and Lian, H and Ye, J},
title = {A surgical therapy for Alzheimer's disease with lymphaticovenular anastomosis.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251384244},
pmid = {41048559},
issn = {2542-4823},
abstract = {BACKGROUND: Deep cervical lymphaticovenular anastomosis (dcLVA) surgery is able to control aging-associated Alzheimer's disease in patients. However, the efficacy rate remains unknown.

OBJECTIVE: This study is designed to test the surgery efficacy in the treatment of mild-to-moderate AD patients.

METHODS: This is a single-center retrospective study of dcLVA treatment of mild-to-moderate AD for 3 months. A total of 41 patients received the surgery, in which lymph vessels and lymph nodes in the district III of cervical area were identified using indocyanine fluorescence dye. The afferent lymphatics of the obstructed lymph nodes were connected to the jugular vein to fix the lymphatic blockage under a fluorescent microscope. The efficacy rate was examined at 3-month post-surgery by clinical scores and biomarkers.

RESULTS: Lymph flow obstruction was observed on both sides of cervical area in the AD patients. The obstruction was successfully resolved through the surgery, and AD progression was attenuated or even reversed in the patients according to improvement in the scales of MMSE, ADL, NPI, CDR-SB, and CGI-EI. The average effectiveness rate was 50% by the CDR-SB score improvement. The efficacy was higher with shorter disease duration but not influenced by age and APOE4 genotype. Aβ42/40 ratio and p-tau181 were improved in more than 67% patients. There were 2 cases of mild adverse reactions that were controlled immediately by regular treatments.

CONCLUSIONS: The data demonstrate that dcLVA surgery is an effective and safe therapy for AD in mild-to-moderate patients with 50% efficacy rate as measured by improvement of the CDR-SB score.},
}

@article {pmid41048558,
year = {2025},
author = {Petek, B and Mo, M and Xu, H and Norgren, J and Hoang, MT and Villa-Lopez, M and Häbel, H and Kele, J and Naia, L and Maioli, S and Pereira, JB and Gregorič Kramberger, M and Winblad, B and Eriksdotter, M and Carrero, JJ and Garcia-Ptacek, S},
title = {Statins, cholesterol and cognition at the time of Alzheimer's disease diagnosis: A cross-sectional study from the Swedish registry for cognitive/dementia disorders.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251385903},
pmid = {41048558},
issn = {2542-4823},
abstract = {BACKGROUND: Evidence suggests statins may influence cognition in Alzheimer's disease (AD), but specific use patterns in AD patients remain unclear.

OBJECTIVE: To identify factors influencing statin use in AD and explore associations between statins, cholesterol, and cognition, evaluated with Mini-Mental State Examination (MMSE) at dementia diagnosis.

METHODS: A cross-sectional study using data from the Swedish Registry for Dementia and Cognitive Disorders (SveDem) and Stockholm Creatinine Measurements (SCREAM) from 2007 to 2018. Multivariable logistic regression examined associations between baseline characteristics and statin use, while linear regression analyzed relationships between statins, cholesterol levels, and MMSE scores.

RESULTS: We included 3074 AD patients (mean age 78.1 years; 59.4% women), of whom 1028 used statins (79.6% simvastatin, 20.4% atorvastatin). Patients with diabetes mellitus, ischemic heart disease, or stroke had greater odds of receiving statins. Older patients had slightly lower odds of receiving any statin at baseline (simvastatin use OR 0.98, 95% CI 0.97-0.99). Simvastatin users had 0.53 points higher MMSE on average at baseline compared to non-users of statins (se 0.23, p = 0.021). Higher low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels were associated with higher MMSE in non-users of statins, but not in statin users.

CONCLUSIONS: Younger AD patients and those with cardiovascular disease were more likely to use statins. Simvastatin use was linked to higher cognitive scores at diagnosis. In non-users, higher LDL-C, TC, and HDL-C levels correlated with better baseline cognitive scores. Longitudinal studies are needed to investigate the effects of statins on cognitive decline in AD.},
}

@article {pmid41048557,
year = {2025},
author = {Jeong, H and Kang, D and Kim, JE and Lim, J and Lee, HW},
title = {Preliminary study on the feasibility of virtual reality-based cognitive training on patients with mild to moderate Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251385901},
pmid = {41048557},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that causes a decline in cognitive functions, considerably affecting a patient's life. Recently, virtual reality (VR) technology has emerged as a new tool used in the cognitive training of patients with AD.

OBJECTIVE: This study aimed to investigate the safety, feasibility, and clinical efficacy of VR-based cognitive training for patients with mild to moderate AD.

METHODS: Thirteen participants diagnosed with mild to moderate AD underwent VR training sessions by using the MentiTree software. Each session was conducted for 30 min twice a week for 9 weeks (total of 540 min). Cognitive functions were assessed before and after the intervention.

RESULTS: Although 1 of the 13 participants experienced adverse effects, the 9-week cognitive training was well tolerated and had a high feasibility of 93%±24.65%. A tendency toward improvement was observed in the visual recognition memory of the participants (p = 0.034), but other domains did not significantly change.

CONCLUSIONS: VR-based cognitive training is safely accepted by patients with mild to moderate AD. The potential of VR in AD treatment should be further explored using a randomized control group.},
}

@article {pmid41048330,
year = {2025},
author = {Puducheri, S and Zhou, OT and Kapadia, K and Romano, MF and Yalamanchili, S and Agrawal, A and Carlota Andreu-Arasa, V and Farris, CW and Mian, AZ and Paul, AB and Rohatgi, S and Setty, BN and Small, JE and Kolachalama, VB},
title = {Augmenting radiological assessment of imaging evident dementias with radiomic analysis.},
journal = {NPJ dementia},
volume = {1},
number = {1},
pages = {27},
pmid = {41048330},
issn = {3005-1940},
abstract = {Accurate differential diagnosis of dementia is essential for guiding timely treatment, particularly as anti-amyloid therapies become more widely available and require precise patient characterization. Here, we developed a radiomics-based machine learning (ML) approach to enhance neuroimaging assessments in distinguishing Alzheimer's disease (AD) from other imaging-evident dementias (OIED). We retrospectively analyzed 1041 individuals from the National Alzheimer's Coordinating Center with confirmed dementia diagnoses and at least one T1 or T2/FLAIR MRI scan. Using FastSurfer and a Lesion Prediction Algorithm, we extracted volumetric and lesion features, which were then used to train ML models. Model performance was compared to the independent evaluations of seven fellowship-trained neuroradiologists. The classifier achieved an AUROC of 0.79 ± 0.01 for AD and 0.66 ± 0.03 for OIED, performing comparably to expert assessments. Interpretation using SHAP values showed strong alignment with imaging features known to align with AD or OIED, respectively. These findings highlight the potential of radiomics to augment neuroimaging workflows.},
}

@article {pmid41048125,
year = {2025},
author = {Zhdankina, VI and Perepelitsa, ES and Blagova, AV and Komleva, YK and Baranich, TI and Salmina, AB},
title = {The involvement of HIF-1α-dependent paracrine factors in Alzheimer's disease.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {41048125},
issn = {2191-0200},
abstract = {Activated HIF-1α is a key regulator of various paracrine factors that influence vascular tone, angiogenesis, and cell survival, including endothelin-1, VEGF, Ang-2, erythropoietin, and SDF-1/CXCL12. These factors not only play established roles in vascular biology but are also critical in modulating neurogenesis. The intricate relationship between the brain's vascular system and its neurogenic niches underscores the importance of HIF-1 in facilitating their interactions. Angiogenesis and proper vessel perfusion are vital for the maintenance and proliferation of neural progenitor cells, especially in the context of neurodegenerative diseases such as Alzheimer's disease (AD). In AD, impaired angiogenesis can negatively impact neurogenesis, exacerbating cognitive decline. Recent transcriptomic and proteomic studies have revealed significant upregulation of HIF-1α expression in AD patients, indicating its potential involvement in the pathophysiology of this disease. This review aims to elucidate the role of HIF-1α and related hypoxia-inducible factors in AD, focusing on their diagnostic and therapeutic implications. We specifically examine two critical neurogenic niches in the adult brain: the subventricular zone (SVZ) and the subgranular zone (SGZ). Understanding how HIF-1α affects neurogenesis in these regions may offer novel insights into potential therapeutic strategies for AD, highlighting the need for further research into the intersection of hypoxia, angiogenesis, and neurogenesis in the context of neurodegeneration. By exploring these connections, we hope to contribute to a better understanding of AD pathophysiology and identify new avenues for intervention.},
}

@article {pmid41048081,
year = {2025},
author = {Palleis, C and Bernhardt, AM and Weidinger, E and Fietzek, UM and Jäck, A and Katzdobler, S and Gnörich, J and Bauer, T and Franzmeier, N and Perneczky, R and , and Brendel, M and Levin, J and Höglinger, GU},
title = {A Biomarker-Based Classification of Corticobasal Syndrome.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70070},
pmid = {41048081},
issn = {1531-8257},
support = {EXC 2145 SyNergy: ID 390857198//Deutsche Forschungsgemeinschaft/ ; BR4580/1-1/RO5194/1-1//Deutsche Forschungsgemeinschaft/ ; 19063p//Alzheimer Forschung Initiative/ ; //German Center for Neurodegenerative Diseases/ ; //German Parkinson's Association/ ; 19063p//Alzheimer Forschung Initiative e.V./ ; 390857198//Munich Cluster for Systems Neurology/ ; FKZ161L0214B//German Ministry of Research and Education/ ; FKZ161L0214C CLINSPECT-M//German Ministry of Research and Education/ ; //NOMIS Foundation/ ; //Volkswagen Stiftung/Lower Saxony Ministry for Science/Petermax-Müller Foundation/ ; //Thiemann Stiftung and Else-Kröner-Fresenius-Stiftung/ ; //Michael J. Fox Foundation/ ; },
abstract = {BACKGROUND: Corticobasal syndrome (CBS) is a clinically defined syndrome with progressive movement and cortical dysfunction, caused by various underlying pathologies, most commonly tau-predominant pathologies such as progressive supranuclear palsy and corticobasal degeneration, or Alzheimer's disease (AD). Lewy-type α-synucleinopathies (LTS), TDP-43 proteinopathies, and mixed pathologies may also underlie CBS. The clinical impact of these pathologies remains poorly understood.

OBJECTIVES: To subclassify CBS patients in vivo using biomarkers for amyloid-β (Aβ), Tau, and α-synuclein (αSyn), and assess the clinical relevance of this stratification.

METHODS: We conducted a prospective cohort study of 50 CBS patients at LMU University Hospital Munich. Biomarker analysis included cerebrospinal fluid (CSF) Aβ42 and Aβ42/40, [[18]F]flutemetamol Aβ-PET, [[18]F]PI-2620 tau-PET, and αSyn seed amplification assays in CSF. CSF neurofilament light chain (NfL) served as a marker of neurodegeneration. Patients were stratified into six groups based on biomarker positivity.

RESULTS: Tau positivity was found in 90% of CBS cases, Aβ in 28%, and αSyn in 24%. Stratification identified: 52% consistent with tau-predominant pathology, 18% with AD, 10% with AD+LTS, 10% with tau-predominant+LTS, 4% with isolated LTS, and 6% unclassified. αSyn positivity was more frequent in AD-CBS (36%) than in tau-predominant-CBS (16%). Aβ-positive cases showed greater cognitive impairment; Tau positivity correlated with worse motor symptoms; αSyn-positive patients had milder motor symptoms, slower progression, and lower NfL levels.

CONCLUSIONS: CBS is molecularly heterogeneous. Biomarker-based classification may enhance diagnostic precision and support personalized therapeutic strategies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.},
}

@article {pmid41047765,
year = {2025},
author = {Jayarathne, H and Manchanayake, DH and Sullivan, R and Chimienti, N and Kadri, O and Gurdziel, K and Kim, S and Jang, H and Ginsburg, BC and Miller, RA and Yakar, S and Sadagurski, M},
title = {Canagliflozin Reprograms the Aging Hippocampus in Genetically Diverse UM-HET3 Mice and Attenuates Alzheimer's-Like Pathology.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70255},
doi = {10.1111/acel.70255},
pmid = {41047765},
issn = {1474-9726},
support = {P30ES020957/ES/NIEHS NIH HHS/United States ; R01ES033171/ES/NIEHS NIH HHS/United States ; RF1AG078170/AG/NIA NIH HHS/United States ; //Impetus Grants for Longevity Research/ ; },
abstract = {Aging is the strongest risk factor for cognitive decline and Alzheimer's disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice. In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana's potential to combat brain aging and AD through sex-specific mechanisms.},
}

@article {pmid41047763,
year = {2025},
author = {Pinto, A and Haytural, H and Loss, CM and Alvarez, C and Ertas, A and Curtis, O and Williams, AR and Murphy, G and Salleng, KJ and Gografe, S and Visavadiya, NP and Khamoui, AV and Altıntaş, A and Kafri, T and Barres, R and Deshmukh, AS and van Praag, H},
title = {Muscle Cathepsin B Treatment Improves Behavioral and Neurogenic Deficits in a Mouse Model of Alzheimer's Disease.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70242},
doi = {10.1111/acel.70242},
pmid = {41047763},
issn = {1474-9726},
support = {NNF19SA0059305//Novo Nordisk Fonden/ ; NNF23SA0084103//Novo Nordisk Fonden/ ; NNF18CC0034900//Novo Nordisk Fonden/ ; RO1HL155986/HL/NHLBI NIH HHS/United States ; 9AZ02//Florida Department of Health/ ; },
abstract = {Increasing evidence indicates skeletal muscle function is associated with cognition. Muscle-secreted protease Cathepsin B (Ctsb) is linked to memory in animals and humans, but has an unclear role in neurodegenerative diseases. To address this question, we utilized an AAV-vector-mediated approach to express Ctsb in skeletal muscle of APP/PS1 Alzheimer's disease (AD) model mice. Mice were treated with Ctsb at 4 months of age, followed by behavioral analyses 6 months thereafter. Here we show that muscle-targeted Ctsb treatment results in long-term improvements in motor coordination, memory function, and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment normalizes hippocampal, muscle, and plasma proteomic profiles to resemble that of wildtype (WT) controls. In AD mice, Ctsb increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes. In muscle, Ctsb treatment elevates protein translation in AD mice, whereas in WT mice mitochondrial proteins decrease. In WT mice, Ctsb treatment causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.},
}

@article {pmid41047679,
year = {2025},
author = {Wang, R and Yang, X},
title = {Research Progress on the Pathogenesis, Therapeutic Strategies, and Phthalocyanine Compounds for Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050406141250822082635},
pmid = {41047679},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a formidable and complex neurodegenerative disorder driven by multifactorial interactions, including amyloid-beta (Aβ) aggregation, neurofibrillary tangles, and neuroinflammation etc. Current therapies mainly consist of cholinesterase inhibitors and NMDA receptor antagonists, which can alleviate symptoms but fail to reverse disease progression. In recent years, emerging approaches such as immunotherapy and gene therapy have shown potential but remain in clinical exploration. Phthalocyanine (Pc) compounds, with their ability to inhibit Aβ fibril formation, favorable biocompatibility, and optical properties, have demonstrated potential in AD diagnosis and treatment. This review discusses the pathogenesis, therapeutic strategies, and research progress of Pc compounds in AD. Furthermore, the elucidation of their mechanisms of action, the optimization of blood-brain barrier penetration, and the promotion of clinical translation are needed to provide new directions for AD therapy.},
}

@article {pmid41047654,
year = {2025},
author = {Shichijo, F},
title = {[Precautions for Neurosurgeons in Administering Anti-Amyloid β Antibody Therapy].},
journal = {No shinkei geka. Neurological surgery},
volume = {53},
number = {5},
pages = {1000-1012},
doi = {10.11477/mf.030126030530051000},
pmid = {41047654},
issn = {0301-2603},
mesh = {Humans ; *Amyloid beta-Peptides/immunology ; *Alzheimer Disease/drug therapy/therapy ; *Neurosurgeons ; *Antibodies, Monoclonal/therapeutic use ; },
abstract = {In Japan, anti-amyloid β (Aβ) monoclonal antibodies, including lecanemab and donanemab, have recently been approved as disease-modifying therapies for early-stage Alzheimer's disease (AD). These drugs, developed based on the amyloid cascade hypothesis, target toxic Aβ aggregates: lecanemab selectively binds to soluble protofibrils, while donanemab targets Aβ plaques. The Ministry of Health, Labour and Welfare (MHLW) has issued Optimal Use Guidelines that specify criteria for administration: informed consent from both patients and caregivers; cognitive assessments (MMSE and CDR); confirmation of Aβ pathology via amyloid PET or cerebrospinal fluid (CSF) testing; and MRI screening to assess the risk of amyloid-related imaging abnormalities (ARIA). ARIA is a significant adverse event and requires regular MRI monitoring. Initial administration is limited to certified facilities staffed by experienced specialists and equipped with the necessary diagnostic infrastructure. After six months, treatment may be continued at collaborating institutions. The APOEε4 genotype is a known risk factor for ARIA but is not covered by insurance. Caution is advised when co-administering anticoagulants or antiplatelet agents. The guidelines also require the use of official treatment cards to inform healthcare providers. This article summarizes the clinical precautions, diagnostic requirements, and facility standards necessary for implementing anti-Aβ antibody therapy in accordance with current MHLW Guidelines in Japan.},
}

Humans
*Amyloid beta-Peptides/immunology
*Alzheimer Disease/drug therapy/therapy
*Neurosurgeons
*Antibodies, Monoclonal/therapeutic use

@article {pmid41047650,
year = {2025},
author = {Miyajima, M and Kawai, Y and Bandai, H},
title = {[Hydrocephalus and Dementia].},
journal = {No shinkei geka. Neurological surgery},
volume = {53},
number = {5},
pages = {969-974},
doi = {10.11477/mf.030126030530050969},
pmid = {41047650},
issn = {0301-2603},
mesh = {Humans ; *Dementia/etiology/diagnosis/surgery ; *Hydrocephalus, Normal Pressure/complications/surgery/diagnosis ; Neuropsychological Tests ; },
abstract = {Idiopathic normal pressure hydrocephalus (iNPH), also known as Hakim's disease, is a major cause of reversible dementia in adults. iNPH primarily affects frontal lobe-related cognitive functions, including attention, executive function, and working memory, even in early stages. Although memory impairment is also present, recognition memory is often preserved, distinguishing iNPH from Alzheimer's disease (AD). Behavioral and psychological symptoms of dementia (BPSD), especially apathy, depression, and anxiety, are common in iNPH and are generally less active than those seen in AD. Neuropsychological assessments reveal significant impairments in frontal lobe tests such as the Frontal Assessment Battery and Trail Making Test-B. Shunt surgery leads to substantial improvement in attention and executive function, reflecting the reversible nature of iNPH. However, memory functions, particularly delayed recall, show limited recovery, indicating possible overlap with neurodegenerative mechanisms. Early surgical intervention is associated with better outcomes, while delayed treatment or advanced brain atrophy may reduce effectiveness. Comprehensive cognitive evaluation is essential for assessing treatment response, planning rehabilitation, and providing appropriate patient and family guidance.},
}

Humans
*Dementia/etiology/diagnosis/surgery
*Hydrocephalus, Normal Pressure/complications/surgery/diagnosis
Neuropsychological Tests

@article {pmid41047647,
year = {2025},
author = {Ota, M and Arai, T},
title = {[Pharmacological Interventions in Dementia].},
journal = {No shinkei geka. Neurological surgery},
volume = {53},
number = {5},
pages = {943-950},
doi = {10.11477/mf.030126030530050943},
pmid = {41047647},
issn = {0301-2603},
mesh = {Humans ; *Dementia/drug therapy ; Cholinesterase Inhibitors/therapeutic use ; },
abstract = {Pharmacological interventions for dementia include medications aimed at alleviating its core symptom: cognitive dysfunction. These medicines are known as anti-dementia drugs. As our understanding of Alzheimer's disease (AD) has advanced, the amyloid hypothesis stating that amyloid proteins are involved in the pathogenesis of AD has been proposed. To date, anti-dementia drugs such as cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists have focused on symptomatic treatment. In recent years, based on the amyloid hypothesis, the development of medicines that target either (1) the enzyme that produces amyloid beta (Aβ) or (2) Aβ itself, has been promoted as a treatment strategy for AD. In 2021, the first drug targeting Aβ, aducanumab, was launched in the USA. In Japan, lecanemab and donanemab are now available as monoclonal antibodies targeting Aβ. Additionally, medications have been used to manage the behavioral and psychological symptoms of dementia (BPSD), Parkinsonism, and rapid eye movement sleep behavior disorder. Furthermore, dementia is a major risk factor for delirium, which often occurs during the course of dementia. In this study, we introduce pharmacotherapy with anti-dementia drugs, BPSD treatment, and delirium.},
}

Humans
*Dementia/drug therapy
Cholinesterase Inhibitors/therapeutic use

@article {pmid41047645,
year = {2025},
author = {Ishiguro, T and Kasuga, K},
title = {[Current Status and Future Perspectives of Biomarkers in Alzheimer's Disease Diagnosis].},
journal = {No shinkei geka. Neurological surgery},
volume = {53},
number = {5},
pages = {923-931},
doi = {10.11477/mf.030126030530050923},
pmid = {41047645},
issn = {0301-2603},
mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; *Biomarkers/cerebrospinal fluid/blood ; Amyloid beta-Peptides ; tau Proteins/blood ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, characterized by the pathological accumulation of amyloid-β (Aβ) and phosphorylated tau in the brain. Recent advances in biomarker technology have significantly improved AD diagnosis and treatment. Cerebrospinal fluid biomarkers and amyloid positron emission tomography imaging are now available in clinical settings and serve as key tools in identifying early-stage AD, especially when considering anti-Aβ monoclonal antibody therapies. In 2024, the Alzheimer's Association proposed revised diagnostic criteria that integrate both biomarker-based and clinical staging systems. This framework introduces a classification of "core biomarkers" that reflect AD-specific pathology and defines biological and clinical symptom stages. Furthermore, blood-based biomarkers, such as plasma p-tau217 and MTBR-tau243, are gaining attention as minimally invasive tools for early diagnosis and disease staging. As these biomarkers become more accessible, proper interpretation within a clinical context remains essential. In Japan, biomarker testing is currently recommended only for symptomatic individuals, and its use requires careful judgment regarding indications and relevance to the clinical setting. This review outlines the evolution of diagnostic criteria, current and emerging biomarkers, and their implications for personalized AD care while emphasizing the need for expert clinical interpretation to ensure responsible and patient-centric use.},
}

Humans
*Alzheimer Disease/diagnosis/metabolism
*Biomarkers/cerebrospinal fluid/blood
Amyloid beta-Peptides
tau Proteins/blood

@article {pmid41047644,
year = {2025},
author = {Shiino, A},
title = {[Neuroimaging in Dementia Diagnosis:Up to Date].},
journal = {No shinkei geka. Neurological surgery},
volume = {53},
number = {5},
pages = {893-922},
doi = {10.11477/mf.030126030530050893},
pmid = {41047644},
issn = {0301-2603},
mesh = {Humans ; *Neuroimaging/methods ; *Dementia/diagnostic imaging/diagnosis ; Positron-Emission Tomography ; Alzheimer Disease/diagnostic imaging/diagnosis ; Magnetic Resonance Imaging ; },
abstract = {With the clinical application of monoclonal antibody therapy for Alzheimer's disease (AD), diagnostic techniques are shifting toward molecular-targeted imaging. The development of tracers for positron emission tomography (PET) targeting abnormal proteins associated with the disease, such as amyloid-beta and tau, has enabled the detection of neuropathological changes in AD in vivo. This study will contribute to the clinical diagnosis, staging, and monitoring of potential therapeutic approaches for AD. In general outpatient care, imaging modalities that employ widely available techniques such as magnetic resonance imaging or single-photon emission computed tomography remain necessary. This article provides a synopsis of the American College of Radiology recommendations concerning the clinical utility of neuroimaging techniques and reviews the temporal progression of in vivo pathologies derived from amyloid and tau PETs. We investigated the methods for distinguishing between the AD continuum and SNAP in patients with mild cognitive impairment using the ADNI database. Accurate assessment of the "cortical signature" is essential for the diagnosis of AD. Voxel-based morphometry is a useful tool because cortical atrophy is associated with the extension of tau PET lesions. Confirmation of cortical atrophy in conjunction with hippocampal atrophy offers diagnostic insights that facilitate the identification of AD.},
}

Humans
*Neuroimaging/methods
*Dementia/diagnostic imaging/diagnosis
Positron-Emission Tomography
Alzheimer Disease/diagnostic imaging/diagnosis
Magnetic Resonance Imaging

@article {pmid41047642,
year = {2025},
author = {Kano, M and Tomita, T},
title = {[Molecular Genetics and Protein Molecules in Dementia].},
journal = {No shinkei geka. Neurological surgery},
volume = {53},
number = {5},
pages = {873-882},
doi = {10.11477/mf.030126030530050873},
pmid = {41047642},
issn = {0301-2603},
mesh = {Humans ; Animals ; *Dementia/genetics/metabolism ; tau Proteins/genetics/metabolism ; Mutation ; Alzheimer Disease/genetics ; Amyloid beta-Peptides/metabolism/genetics ; },
abstract = {Alzheimer's disease (AD), the most common cause of dementia, is marked by the pathological accumulation of misfolded proteins in the brain. Its key pathological features include extracellular amyloid β (Aβ) plaques and intracellular tau neurofibrillary tangles, both of which contribute to synaptic dysfunction and neuronal death. Familial AD is linked to mutations in the APP, PSEN1, or PSEN2 genes, which promote increased Aβ production or aggregation. In contrast, frontotemporal dementia (FTD), including FTDP-17, is associated with MAPT mutations that lead to tau fibril accumulation independent of Aβ pathology. Recent advances in cryo-electron microscopy (cryo-EM) have revealed disease-specific conformations of Aβ and tau fibrils at atomic resolution, highlighting the role of structural polymorphism in disease progression. Aβ contributes to synaptic deficits and activates glial cells, thereby initiating neuroinflammatory responses. Genetic risk factors such as APOE and TREM2 influence these pathological processes. Transgenic mouse models carrying familial mutations have replicated certain aspects of AD pathology. However, most models fail to fully reproduce the human-like filament structures or the sequential progression from Aβ to tau pathology. Novel knock-in models, combined with cryo-EM-based validation, now provide a more accurate platform for studying disease mechanisms and developing targeted therapies.},
}

Humans
Animals
*Dementia/genetics/metabolism
tau Proteins/genetics/metabolism
Mutation
Alzheimer Disease/genetics
Amyloid beta-Peptides/metabolism/genetics

@article {pmid41047641,
year = {2025},
author = {Saito, Y},
title = {[Neuropathology of Argyrophilic Grain Disease].},
journal = {No shinkei geka. Neurological surgery},
volume = {53},
number = {5},
pages = {863-872},
doi = {10.11477/mf.030126030530050863},
pmid = {41047641},
issn = {0301-2603},
mesh = {Humans ; *Dementia/pathology/diagnosis ; },
abstract = {Dementia is classified into various types with corresponding underlying pathologies, including Alzheimer's disease, dementia wiht Lewy bodies, and vascular dementia; final diagnosis is often possible only after a pathological examination during an autopsy. Furthermore, older adults often have comorbid pathologies that make clinical diagnosis even more difficult. While protein-targeted treatments are emerging, different dementia types have varying pathologies and prognoses, necessitating efforts to improve diagnostic accuracy while the patient is alive. To achieve this, autopsy diagnosis information must be correlated with clinical biomarker data.},
}

Humans
*Dementia/pathology/diagnosis

@article {pmid41047640,
year = {2025},
author = {Tamaoka, A},
title = {[Classification and Clinical Characteristics of Dementia].},
journal = {No shinkei geka. Neurological surgery},
volume = {53},
number = {5},
pages = {853-862},
doi = {10.11477/mf.030126030530050853},
pmid = {41047640},
issn = {0301-2603},
mesh = {Humans ; *Dementia/classification/diagnosis ; Lewy Body Disease/diagnosis ; },
abstract = {Community-based surveys conducted in Japan investigating the prevalence of dementia and its underlying causes revealed that dementia of Alzheimer's type (DAT) is the most common, followed by vascular dementia (VaD), dementia with Lewy bodies (DLB), mixed dementia, and other conditions including frontotemporal lobar degeneration (FTLD). Accurate differential diagnosis of these disorders requires clarification of their clinical characteristics. The initial symptoms of DAT typically include recent memory loss, episodic memory impairment, and temporal disorientation. Behavioral and psychological symptoms often observed in DAT include delusions of theft, "saving appearance" responses, and head-turning signs. Vascular dementia develops in association with cerebrovascular disease and frequently exhibits a stepwise progression. DLB is characterized by core clinical features such as cognitive fluctuations, visual hallucinations, parkinsonism, and REM sleep behavior disorder. Diagnostic tools such as [123]Iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy and dopamine transporter (DAT) imaging may aid in diagnosis. In Parkinson's disease with dementia (PDD), cognitive impairment appears more than one year after the onset of parkinsonism. FTLD involves degeneration of the frontal and temporal lobes, leading to prominent changes in personality, behavior, and language function. Several subtypes of FTLD exist depending on the affected brain region, including the behavioral variant of frontotemporal dementia, semantic dementia, and progressive non-fluent aphasia. Idiopathic normal-pressure hydrocephalus (iNPH) is characterized by gait disturbance, urinary incontinence, and dementia, resulting from an abnormal accumulation of cerebrospinal fluid. Pathologically confirmed cases of DLB and progressive supranuclear palsy (PSP) may occasionally present with symptoms resembling iNPH.},
}

Humans
*Dementia/classification/diagnosis
Lewy Body Disease/diagnosis

@article {pmid41047467,
year = {2025},
author = {Wijesinghe, P and Hosseini, A and Campbell, M and Tejpal, S and Haynes, J and Xi, J and Mackenzie, IR and Hirsch-Reinshagen, V and Hsiung, GR and Spiller, BW and Wadzinski, BE and Pham, W and Matsubara, JA},
title = {Decoding amyloid beta clearance systems at inner blood-retina barrier using three-dimensional ex vivo retinal imaging in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {9},
pages = {e70592},
doi = {10.1002/alz.70592},
pmid = {41047467},
issn = {1552-5279},
support = {//Alzheimer Society of Canada and Brain Canada/ ; //Canadian Institute of Health Research/ ; //National Sciences and Engineering Research Council of Canada/ ; NIA R01 AG061138/NH/NIH HHS/United States ; UL1TR002243//Vanderbilt CTSA Grant/ ; //NCATS/NIH/ ; //Vanderbilt-Ingram Cancer Center Shared Resource Scholarship/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism/diagnostic imaging ; Animals ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Blood-Retinal Barrier/metabolism/pathology/diagnostic imaging ; Humans ; *Retina/metabolism/pathology/diagnostic imaging ; Mice ; Imaging, Three-Dimensional ; Amyloid beta-Protein Precursor/genetics/metabolism ; Presenilin-1/genetics ; Disease Models, Animal ; Male ; Female ; Blood-Brain Barrier/metabolism ; Microglia/metabolism/pathology ; Aged ; },
abstract = {INTRODUCTION: Impaired amyloid beta (Aβ) clearance contributes to sporadic Alzheimer's disease (AD). This study investigated retinal Aβ clearance involving neuronal, glial, and vascular interactions at the inner blood-retina barrier (iBRB), a functional analog of the blood-brain barrier (BBB).

METHODS: Retinal wholemounts from AD donors and controls were analyzed alongside transgenic amyloid precursor protein/presenilin 1 (APP-PS1) and non-carrier control mouse retinal cross-sections using three- and two-dimensional ex vivo imaging.

RESULTS: AD neuroretinas displayed increased larger Aβ42 deposits, microglial elongation, and substantial reductions in macroglial support and water channel expression. The uptake of soluble Aβ oligomers (SAβOs) by peripheral macrophage-like, Aβ-binding myeloid lineage cells was also diminished. In APP-PS1 mice, elevated glia levels, alongside increased APP/Aβ expression, suggest gliosis and failures in clearance processes with disease progression.

DISCUSSION: Ex vivo three-dimensional retinal imaging at the iBRB provides novel insights into Aβ clearance in AD, which is difficult to replicate in ex vivo brain studies at the BBB.

HIGHLIGHTS: Impaired clearance mechanisms play a key role in sporadic AD. The iBRB serves as a functional analog to the BBB. At the iBRB, the glymphatic system and microglial phagocytosis help mitigate Aβ burden. Peripheral macrophage-like myeloid lineage cells may aid SAβO clearance. The imaging plane (surface vs cross-section) may affect AD pathogenesis findings.},
}

*Alzheimer Disease/pathology/metabolism/diagnostic imaging
Animals
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Blood-Retinal Barrier/metabolism/pathology/diagnostic imaging
Humans
*Retina/metabolism/pathology/diagnostic imaging
Mice
Imaging, Three-Dimensional
Amyloid beta-Protein Precursor/genetics/metabolism
Presenilin-1/genetics
Disease Models, Animal
Male
Female
Blood-Brain Barrier/metabolism
Microglia/metabolism/pathology
Aged

@article {pmid41047224,
year = {2025},
author = {Graham, N and Zimmerman, K and Hain, J and Rooney, E and Lee, Y and Del Giovane, M and Parker, T and Wilson, M and Patel, M and Veleva, E and Swann, O and Heslegrave, AJ and Li, LM and Zetterberg, H and Friedland, D and Sylvester, R and Sharp, D},
title = {Midlife plasma proteomic profiles indicate altered amyloid and tau processing in former elite rugby players.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-336593},
pmid = {41047224},
issn = {1468-330X},
abstract = {BACKGROUND: Contact sports, including rugby union, are associated with higher rates of neurodegenerative dementia, due to various underlying pathologies such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). New ultrasensitive multiplexed immunoassays may clarify disease mechanisms after repetitive head impacts (RHI) and traumatic brain injury, potentially aiding risk-stratification, early diagnosis and dementia treatment.

METHODS: Midlife participants in the ABHC cohort underwent plasma biomarker quantification (NULISA - NUcleic acid Linked Immuno-Sandwich Assay; n=124 markers), 3T MRI, trauma exposure ascertainment and phenotyping. Regressions quantified exposure-specific protein expression, relationship to trauma (including position) and brain atrophy, using cluster analysis to test correlates of traumatic encephalopathy syndrome (TES).

RESULTS: 197 former elite rugby players and 33 controls were assessed. 24 (12.2%) met criteria for TES but none had dementia. Ex-players returned reduced plasma glial fibrillary acidic protein (GFAP), kallikrein-6 (KLK6) and synaptosomal-associated protein 25 (SNAP25). Ex-forwards specifically showed reduced plasma beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid beta-38 (Aβ38), and increased phospho-tau181 (p-tau181). KLK6 was lower in ex-backs than controls. No biomarkers related to career duration, concussion load or regional brain volume, nor did clustering relate to TES.

CONCLUSIONS: Ex-players showed distinctive plasma biomarker changes, more prominently in ex-forwards, possibly reflecting greater RHI exposure. Plasma KLK6, an endothelial serine protease, was reduced across the ex-player group, with potential diagnostic or prognostic utility in future. Reduced GFAP and SNAP25 in ex-forwards has an uncertain basis, while elevated p-tau-181 more so than p-tau217 points towards non-AD tau pathology. Our findings motivate longitudinal characterisation, including comparison with other neurodegenerative diseases.},
}

@article {pmid41047159,
year = {2025},
author = {Zoatier, B and Yildiztekin, G and Alagoz, MA and Hepokur, C and Dilek, E and Algul, O},
title = {Benzoxazole Derivatives as Dual p38α Mitogen-Activated Protein Kinase and Acetylcholinesterase Inhibitors: Design, Synthesis, and Evaluation for Alzheimer's Disease and Cancer Therapy.},
journal = {ChemMedChem},
volume = {},
number = {},
pages = {e202500669},
doi = {10.1002/cmdc.202500669},
pmid = {41047159},
issn = {1860-7187},
support = {2020-1-TP3-4028//Mersin Üniversitesi/ ; },
abstract = {Alzheimer's disease (AD), the most prevalent form of dementia, leads to progressive cognitive decline due to pathological hallmarks including amyloid plaques, neurofibrillary tangles, synaptic loss, neuroinflammation, and neuronal cell death, highlighting the urgent need for multitarget therapeutic strategies. The p38α mitogen-activated protein kinase (p38α MAPK) pathway is a key regulator of neuroinflammation and has been implicated in AD pathogenesis. Additionally, dysregulation of p38α MAPK is associated with tumorigenesis, making it a promising target for both neurodegenerative and proliferative diseases. In this article, a series of benzoxazole derivatives is designed and synthesized to evaluate their dual inhibitory potential against p38α MAPK and acetylcholinesterase (AChE), aiming for a multifaceted therapeutic approach to AD. A total of 31 compounds are synthesized and assessed for their antiproliferative activity, p38α MAPK inhibition, and AChE inhibitory effects. In vitro assays demonstrate that several compounds exhibit potent dual inhibition of p38α MAPK and AChE, while molecular docking studies provide insights into their binding interactions within the active sites. These findings suggest that benzoxazole-based scaffolds offer a promising framework for the development of dual-acting inhibitors targeting both neuroinflammation and tumorigenesis. Further in vivo and mechanistic studies are warranted to explore their therapeutic potential.},
}

@article {pmid41047157,
year = {2025},
author = {Grishchenko, MV and Makhaeva, GF and Burgart, YV and Kovaleva, NV and Boltneva, NP and Skornyakova, TS and Rudakova, EV and Astakhova, TY and Timokhina, EN and Pronkin, PG and Shchegolkov, EV and Saloutin, V and Charushin, VN},
title = {Synthesis of Tacrine/Amiridine Conjugates with Aminomethylidene Derivatives of Trifluoroacetoacetic Ester and their Biological Potential for the Therapy of Alzheimer's Disease.},
journal = {ChemMedChem},
volume = {},
number = {},
pages = {e202500723},
doi = {10.1002/cmdc.202500723},
pmid = {41047157},
issn = {1860-7187},
support = {24-63-00016//Russian Science Foundation/ ; },
abstract = {To assess the influence of the nature of the anticholinesterase pharmacophore on the properties of potential multitarget Alzheimer's disease (AD) agents, new conjugates of tacrine (3a, b) and amiridine (5a, b) with ethyl-2-aminomethylidene-4,4,4-trifluoro-3-oxobutanoate linked by an alkylene spacer with n = 4,6 were synthesized. All conjugates are effective cholinesterase inhibitors with predominant inhibition of butyrylcholinesterase (BChE). The inhibitory activity of tacrine conjugates 3a, b toward acetylcholinesterase (AChE) and BChE increases with spacer elongation: IC50 AChE up to 0.185 µM, IC50 BChE up to 0.0806 µM. Amiridine conjugates 5a, b are less active as AChE inhibitors and their anti-AChE activity (IC50 up to 3.09 µM) remains virtually unchanged with spacer elongation, while anti-BChE activity increases significantly (n = 6, IC50 = 0.063 µM), which leads to increased selectivity toward BChE (up to 56). The effects are consistent with the results of kinetic studies and molecular docking of 3b and 5b. Both types of conjugates displace propidium from the AChE peripheral anionic site at the level of and above that of donepezil, and are capable of blocking self-aggregation of β-amyloid (up to 49.5%). The compounds demonstrate very weak antioxidant activity (tacrine conjugates) or its absence (amiridine). Thus, new conjugates are potential multitarget anti-AD agents with high selectivity toward BChE for amiridine derivative 5b.},
}

@article {pmid41047041,
year = {2025},
author = {Fan, X and Wang, H and Ping, J and Li, M and Gu, J and Qian, W},
title = {Synaptic scaffold protein PSD-95: a therapeutic target for Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117401},
doi = {10.1016/j.bcp.2025.117401},
pmid = {41047041},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder marked by gradual cognitive deterioration and distinct neuropathological characteristics. The abnormal accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are the hallmarks of AD. In fact, synaptic loss and damage occur earlier than amyloid plaques and NFTs in the progression of AD and are most closely associated with the cognitive deficits exhibited by AD patients. In this review, we discuss the expression level, localization, posttranslational modification and interaction proteins of PSD-95, as well as their roles in synaptic plastisity. We also review the mechanisms through which PSD-95 contributes to synaptic dysfunction in AD. Moreover, the potential of PSD-95 as an early biomarker for AD is also discussed, along with the therapeutic approaches that target PSD-95 for patients afflicted with the disease. The objective of this review is to offer comprehensive insights into the early pathogenesis of Alzheimer's disease and to aid in the development of novel diagnostic and treatment methodologies grounded in this understanding.},
}

@article {pmid41047006,
year = {2025},
author = {Stefano, GB and Büttiker, P and Weissenberger, S and Raboch, J and Anders, M},
title = {Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.},
journal = {Frontiers in neuroendocrinology},
volume = {},
number = {},
pages = {101217},
doi = {10.1016/j.yfrne.2025.101217},
pmid = {41047006},
issn = {1095-6808},
abstract = {While mitochondria provide critical energy resources, mitochondrial dysfunction can lead to both metabolic and neurodegenerative disorders. Primary mitochondrial disorders (e.g., Leigh syndrome) are uniformly associated with profound neurodegeneration. Recent studies have also implicated mitochondrial dysfunction as a central feature of progressive neurodegenerative diseases, notably Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease. In addition to its profound impact on metabolic disease, the glucagon-like peptide-1 receptor agonist, semaglutide, has significant neuroprotective features and may limit the progression of one or more of these disorders. These observations might be explained at least in part by the impact of this drug on mitochondrial function and energy production. Collectively, these observations highlight disrupted energy homeostasis as a critical feature of neurodegenerative disease and suggest novel targets for the development of much-needed new neuropharmaceutical strategies.},
}

@article {pmid41046825,
year = {2025},
author = {Manful, EE and Adu-Amankwaah, F and Madhvi, A and Bubb, K and Pietersen, RD and Baker, B},
title = {Therapeutic potential of IFIT2 in human diseases.},
journal = {Cytokine},
volume = {196},
number = {},
pages = {157049},
doi = {10.1016/j.cyto.2025.157049},
pmid = {41046825},
issn = {1096-0023},
abstract = {The interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is a crucial member of the interferon-stimulated gene (ISG) family, widely acknowledged for its antiviral activity. IFIT2 functions primarily through AU-rich RNA binding, aiding in viral suppression by inhibiting protein translation and promoting apoptosis via mitochondrial pathways. While traditionally known for its role in antiviral defence, emerging research highlights its broader significance in cancer, bacterial and fungal infections, autoimmune diseases, neurological disorders, and metabolic and cardiovascular conditions. Notably, IFIT2 is the only IFIT family member with established tumour suppressor properties, demonstrating anti-proliferative effects in multiple cancers, including lung, renal, colorectal, breast, and gallbladder cancers. Beyond oncology, IFIT2 has been implicated in the host response to Mycobacterium tuberculosis, Plasmodium spp., Candida albicans, and Treponema pallidum, where it modulates immune responses and infection outcomes. It is upregulated in several autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, and multiple sclerosis, suggesting its potential as a diagnostic and therapeutic biomarker. Furthermore, transcriptomic analyses have linked IFIT2 to disease progression and treatment response in conditions like diabetic ulcers, gestational diabetes, ischaemic cardiomyopathy, schizophrenia, and Alzheimer's disease. This review thoroughly examines the molecular structure, regulatory mechanisms, and diverse roles of IFIT2 in human diseases. It addresses its interaction with key immune pathways, its ability to modulate apoptosis and inflammation, and its potential as a prognostic marker and therapeutic target. Although its mechanistic functions in numerous diseases remain only partly understood, IFIT2 emerges as a versatile immune effector with considerable translational promise. Further investigation into its biological roles will be crucial for utilising its therapeutic potential across infectious, inflammatory, metabolic, and neoplastic diseases.},
}

@article {pmid41046731,
year = {2025},
author = {Adeoye, T and Ullah, G},
title = {Pathological calcium influx through amyloid beta pores disrupts synaptic function.},
journal = {Cell calcium},
volume = {132},
number = {},
pages = {103083},
doi = {10.1016/j.ceca.2025.103083},
pmid = {41046731},
issn = {1532-1991},
abstract = {Alzheimer's disease (AD) is characterized by profound disruption of synaptic function, with mounting evidence suggesting that amyloid-β (Aβ) oligomers disrupt calcium (Ca[2+]) homeostasis through membrane pore formation. While these pores are known to alter intracellular Ca[2+] dynamics, their immediate impact on synaptic transmission and potential interaction with Familial AD (FAD)-associated endoplasmic reticulum (ER) dysfunction remains unclear. Here, we extend our previously developed model of presynaptic Ca[2+] dynamics to examine how Aβ pores alter exocytosis and how such disruptions may manifest in the presence of FAD-associated ER dysfunction. Our model reveals that Aβ pores fundamentally alter both the timing and strength of neurotransmitter release. Unexpectedly, the impact of pores on synaptic function depends critically on their pattern of activity, where continuous pore activity leads to synaptic hyperactivation, while brief periods of intense pore activity trigger lasting hypoactivation at short timescales. These effects manifest most strongly in synapses with low and intermediate release probabilities, highlighting the established selective vulnerability of such synaptic configurations. We find that Aβ pores and FAD-driven ER Ca[2+] dysregulation form an integrated pathological unit through bidirectional coupling of their respective Ca[2+] microdomains to create complex patterns of disruptions. This coupling creates a feedback loop that produces an additive effect on neurotransmitter release during brief stimulations, but non-additive effects during sustained activity that promotes a shift towards asynchronous release. Surprisingly, our simulations predict that extended pore activity does not worsen indefinitely but only produces a modest additional disruption beyond initial pore formation that is likely determined by the intrinsic properties of the synapse. These findings indicate that early synaptic dysfunction in AD may arise from subtle perturbations in the temporal coordination of release rather than gross Ca[2+] dysregulation, providing new mechanistic insights into the progressive nature of Aβ-driven synaptic failure in AD.},
}

@article {pmid41046686,
year = {2025},
author = {Wang, S and Zhang, Z and Liu, Y and Gao, S and Wang, L and Yang, J and Wang, Y},
title = {Phytochemicals as modulators of Astrocytes in Alzheimer's disease: A therapeutic perspective.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {148},
number = {},
pages = {157347},
doi = {10.1016/j.phymed.2025.157347},
pmid = {41046686},
issn = {1618-095X},
abstract = {BACKGROUND: Astrocytes play a crucial role in Alzheimer's disease (AD) pathogenesis, contributing to inflammation, amyloid plaque formation, and disease progression, making them promising therapeutic targets. Despite extensive research, the mechanisms underlying astrocytic dysfunction in AD and their modulation by phytochemicals remain incompletely understood, representing a critical gap in current knowledge.

PURPOSE: This review aims to elucidate the pathological mechanisms involving astrocytes in AD and evaluate the therapeutic potential of phytochemicals in modulating astrocytic activity.

METHODS: We systematically analysed recent studies on astrocytic activation, target receptors, and signalling pathways in AD and their regulation by phytochemicals. The studies were identified through searches of databases including PubMed, Web of Science, ScienceDirect, and Google Scholar.

RESULTS: Our findings reveal that abnormal activation of astrocytic receptors and downstream signaling pathways, such as RAGE/NF-κB, ERK/c-fos/NFATc1, AKT/Nrf2/NF-κB, and PI3K/Akt/GSK-3β, disrupt immune homeostasis in AD models. Phytochemicals, including tanshinone IIA, honokiol, aucubin, cornuside, luteolin, naringenin, daphnetin, and gelsemine, show promising effects in delaying AD progression. These effects are mediated through multiple mechanisms, such as inhibiting pro-inflammatory pathways, enhancing anti-inflammatory responses, promoting Aβ clearance, stimulating synaptogenesis, regulating neurotrophic factors, and reducing oxidative stress. These findings highlight the pivotal role of astrocytes in AD pathophysiology and the potential of phytochemicals to modulate astrocytic dysfunction.

CONCLUSIONS: By providing a comprehensive overview of astrocytic mechanisms and therapeutic interventions, this review offers a theoretical foundation for developing phytochemical-based strategies in AD therapy and underscores the need for further preclinical and clinical investigations to translate these findings into practical treatments.},
}

@article {pmid41046632,
year = {2025},
author = {Fuh, JL and Wang, SJ and Wang, PN and Wu, HM and Su, WS and Lin, HM and Yang, FY},
title = {Safety and efficacy of transcranial ultrasound stimulation for the treatment of Alzheimer's disease: A randomized, double-blind, placebo-controlled trial.},
journal = {Ultrasonics},
volume = {159},
number = {},
pages = {107844},
doi = {10.1016/j.ultras.2025.107844},
pmid = {41046632},
issn = {1874-9968},
abstract = {Transcranial ultrasound stimulation (TUS) has emerged as a potential neuromodulatory intervention for Alzheimer's disease (AD). This pilot randomized, double-blind, placebo-controlled trial evaluated TUS's safety and preliminary efficacy in patients with mild AD. Patients aged 50-90 years were enrolled and randomly assigned at a 2:1 ratio to receive TUS treatment for 30 sessions (15 min/day, 5 days/week for 6 weeks) or a placebo procedure. Safety was monitored through magnetic resonance imaging, adverse event reporting, and laboratory assessments. Efficacy was assessed with the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Mini-Mental State Examination (MMSE). Nine of 30 patients screened were enrolled (six TUS, three placebo). All patients completed the study, and no serious clinical or radiographic adverse events related to TUS were observed. At 52 weeks, the change in ADAS-cog score from baseline remained relatively stable in the TUS group compared to worsening in the placebo group (0.5 ± 4.7 vs. 5.0 ± 4.0, p = 0.237), particularly in the memory domain. The change in MMSE score from baseline showed a significant benefit in the TUS group at 24 weeks compared to placebo (2.2 ± 2.2 vs. -3.0 ± 2.6, p < 0.05), and this improvement persisted to 52 weeks. This study demonstrates the safety and feasibility of repeated TUS sessions in AD and suggests potential benefits in preserving cognitive function. Larger, adequately powered trials are required to validate these preliminary findings and further define the therapeutic potential of TUS in AD.},
}

@article {pmid41046322,
year = {2025},
author = {Wu, KC and Lin, CY and Tran, T and Lin, JH and Yeh, HH and Ho, CJ and Chern, Y and Lin, CJ},
title = {Preclinical Evaluation of a Novel Molecule Targeting Nucleoside Homeostasis to Restore Energy Metabolism and Cognitive Function in Alzheimer's Disease.},
journal = {Pharmacology research & perspectives},
volume = {13},
number = {5},
pages = {e70176},
pmid = {41046322},
issn = {2052-1707},
support = {AS-BRPT-110-11//Academia Sinica, Taiwan/ ; AS-KPQ-111-KNT//Academia Sinica, Taiwan/ ; MOST 110-3111-Y-001-002//Ministry of Science and Technology, Taiwan/ ; MOST 110-3111-Y-001-003//Ministry of Science and Technology, Taiwan/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Energy Metabolism/drug effects ; Mice ; Disease Models, Animal ; *Nucleosides/metabolism ; Homeostasis/drug effects ; Brain/metabolism/drug effects ; Mice, Transgenic ; *Cognition/drug effects ; Male ; Equilibrative Nucleoside Transporter 1/metabolism ; Mice, Inbred C57BL ; Humans ; Cognitive Dysfunction/drug therapy ; Positron-Emission Tomography ; },
abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia, characterized by progressive cognitive decline and cerebral metabolic impairment. Yet, the therapeutic options for addressing the disease pathogenesis are limited. Here, we report an approach by targeting brain nucleoside homeostasis and energy metabolism to alleviate AD-associated cognitive deficits. A compound, J4, was designed to modulate nucleoside homeostasis by interacting with the equilibrative nucleoside transporter-1 (ENT1). The effects of J4 on brain nucleoside homeostasis and energy metabolism were examined in mice. Two AD animal models, THY-Tau22 and APP/PS1 mice, were used to evaluate the translational potential of J4 for the treatment of AD. Cognitive function and functional ability were assessed using the Morris water maze, Y-maze, and nesting behavior tests. The pharmacodynamic marker was explored, and the pharmacokinetic and safety properties of J4 were evaluated. As a result, being administered after disease onset, oral J4 administration rescued memory and cognitive dysfunction in both tau and amyloid AD mouse models. Metabolomic analysis showed that J4 increased brain nucleoside levels and facilitated brain primary metabolism, including glucose metabolism and the pentose phosphate pathway. The [[18]F]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging further demonstrated that glucose metabolism can be used as a pharmacodynamic biomarker for the target engagement of J4 on ENT1. The nonclinical studies also demonstrated the ideal pharmacokinetic and safety profiles of J4, supporting that targeting nucleoside homeostasis can improve brain energy metabolism and is a promising approach for AD treatment.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
*Energy Metabolism/drug effects
Mice
Disease Models, Animal
*Nucleosides/metabolism
Homeostasis/drug effects
Brain/metabolism/drug effects
Mice, Transgenic
*Cognition/drug effects
Male
Equilibrative Nucleoside Transporter 1/metabolism
Mice, Inbred C57BL
Humans
Cognitive Dysfunction/drug therapy
Positron-Emission Tomography

@article {pmid41046300,
year = {2025},
author = {Wallgren, HA and Kivipelto, M and Plavén-Sigray, P and Svensson, JE},
title = {Pharmacokinetic analysis of intermittent rapamycin administration in early-stage Alzheimer's Disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41046300},
issn = {2509-2723},
abstract = {Rapamycin, an mTOR inhibitor used clinically for immunosuppression, shows promise for repurposing in age-related disorders, including Alzheimer's disease (AD). While the pharmacokinetics of daily rapamycin are well-characterized in transplant populations, limited data exist on intermittent dosing regimens in patients with neurodegenerative conditions. This open-label pilot study investigated the pharmacokinetic properties of weekly oral rapamycin in 13 patients with early-stage AD. Participants received 7 mg weekly (11 patients) or reduced doses (2 mg and 4 mg; 2 patients) for 26 weeks. Blood concentrations were measured at four timepoints (pre-dose/Cmin, and 1-, 3-, and 48-h post-dose) during week 13. Moderate interindividual variability was observed across timepoints (coefficient of variation was 0.28-0.40), with the 48-h sample showing the lowest variability (CoV = 0.28) and strongest correlation with Cmin from the previous dosing (r = 0.72). Estimate of terminal half-life (68.9 ± 13.6 h) aligned with previous studies. Blood concentrations at Cmin were below immunosuppressive levels in all participants. Our findings suggest that weekly rapamycin administration in AD patients results in acceptable pharmacokinetic variability, supporting fixed-dose regimens in future trials. The 48-h post-dose measurement appears optimal for monitoring blood concentrations. Additionally, our investigation into cerebrospinal fluid rapamycin quantification revealed methodological challenges due to analytical sensitivity limitations. The foremost limitation of this study was the sparse blood sampling schedule, with Cmin collected from the previous dosing occasion which prevented a complete AUC-calculation. ClinicalTrials.gov (NCT06022068) and EudraCT (2023-000127-36).},
}

@article {pmid41046244,
year = {2025},
author = {Chatterjee, S and Soria, M and Norville, ZC and Thompson, KR and Lillie, J and Kreitzer, AC and Wood, MW},
title = {Preclinical efficacy of the muscarinic agonist ML-007 in psychosis models depends on both M1 and M4 receptors.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41046244},
issn = {1740-634X},
abstract = {Muscarinic agonists represent a new class of treatments for psychosis with a mechanism distinct from typical and atypical antipsychotics. The muscarinic subtype M4 has been proposed as the primary mediator of efficacy but results from recent clinical trials with M4-selective compounds have drawn this hypothesis into question. Instead, activation of both M1 and M4 receptor subtypes may be required for robust treatment effects. Here, we characterize the clinical-stage muscarinic agonist ML-007 in preclinical models and explore its therapeutic potential for treating psychosis in schizophrenia and Alzheimer's disease. ML-007 is a potent brain-penetrant agonist at both M1 and M4 muscarinic receptors that has demonstrated compelling efficacy across a range of preclinical models of psychosis in schizophrenia including amphetamine-induced hyperlocomotion, PCP-induced hyperlocomotion, and conditioned avoidance response. Moreover, ML-007 is approximately ten-fold more potent than the comparator xanomeline in all animal models. Dose-response experiments in M1 and M4 knockout mice reveal that the efficacy of ML-007 is dependent on both M1 and M4 receptors. Taken together, our data suggest that both M1 and M4 receptors contribute to the potent efficacy of ML-007 in preclinical rodent models of psychosis.},
}

@article {pmid41046022,
year = {2025},
author = {Zhou, X and Lin, X and He, Y and Huang, N and Luo, Y},
title = {TDP-43 in Alzheimer's disease: Pathophysiology and therapeutic strategies.},
journal = {Pharmacological research},
volume = {221},
number = {},
pages = {107977},
doi = {10.1016/j.phrs.2025.107977},
pmid = {41046022},
issn = {1096-1186},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the dysregulation of multiple molecular mechanisms. In recent years, transactive response DNA-binding protein 43 kDa (TDP-43) has increasingly been recognized as a critical pathological protein and has become a prominent focus in AD research. TDP-43 is involved not only in physiological processes such as RNA metabolism, protein quality control, and mitochondrial regulation but also in AD pathology through abnormal aggregation, dysregulated nucleocytoplasmic transport, and aberrant posttranslational modifications, leading to neurotoxicity, mitochondrial dysfunction, and disrupted protein homeostasis. Studies have shown that TDP-43 closely interacts with two core pathological hallmarks of AD, β-amyloid (Aβ) and tau. By promoting Aβ oligomerization and tau hyperphosphorylation, TDP-43 accelerates the pathological progression of this disease. Given the multifaceted role of TDP-43 in AD, therapeutic strategies targeting TDP-43 have shown great potential. Approaches such as modulating its RNA splicing activity, inhibiting pathological aggregation, restoring the balance of nucleocytoplasmic transport, and preventing its mitochondrial localization offer new avenues for AD treatment. This review systematically summarizes the pathological mechanisms of TDP-43 in AD and its interactions with Aβ and tau and discusses the feasibility of targeting TDP-43 as a therapeutic strategy. Future studies should further elucidate the role of TDP-43 in the early stages of AD and develop specific therapeutic agents that target TDP-43, with the aim of providing new insights for precision treatment of AD.},
}

@article {pmid41046015,
year = {2025},
author = {Hari, E and Ulasoglu-Yildiz, C and Kurt, E and Yılmaz, N and Gurvit, H and Demiralp, T},
title = {Cortical functional connectivity changes in amnestic mild cognitive impairment.},
journal = {International journal of psychophysiology : official journal of the International Organization of Psychophysiology},
volume = {},
number = {},
pages = {113260},
doi = {10.1016/j.ijpsycho.2025.113260},
pmid = {41046015},
issn = {1872-7697},
abstract = {OBJECTIVE: Amnestic mild cognitive impairment (aMCI) is characterized by episodic memory deficits and is defined as the prodromal phase of Alzheimer's disease. Therefore, it is critical to reveal the dysfunction in large-scale networks during the dementia phase of the disease. This study aimed to examine the resting-state functional connectivity changes between aMCI and healthy control groups.

METHODS: MRI and clinical data from 25 individuals with aMCI and 25 healthy controls (HC) were used. Seed-to-seed functional connectivity analyses were performed between all histologically classified Brodmann areas using the CONN toolkit. False Discovery Rate (FDR) correction was used to correct for multiple comparisons, and the significance threshold was set at pFDR-corr < 0.05.

RESULTS: We found that, compared to HC, the aMCI group showed reduced functional connectivity between BA7 and both bilateral BA33 and right BA32, and these reductions were positively correlated with memory decline.

CONCLUSION: Our study suggests that the connectivity between the precuneus (BA7) and anterior cingulate cortex (BA32-33) is affected in the prodromal stage of Alzheimer's disease dementia. Investigating intrinsic functional connectivity changes between distant anatomical regions by using histological atlases might be useful for investigating the progress of dementia.},
}

@article {pmid41045929,
year = {2025},
author = {Luo, YJ and Li, L and Chen, ZK and Dong, P and Xie, L and Farmer, WT and Yu, QS and Jiang, LX and Su, WK and Liu, HS and Wang, HZ and Jiao, ZL and Melville, DJ and Penel, E and Sheehy, RN and Landry, T and Wang, J and Jiang, H and Xu, XH and Chen, X and Xu, NJ and Xue, T and Xu, TL and Li, YD and Song, J},
title = {Segregated supramammillary-dentate gyrus circuits modulate cognitive and affective function in healthy and Alzheimer's disease model mice.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2025.09.006},
pmid = {41045929},
issn = {1097-4199},
abstract = {While progressive cognitive decline is the defining feature of Alzheimer's disease (AD), many patients also develop prominent neuropsychiatric symptoms, including anxiety and depression. The circuit-level mechanisms underlying these distinct symptom domains remain poorly understood, and treatments that address both cognitive and noncognitive aspects of AD are limited. Here, we identify anatomically, molecularly, and functionally distinct subpopulations of supramammillary (SuM) neurons that project to either the dorsal or ventral dentate gyrus (dDG or vDG). These distinct SuM neurons and their SuM-DG subcircuits selectively regulate memory and emotion, respectively. In AD model mice, SuM neurons targeting dDG or vDG display aberrant activity during memory or emotional processing, and importantly, targeted optogenetic activation of SuM-dDG or SuM-vDG pathways selectively restores cognitive or affective function. These findings reveal SuM-DG subcircuits as parallel modulators of cognitive and emotional states and highlight their potential as therapeutic targets for addressing the multifaceted symptomatology of AD.},
}

@article {pmid41045719,
year = {2025},
author = {Swerdlow, NR and Sprock, J and Gonzalez, CE and Din, JM and Minhas, J and Talledo, J and Molina, JL and Joshi, YB and Léger, GC and Powell, L and Rana, B and Delano-Wood, L and Light, GA},
title = {Do cognitive and neurophysiological effects of acute memantine "challenge" predict its clinical benefits in Alzheimer's Disease?.},
journal = {Psychiatry research},
volume = {353},
number = {},
pages = {116740},
doi = {10.1016/j.psychres.2025.116740},
pmid = {41045719},
issn = {1872-7123},
abstract = {"Personalized" interventions based on patients' "biomarkers" may be valuable for treatments that benefit only subsets of patients. The NMDA antagonist, memantine, slows clinical progression of Alzheimer's disease (AD); this effect is heterogeneous in magnitude and duration. This study tested whether acute cognitive or neurophysiological responses to memantine challenge predicted sensitivity to memantine's therapeutic effects. Thirty individuals with mild-to-moderate severity AD (M:F = 13:17) and 24 comparably aged healthy subjects (HCS) (M:F = 12:12) were enrolled. Participants with AD were characterized on 9 experimental measures and their changes after acute memantine "challenge" (20 mg). We then assessed whether acute memantine effects on these measures predicted clinical change over a 24-week open-label trial of memantine. Baseline cognitive (Repeatable Battery for the Assessment of Neuropsychological Status) and neurophysiological measures (prepulse inhibition, P3a latency and auditory steady state response power and coherence) were impaired in participants with AD (p's<0.05-0.0001); neurophysiological deficits were modestly reduced by acute memantine challenge. As a group, participants with AD showed no significant clinical changes across 24 weeks of memantine treatment; subgroups exhibited either small gains or deterioration. With one exception (mismatch negativity latency, p < 0.017), sensitivity of experimental measures to acute memantine challenge did not significantly predict clinical sensitivity to memantine. In summary, a challenge dose design identified neurophysiological measures sensitive to memantine in mild-to-moderate severity AD; acute memantine effects on one measure weakly predicted clinical outcomes over 24 weeks. Impairment in specific measures among participants with AD, and their opposition by memantine, might inform future efforts to identify treatment biomarkers in AD.},
}

@article {pmid41045626,
year = {2025},
author = {Mashkani, SMH and Bishop, D and Adlard, PA and Mojtaba Golzan, S},
title = {Zinc transporter proteins in the retina as potential biomarkers for staging early Alzheimer's disease: Comparative analysis in human and mouse models.},
journal = {Neurobiology of aging},
volume = {157},
number = {},
pages = {26-35},
doi = {10.1016/j.neurobiolaging.2025.09.010},
pmid = {41045626},
issn = {1558-1497},
abstract = {Zinc plays a critical role in memory, learning, and neuronal function, with dysregulation increasingly implicated in neurodegenerative diseases such as Alzheimer's disease (AD). This study aimed to investigate whether changes in the expression of zinc transporter proteins, ZnT3 and ZIP3, in the retina mirror those in the brain, and to explore their potential as non-invasive biomarkers for early AD detection. Immunofluorescence and Western blotting were used to assess ZnT3 and ZIP3 expression in the retina and hippocampus of APP/PS1 and WT mice (9 and 18 months), as well as in human post-mortem tissues (9 AD and 6 control cases). To further investigate the regulatory role of ZnT3 in zinc homeostasis and its influence on tissue zinc concentrations, we quantified zinc levels in retinal and hippocampal tissues from WT and ZnT3 knockout mice using inductively coupled plasma-mass spectrometry (ICP-MS). ZnT3 and ZIP3 levels were significantly higher in the retina and hippocampus of healthy controls compared to AD cases across both mouse and human samples. ICP-MS analysis confirmed significantly lower zinc concentrations in ZnT3 knockout mice compared to WT controls in both the These findings demonstrate that retinal ZnT3 and ZIP3 expression changes mirror those observed in the hippocampus during AD progression. This suggests their potential as retinal biomarkers for Alzheimer's disease. Notably, ZnT3 shows strong promise for early, non-invasive detection of AD. Further validation in larger cohorts is warranted.},
}

@article {pmid41045606,
year = {2025},
author = {Montargil, CA and Pinto, M and Resende, R and Carreiro, EP and García-Sosa, AT and Santos, AE and Burke, AJ},
title = {Exploring the potential of new acetylated unsaturated Oxindole derivatives as multi-target inhibitors for BACE1 and BuChE.},
journal = {Bioorganic & medicinal chemistry},
volume = {131},
number = {},
pages = {118419},
doi = {10.1016/j.bmc.2025.118419},
pmid = {41045606},
issn = {1464-3391},
abstract = {Alzheimer's disease (AD) is the most common form of dementia worldwide, accounting for an estimated 60-70 % of cases. β-secretase 1 (BACE1), is one of the main therapeutic targets involved in the disease's pathology, as it is involved in the production of amyloid β. Butrylcholinesterase (BuChE) which is active in the advanced stages of the disease, is targeted for symptomatic relief. AD is a complex illness that needs to be tackled from different angles for which the Multi-target inhibitor approach is a viable current strategy. This work focuses on the development of novel acyl-oxindole molecules - some containing fluorine units, obtained via a structure-based drug design approach, for inhibition of BACE1 and BuChE. This study explored the development of a sustainable metal-based synthetic procedure for rapid and sustainable assess of libraries of these new oxindole derivatives. The compounds were screened to determine their ability to inhibit BACE1, and demonstrated reasonable levels of inhibition, with some of these inhibitors being selected for docking studies to determine the binding mode to the target's active site. One of the key molecules 12a underwent a cytotoxicity screen in a mouse neuroblastoma cell line expressing the APPswe protein (N2A-APPswe cells) and was an inhibitor of both AChE and BuChE (more potent against the latter, including the human version). Some compounds (3a, 3b, 3i and 12a) have shown moderate BuChE inhibitory activity.},
}

@article {pmid41045521,
year = {2025},
author = {Garg, S and Gopal, KM},
title = {Alzheimer's Disease in India: A Public Health Call to Action.},
journal = {Indian journal of public health},
volume = {69},
number = {3},
pages = {241-242},
doi = {10.4103/ijph.ijph_1126_25},
pmid = {41045521},
issn = {0019-557X},
}

@article {pmid41045350,
year = {2025},
author = {Alsaadi, T and Almadani, A and AlRukn, S and Hassan, A and Sarathchandran, P and Shatila, A and Szolics, M and Benito, D and Ince, S and Krieger, DW},
title = {Expert Guidance on Cognitive Impairment in Alzheimer's Disease: A Practical Seven-Step Approach from the United Arab Emirates.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {41045350},
issn = {2193-8253},
abstract = {INTRODUCTION: Cognitive impairment (CI) spans a spectrum from mild CI to severe dementia, with Alzheimer's disease (AD) the most prevalent cause of CI and dementia. Although dementia burden and prevalence in Arab countries reflect general global trends, the United Arab Emirates (UAE) differs from Western countries both culturally and regarding management resources. Further guidance is therefore needed for the diagnosis and management of CI in the UAE.

METHODS: A task force of eight neurologists and two non-voting collaborators with special dementia expertise was convened to develop evidence-based position statements/recommendations to guide the diagnosis and management of AD, including the use of amyloid-targeting therapies (ATTs), in the UAE clinical setting. A modified Delphi survey method was chosen to obtain a consensus, ensuring that drafted expert statements reflected diverse perspectives and experiences. Discordance was predefined as > 25% of panelists rating an expert statement as ≤ 3 on the Likert scale. Consensus was predefined as a median rating ≥ 7 without discordance. Expert statements achieving consensus were adopted.

RESULTS: A seven-step framework for diagnosing and managing CI in the UAE was developed, with consensus achieved on all statements. Recommendations largely aligned with international guidelines on AD dementia management and treatment, combined with UAE-specific guidance. The framework spans the full patient journey from initial symptoms to diagnosis (including biomarker use), initial treatment (including ATTs where appropriate), and subsequent monitoring and management as the disease progresses.

CONCLUSIONS: Management of CI and dementia in UAE requires consideration of international guidelines in the context of regional and local cultural sensitivities and healthcare resources. A holistic approach is recommended, combining appropriate pharmacological treatment with lifestyle interventions, education, and support for patients and care partners. Patients require ongoing monitoring to ensure the approach is tailored to the disease stage and provides optimal quality of life and reduced burden for patients and care partners.},
}

@article {pmid41045341,
year = {2025},
author = {Mustafa, AM and Sayed, GA and Hatem, S and Moussa, RA and Hal, DM and Mansour, MA and Abd El Hafeez, MS},
title = {Therapeutic potential of purpurin, a natural anthraquinone dye, in neuroprotection and neurological disorders.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41045341},
issn = {1568-5608},
abstract = {Purpurin (1,2,4-trihydroxy-9,10-anthraquinone) is a naturally occurring anthraquinone pigment derived primarily from Rubia species. Beyond its traditional use as a natural dye, purpurin has recently gained attention for its multifaceted pharmacological activities, particularly in neuroprotection. This review outlines the biosynthetic pathways leading to anthraquinone formation via the shikimate, mevalonate, and methylerythritol phosphate routes, culminating in the generation of purpurin. Structure-activity relationship analyses highlight the critical role of hydroxyl substitutions in modulating antioxidant, anticancer, antibacterial, and neuroprotective properties through radical stabilization, DNA intercalation, and metal chelation. Evidence from preclinical studies indicates that purpurin exerts beneficial effects in Alzheimer's disease, depression, ischemic stroke, and age-related cognitive decline, primarily through anti-tau aggregation, cholinesterase inhibition, serotonergic modulation, antioxidant activity, and anti-inflammatory mechanisms. While purpurin exhibits low acute toxicity and promising pharmacodynamics, its therapeutic translation remains limited by poor solubility, rapid metabolism, and low brain bioavailability. Nanotechnology-based formulations and molecular modifications are being explored to overcome these challenges. Collectively, purpurin represents a versatile bioactive scaffold with considerable potential for the development of multifunctional neuroprotective agents.},
}

@article {pmid41044993,
year = {2025},
author = {Yan, Q and Qin, Q and Zhang, S and Chen, F and Ru, Y and Zhong, Y and Wu, G},
title = {Glial cell nutrient sensing: mechanisms of nutrients regulating Alzheimer's pathogenesis and precision intervention.},
journal = {Critical reviews in food science and nutrition},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/10408398.2025.2568606},
pmid = {41044993},
issn = {1549-7852},
abstract = {Modern nutrition is a core element of clinical treatment. Although some literature addresses neuro-nutrition's effects on Alzheimer's disease (AD), a systematic discussion of how the body's six essential nutrients impact AD is lacking. Moreover, neural glial cells directly participate in the pathological regulation of AD. A novel conceptual framework linking "essential nutrients - glial cells - AD" needs to be summarized. Therefore, this review examines the regulatory roles of glial cells (astrocytes, microglia, and their networks) in AD and explores how essential nutrients impact AD via glial cells. Specifically, vitamins (NR, NMN, etc.), minerals (copper, iron, selenium, etc.), proteins and amino acids (arginine, citrulline, methionine, etc.), lipids (fatty acids, phosphatidylinositol, etc.), and carbohydrates (trehalose, oligosaccharides, plant polysaccharides, etc.) can influence important functions such as brain energy metabolism remodeling, inflammatory factor secretion, and phagocytic clearance by regulating microglia and astrocytes. Moreover, a significant strength of this review is its clear exposition of nutrient alterations observed in AD patients, coupled with detailed recommendations for nutritional interventions targeting AD prevention and management. Furthermore, it also investigated beneficial dietary patterns for improving AD. In conclusion, this review explores the "essential nutrients -glial cell" molecular interactions, laying the foundation for precision nutrition-based AD strategies.},
}

@article {pmid41044681,
year = {2025},
author = {Zielinski, M and Peralta Reyes, FS and Gremer, L and Sommerhage, S and Pagnon de la Vega, M and Röder, C and Heidler, TV and Syvänen, S and Willbold, D and Sehlin, D and Ingelsson, M and Schröder, GF},
title = {Cryo-EM studies of amyloid-β fibrils from human and murine brains carrying the Uppsala APP mutation (Δ690-695).},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {209},
pmid = {41044681},
issn = {2051-5960},
mesh = {Animals ; Humans ; Cryoelectron Microscopy ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Mice, Transgenic ; *Brain/metabolism/ultrastructure/pathology ; *Amyloid beta-Peptides/ultrastructure/metabolism/genetics ; Mutation/genetics ; Mice ; *Alzheimer Disease/genetics/pathology/metabolism ; Female ; *Amyloid/ultrastructure/metabolism ; },
abstract = {Today, 13 intra-amyloid-β (Aβ) amyloid precursor protein (APP) gene mutations are known to cause familial Alzheimer's disease (AD). Most of them are point mutations causing an increased production or a change in the conformation of Aβ. The Uppsala APP mutation (Δ690-695 in APP, Δ19-24 in Aβ) is the first known multi-codon deletion causing autosomal dominant AD. Here, we applied cryo-electron microscopy (cryo-EM) to investigate the structure of Aβ fibrils with the Uppsala APP mutation from tg-UppSwe mouse brain tissue. Murine AβUpp(1-42)Δ19-24 are made of two identical S-shaped protofilaments with an ordered fibril core of S8-A42. The murine Aβ fold is almost identical to previously described human type II filaments, although the amino acid sequences differ considerably. In addition, we report the cryo-EM structure of Aβ fibrils from the temporal cortex of a patient with the Uppsala APP mutation. The observed structure of the human Aβ fold closely resembles previously described type I fibrils. Structural modeling suggests that these fibrils are composed of wild-type Aβ, which implies that AβUpp may be less soluble and thus not readily accessible for cryo-EM image processing and structure determination. Additionally, from the human sample we determined the structures of tau paired helical filaments and tau straight filaments, which are identical to those found in sporadic AD cases. Finally, we present the 3D cryo-EM structures of four dominant AβUpp(1-42)Δ19-24 fibril polymorphs, formed in vitro. All four polymorphs differ from the observed folds of Uppsala Aβ in murine and human brain tissue, respectively.},
}

Animals
Humans
Cryoelectron Microscopy
*Amyloid beta-Protein Precursor/genetics/metabolism
Mice, Transgenic
*Brain/metabolism/ultrastructure/pathology
*Amyloid beta-Peptides/ultrastructure/metabolism/genetics
Mutation/genetics
Mice
*Alzheimer Disease/genetics/pathology/metabolism
Female
*Amyloid/ultrastructure/metabolism

@article {pmid41044651,
year = {2025},
author = {Liu, H and Yin, Z and Chen, X and Wang, Z},
title = {Exploring causal relationships between epigenetic age acceleration and Alzheimer's disease: a bidirectional Mendelian randomization study.},
journal = {Clinical epigenetics},
volume = {17},
number = {1},
pages = {164},
pmid = {41044651},
issn = {1868-7083},
mesh = {Humans ; *Mendelian Randomization Analysis/methods ; *Alzheimer Disease/genetics ; Genome-Wide Association Study/methods ; *Epigenesis, Genetic/genetics ; DNA Methylation/genetics ; Male ; Female ; Aged ; *Aging/genetics ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is identified by a distinct progression of aging-associated cognitive and functional impairment. Recent advances recognize the DNA methylation-based epigenetic clock as a precise predictor of aging processes and their related health outcomes. However, observational studies exploring this link are often compromised by confounding factors and reverse causality bias. To address the question, our study employs a bidirectional Mendelian randomization (MR) analysis to explore the causal relationship between epigenetic age acceleration (EAA) and AD.

METHODS: Genome-wide association study (GWAS) statistics for epigenetic clocks (GrimAge, PhenoAge, HorvathAge, and HannumAge) were sourced from Edinburgh DataShare and the Alzheimer Disease Genetics Consortium (ADGC). The dataset comprised 63,926 participants, and among them, 21,982 cases were AD patients and 41,944 were controls. The primary analytical method for the MR was the inverse variance weighted (IVW). The potential pleiotropy and heterogeneity among the instrumental variables were evaluated by additional sensitivity analyses.

RESULTS: Employing the random-effects IVW approach, we found that, as indicated by GrimAge, EAA was associated with an increased risk of AD (Odds Ratio [OR] = 1.025, 95% Confidence Interval [CI]: 1.006-1.044, p = 0.009). Quality control assessments confirmed the reliability and robustness of our findings. However, the evidence did not support a causal relationship between AD and epigenetic aging in the reverse direction.

CONCLUSIONS: Our MR study indicates a positive causal relationship between EAA and AD. Further research is necessary to explore the underlying physiological mechanisms.},
}

Humans
*Mendelian Randomization Analysis/methods
*Alzheimer Disease/genetics
Genome-Wide Association Study/methods
*Epigenesis, Genetic/genetics
DNA Methylation/genetics
Male
Female
Aged
*Aging/genetics
Genetic Predisposition to Disease

@article {pmid41044568,
year = {2025},
author = {Godoy, JB and Vialle, RA and Dos Santos, L and Raittz, RT and Wang, Y and Menon, V and De Jager, PL and Schneider, JA and Tasaki, S and Bennett, DA and Guizelini, D and de Paiva Lopes, K},
title = {Cytokine expression profile in the human brain of older adults.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {224},
pmid = {41044568},
issn = {1742-2094},
support = {Student fellowship//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; U01AG46152/AG/NIA NIH HHS/United States ; P30AG72975/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Aged ; Female ; Male ; Aged, 80 and over ; *Cytokines/genetics/biosynthesis/metabolism ; *Alzheimer Disease/genetics/metabolism/pathology ; *Brain/metabolism/pathology ; Transcriptome ; Gene Expression Profiling ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition linked to chronic neuroinflammation. This study investigates the cytokine gene expression profile in cortical tissue samples from elderly individuals with and without AD to identify potential biomarkers and enhance our understanding of disease pathogenesis. Utilizing high-depth RNA sequencing data, we identified a set of cytokines whose expression significantly associated with different aspects of the AD phenotype, including measures of neurofibrillary tangles, amyloid-β deposition, and a person-specific rate of cognitive decline. Single-nucleus transcriptomics data facilitated the identification of specific cell types, such as microglia and astrocytes, that significantly contribute to the inflammatory response in AD. Additionally, we observed a correlation between the expression of certain cytokines and genetic risk for the disease. Our findings indicate that cytokine-mediated neuroinflammation may play an important role in neurodegeneration and that modulating the immune response may offer a promising strategy for developing new therapies.},
}

Humans
Aged
Female
Male
Aged, 80 and over
*Cytokines/genetics/biosynthesis/metabolism
*Alzheimer Disease/genetics/metabolism/pathology
*Brain/metabolism/pathology
Transcriptome
Gene Expression Profiling

@article {pmid41044395,
year = {2025},
author = {Piot, E and Renard, F and Attyé, A and Krainik, A and , and , },
title = {Estimation of reference curves for brain atrophy and analysis of robustness to machine effects.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {34585},
pmid = {41044395},
issn = {2045-2322},
support = {CIFRE No. 2022/0918//Association Nationale de la Recherche et de la Technologie/ ; },
mesh = {Humans ; Atrophy ; Magnetic Resonance Imaging/methods ; Male ; Female ; *Brain/pathology/diagnostic imaging ; Algorithms ; Hippocampus/pathology/diagnostic imaging ; Middle Aged ; Aged ; Alzheimer Disease/diagnostic imaging/pathology ; Image Processing, Computer-Assisted/methods ; Adult ; Reference Values ; },
abstract = {Neurodegenerative diseases like Alzheimer's are difficult to diagnose due to brain complexity and imaging variability. However, volumetric analysis tools, using reference curves, help detect abnormal brain atrophy and support diagnosis and monitoring. This study evaluates the robustness of three segmentation algorithms, AssemblyNet, FastSurfer and FreeSurfer, in constructing brain volume reference curves and detecting hippocampal atrophy. Using data from 3,730 cognitively normal subjects, we built reference curves and assessed robustness to magnetic field strength (1.5T vs. 3T) using four error metrics (sMAPE, sMSPE, wMAPE, sMdAPE) with bootstrap validation. We evaluated classification performance using hippocampal atrophy rates and HAVAs scores (Hippocampal-Amygdalo-Ventricular Atrophy scores). AssemblyNet shows the lowest errors across all robustness metrics. In contrast, FastSurfer and FreeSurfer exhibit greater deviations, indicating higher sensitivity to field strength variability. AssemblyNet provides consistent hippocampal atrophy rates across all reference models, despite slightly lower sensitivity, while FastSurfer and FreeSurfer display greater variability. Specificity ranges from 0.87 to 0.91 for AssemblyNet, compared to 0.76-0.93 for FastSurfer and 0.86-0.93 for FreeSurfer. Using the HAVAs score, all methods detect high atrophy rates in Alzheimer's patients. FastSurfer achieves the highest sensitivity (0.98), while AssemblyNet reaches the best specificity (0.95) and the highest balanced accuracy (0.91). This study underscores the importance of algorithm choice for reliable brain volumetric analysis in heterogeneous imaging environments. Among the methods tested, AssemblyNet stands out as both sensitive to Alzheimer's-related atrophy and robust to acquisition variability, making it a strong candidate when analyzing hippocampal volumes in large, multi-site datasets.},
}

Humans
Atrophy
Magnetic Resonance Imaging/methods
Male
Female
*Brain/pathology/diagnostic imaging
Algorithms
Hippocampus/pathology/diagnostic imaging
Middle Aged
Aged
Alzheimer Disease/diagnostic imaging/pathology
Image Processing, Computer-Assisted/methods
Adult
Reference Values

@article {pmid41044200,
year = {2025},
author = {Jawinski, P and Forstbach, H and Kirsten, H and Beyer, F and Villringer, A and Witte, AV and Scholz, M and Ripke, S and Markett, S},
title = {Genome-wide analysis of brain age identifies 59 associated loci and unveils relationships with mental and physical health.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {41044200},
issn = {2662-8465},
abstract = {Neuroimaging and machine learning are advancing research into the mechanisms of biological aging. In this field, 'brain age gap' has emerged as a promising magnetic resonance imaging-based biomarker that quantifies the deviation between an individual's biological and chronological age of the brain. Here we conducted an in-depth genomic analysis of the brain age gap and its relationships with over 1,000 health traits. Genome-wide analyses in up to 56,348 individuals unveiled a heritability of 23-29% attributable to common genetic variants and highlighted 59 associated loci (39 novel). The leading locus encompasses MAPT, encoding the tau protein central to Alzheimer's disease. Genetic correlations revealed relationships with mental health, physical health, lifestyle and socioeconomic traits, including depressed mood, diabetes, alcohol intake and income. Mendelian randomization indicated a causal role of high blood pressure and type 2 diabetes in accelerated brain aging. Our study highlights key genes and pathways related to neurogenesis, immune-system-related processes and small GTPase binding, laying the foundation for further mechanistic exploration.},
}

@article {pmid41044176,
year = {2025},
author = {Varzaneh, ZA and Mousavi, SM and Khoshkangini, R and Moosavi Khaliji, SM},
title = {An ensemble model based on transfer learning for the early detection of Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {34634},
pmid = {41044176},
issn = {2045-2322},
mesh = {*Alzheimer Disease/diagnosis ; Humans ; Early Diagnosis ; Cognitive Dysfunction/diagnosis ; *Deep Learning ; Aged ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the gradual decline in cognitive functions, particularly memory and reasoning. Early detection, especially during cognitive impairment (MCI) stage, is crucial for timely intervention and management. Enhanced diagnostic methods are essential for facilitating early identification and improving patient outcomes. This study presents a robust deep learning framework for the early detection of Alzheimer's disease. It employs transfer learning and hyperparameter-tuning of InceptionResnetV2, InceptionV3, Xception architectures to enhance feature extraction by leveraging their pre-trained capabilities. An ensemble voting mechanism has been integrated to combine predictions from different models, optimizing both accuracy and robustness. The proposed ensemble voting approach demonstrated exceptional performance, achieving 98.96% accuracy and 100% precision for predicting classes Mildly Demented and Moderately Demented. It outperformed baseline and state-of-the-art models, highlighting its potential as a reliable tool for early diagnosis and intervention.},
}

*Alzheimer Disease/diagnosis
Humans
Early Diagnosis
Cognitive Dysfunction/diagnosis
*Deep Learning
Aged

@article {pmid41044155,
year = {2025},
author = {Han, M and Frieg, B and Matthes, D and Leonov, A and Ryazanov, S and Giller, K and Nimerovsky, E and Stampolaki, M and Xue, K and Overkamp, K and Dienemann, C and Riedel, D and Giese, A and Becker, S and de Groot, BL and Schröder, GF and Andreas, LB and Griesinger, C},
title = {Anle138b binds predominantly to the central cavity in lipidic Aβ40 fibrils and modulates fibril formation.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {8850},
pmid = {41044155},
issn = {2041-1723},
support = {EXC 2067/1-0390729940//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; },
mesh = {*Amyloid beta-Peptides/metabolism/chemistry/ultrastructure ; Molecular Dynamics Simulation ; Cryoelectron Microscopy ; Humans ; Alzheimer Disease/metabolism/drug therapy ; *Amyloid/metabolism/ultrastructure/chemistry ; Protein Binding ; Magnetic Resonance Spectroscopy ; *Peptide Fragments/metabolism/chemistry ; },
abstract = {Alzheimer's disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (Aβ) fibrils. Therapeutic antibodies can slow down the disease, but are associated with potential severe side effects, motivating the development of small molecules to halt disease progression. This study investigates the interaction between the clinical drug candidate small molecule anle138b and lipidic Aβ40 fibrils of type 1 (L1). L1 fibrils were previously shown to closely resemble fibrils from Alzheimer's patients. Using high-resolution structural biology techniques, including cryo-electron microscopy (cryo-EM), nuclear magnetic resonance (NMR) spectroscopy enhanced by dynamic nuclear polarization (DNP), and molecular dynamics (MD) simulations, we find that anle138b selectively binds to a cavity within the fibril. This structural insight provides a deeper understanding of a potential drug-binding mechanism at the atomic level and may inform the development of therapies and diagnostic approaches. In addition, anle138b reduces fibril formation in the presence of lipids by approximately 75%. This may suggest a mechanistic connection to its previously reported activity in animal models of Alzheimer's disease.},
}

*Amyloid beta-Peptides/metabolism/chemistry/ultrastructure
Molecular Dynamics Simulation
Cryoelectron Microscopy
Humans
Alzheimer Disease/metabolism/drug therapy
*Amyloid/metabolism/ultrastructure/chemistry
Protein Binding
Magnetic Resonance Spectroscopy
*Peptide Fragments/metabolism/chemistry

@article {pmid41043800,
year = {2025},
author = {Koivula, A and Perkiömäki, V and Aho, M and Rasila, A and Poltojainen, V and Korhonen, V and Järvelä, M and Huotari, N and Helakari, H and Tuunanen, J and Raitamaa, L and Väyrynen, T and Kruger, J and Kiviniemi, V and Kananen, J},
title = {Reduced harmonic complexity of brain parenchymal cardiovascular pulse waveforms in Alzheimer's disease.},
journal = {NeuroImage},
volume = {321},
number = {},
pages = {121503},
doi = {10.1016/j.neuroimage.2025.121503},
pmid = {41043800},
issn = {1095-9572},
abstract = {Alzheimer's disease (AD) is characterized by specific neuropathologies, and is associated with arterial wall β-amyloid accumulations, which lead to radiologically detectable amplitude increases and variable propagation speed of cardiovascular impulses in brain. In this study, we developed a fast frequency domain imaging method know as relative harmonic power of magnetic resonance encephalography (MREGRHP), aiming to investigate the configuration of the cardiovascular impulses independently of the mean magnetic resonance signal intensity and physiological impulse amplitude. In the initial analyses in healthy controls, we found that a wide 0.8 - 5 Hz bandpass produced the most physiologically realistic cardiovascular waveforms. Whereas the data recorded in cerebrospinal fluid (CSF) with flip angle (FA) of 25° yielded up to 7-fold higher cardiac signal intensity as compared to FA of 5°, within the brain tissue recordings with FA of 5° were markedly more sensitive to cardiac waveform. We detected arterial impulses originating from major arteries and extending into the surrounding brain parenchyma, with simultaneous dampening of amplitude as a function of distance from source. Finally, we compared MREGRHP results in 34 CE patients (mean age: 60.7 ± 4.7 years; 53 % female) against 29 controls (mean age: 56.9 ± 7.9 years; 66 % female). We show that the harmonic power of cardiovascular brain pulses is significantly reduced in cortical frontoparietal areas of AD patients, indicating monotonous impulse patterns colocalizing with the previously reported areas of increased impulse propagation speed. In conclusion, the MREGRHP offers a fast Fourier transform (FFT)-based method to non-invasively quantify and locate human arterial blood vessel wall pathology.},
}

@article {pmid41043620,
year = {2025},
author = {Takahashi, T and Nonaka, T and Ohtani, R and Hasegawa, M and Hori, Y and Tomita, T and Kurita, R},
title = {Hindering Tau Fibrillization by Disrupting Transient Precursor Clusters.},
journal = {Neuroscience research},
volume = {},
number = {},
pages = {104968},
doi = {10.1016/j.neures.2025.104968},
pmid = {41043620},
issn = {1872-8111},
abstract = {Tau protein, a central player in Alzheimer's disease (AD), exhibits cytotoxicity upon fibril formation. Understanding the early stages of tau fibrillization is therefore critical for the development of effective thera- peutics. Previous work [Rasmussen. et. al, J. Mol. Biol., 2023] reported the rapid formation of Thioflavin T (ThT)-inactive clusters upon mixing tau with anionic polymers, yet the functional role of these clusters remained unclear. Here, we demonstrate that these transient clusters act as obligatory precursors in the fibrillization pathway. Using small-angle X-ray scattering (SAXS) and ThT fluorescence, we show that disrupting the clusters via NaCl addition hinders fibril formation, highlighting their reversible and targetable nature. This behavior is analogous to polymer crystallization, in which disordered chains undergo structural ordering through intermediate precursor states. We propose that similar physical principles underlie the aggregation of other intrinsically disordered pro- teins such as α-synuclein.},
}

@article {pmid41043545,
year = {2025},
author = {Wu, P and Chen, D and Wang, F and Lu, K and Sigurdsson, EM and Jin, C},
title = {Formaldehyde induces and promotes Alzheimer's disease pathologies in a 3D human neural cell culture model.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {},
number = {},
pages = {115777},
doi = {10.1016/j.fct.2025.115777},
pmid = {41043545},
issn = {1873-6351},
abstract = {Formaldehyde, a reactive aldehyde widely present in the environment and associated with occupational exposure, has been linked to cognitive impairment and Alzheimer's disease (AD) in multiple epidemiological and animal studies. However, its contribution to AD-like pathology in human neural models remains poorly understood. We utilized a 3D culture system of human neural progenitor cells (ReNcell VM) differentiated into neurons and glial cells to model chronic formaldehyde exposure. Additionally, we established a 3D human AD model by transducing ReN cells with APP and PSEN1 mutations to assess the effects of formaldehyde in an AD genetic background. Long-term formaldehyde exposure (up to 12 weeks) induced a dose-dependent increase in Aβ40, Aβ42, APP, and phosphorylated tau levels in both wild-type and AD-mutant 3D cultures. These changes mimic hallmark features of AD neuropathology, suggesting that formaldehyde acts as a pathological driver in both sporadic and familial contexts. Our study provides direct evidence that chronic formaldehyde exposure may initiate and accelerate amyloid and tau pathologies in 3D human neural cell models. These findings support growing concerns about formaldehyde as a modifiable risk factor in neurodegeneration.},
}

@article {pmid41043404,
year = {2025},
author = {Coleman, K and Tatonetti, NP},
title = {Decoding Alzheimer's disease at the cellular level reveals promising combination therapy.},
journal = {Cell},
volume = {188},
number = {20},
pages = {5433-5435},
doi = {10.1016/j.cell.2025.08.037},
pmid = {41043404},
issn = {1097-4172},
mesh = {*Alzheimer Disease/drug therapy/genetics/pathology ; Humans ; Animals ; Mice ; Single-Cell Analysis ; Drug Repositioning ; Disease Models, Animal ; Drug Therapy, Combination ; },
abstract = {Alzheimer's disease (AD) has long resisted effective treatments due to its pathological heterogeneity and cell-type-specific regulatory changes. In this issue of Cell, Li et al. leverage single-cell RNA sequencing and drug repurposing to propose a promising combination therapy, validated through real-world evidence and mouse models, that targets multiple AD-relevant cell types.},
}

*Alzheimer Disease/drug therapy/genetics/pathology
Humans
Animals
Mice
Single-Cell Analysis
Drug Repositioning
Disease Models, Animal
Drug Therapy, Combination

@article {pmid41043097,
year = {2025},
author = {Mourtzi, N and Charisis, S and Ntanasi, E and Hatzimanolis, A and Ramirez, A and Sampatakakis, SN and Yannakoulia, M and Kosmidis, MH and Dardiotis, E and Hadjigeorgiou, G and Sakka, P and Mamalaki, E and Papandreou, C and Georgakis, MK and Scarmeas, N},
title = {Longitudinal Association of a Polygenic Risk Score for Plasma T-Tau With Incident Alzheimer Dementia and Mild Cognitive Impairment.},
journal = {Neurology},
volume = {105},
number = {9},
pages = {e213904},
doi = {10.1212/WNL.0000000000213904},
pmid = {41043097},
issn = {1526-632X},
mesh = {Humans ; *Cognitive Dysfunction/blood/genetics/epidemiology ; Aged ; Female ; Male ; *Alzheimer Disease/blood/genetics/epidemiology ; *tau Proteins/blood/genetics ; Longitudinal Studies ; *Multifactorial Inheritance ; Aged, 80 and over ; Incidence ; Biomarkers/blood ; Risk Factors ; Middle Aged ; Cohort Studies ; Genetic Risk Score ; },
abstract = {BACKGROUND AND OBJECTIVES: Elevated levels of total tau (t-tau) are a key biomarker of neurodegeneration, often seen in Alzheimer disease (AD). Identifying individuals at increased risk of AD using minimally invasive biomarkers can enable early intervention. We developed a polygenic risk score (PRS) for plasma t-tau and examined its association with the risk for developing clinical endophenotypes of AD pathology.

METHODS: This longitudinal cohort study used data from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) study, involving individuals aged 65 years or older, free of AD, or amnestic mild cognitive impairment (aMCI-an AD prodrome) at baseline. Our primary exposure was PRStau, a PRS based on common genetic variants linked to plasma tau levels. The primary outcome was aMCI or AD incidence. We assessed the association between PRStau levels and aMCI/AD risk using Cox regression models adjusted for age, sex, education, APOE ε4 allele carriership, and population structure. We sought replication in a sample of UK Biobank (UKB) participants aged 60 years or older without prevalent dementia.

RESULTS: In the HELIAD sample, among 618 cognitively healthy participants (mean age 73.37 years, 58.4% female), followed for 2.92 ± 0.80 years, 73 developed AD/aMCI. A 1 SD increase in PRStau was linked to a 29% higher AD/aMCI risk (hazard ratio [HR] 1.290, 95% CI 1.006-1.654). Stratified analyses revealed greater effect estimates in women (HR 1.451, 95% CI 1.023-2.058) and younger participants (HR 1.866, 95% CI 1.175-2.962), whereas results in men and older participants did not reach statistical significance. In the UKB sample (n = 142,637, mean age 64.2 years, 52% female), 2,737 participants developed AD over 12.9 ± 2.4 years of follow-up. Higher PRStau was also linked to increased AD risk (HR 1.046, 95% CI 1.007-1.086).

DISCUSSION: These results support the potential utility of PRS for plasma t-tau in predicting AD/aMCI incidence. The relationship between genetic predisposition for elevated plasma t-tau levels and AD pathology might be influenced by sex and age, suggesting that these factors should be considered in AD genetic risk modeling. PRS could serve as an early indicator of genetic propensity for tau pathology, enhancing existing AD diagnostic and risk stratification algorithms.},
}

Humans
*Cognitive Dysfunction/blood/genetics/epidemiology
Aged
Female
Male
*Alzheimer Disease/blood/genetics/epidemiology
*tau Proteins/blood/genetics
Longitudinal Studies
*Multifactorial Inheritance
Aged, 80 and over
Incidence
Biomarkers/blood
Risk Factors
Middle Aged
Cohort Studies
Genetic Risk Score

@article {pmid41042932,
year = {2025},
author = {Viada, C and Fors, M and Capote, E and Santiesteban, Y and Santiesteban, Y and Estévez, D and Rodríguez, T and Pérez, L},
title = {Bayesian predictive probability for binary outcomes in neurodegenerative diseases.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251382608},
doi = {10.1177/13872877251382608},
pmid = {41042932},
issn = {1875-8908},
abstract = {BACKGROUND: Adaptive clinical trials enable modifications to the study design based on accumulating evidence. The Bayesian predictive probability approach offers a framework for estimating the likelihood of achieving a successful outcome in a future analysis, based on current interim data.

OBJECTIVE: To estimate the predictive probability of success for binary outcomes in patients with Alzheimer's disease or Ataxia treated with NeuroEPO plus.

METHODS: A retrospective Bayesian analysis was conducted using data from exploratory phase II trials as prior information for confirmatory phase III trials in Alzheimer's disease. Predictive probabilities were calculated at interim points with sample sizes of 50, 100, 150, and 176 patients.

RESULTS: The analysis demonstrated that the trial could have been stopped early due to a high probability of success or failures before reaching the full planned sample size.

CONCLUSIONS: Bayesian predictive probability is a valuable tool for decision-making in rare diseases, particularly when alternative treatments are limited or ineffective, or when baseline heterogeneity affects outcomes unevenly. This approach enhances interim evaluations by incorporating historical or non-informative priors, allowing for more accurate and efficient trial designs.},
}

@article {pmid41042920,
year = {2025},
author = {McGuire, LC and Holt, HL},
title = {Healthy Brain Initiative (HBI) and Building our Largest Dementia Infrastructure (BOLD) Initiatives: 20 Years of Building a Strong Public Health Infrastructure.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnaf225},
pmid = {41042920},
issn = {1758-5341},
}

@article {pmid41042919,
year = {2025},
author = {Remelli, F and Triolo, F and Grande, G and Barbieri, MG and Barbieri, E and Galuppi, C and Pampolini, G and Volpato, S and Trevisan, C},
title = {Validity and reliability of the Italian version of the Mild Behavioral Impairment Checklist in cognitively unimpaired and mild cognitive impairment individuals.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251380299},
doi = {10.1177/13872877251380299},
pmid = {41042919},
issn = {1875-8908},
abstract = {BackgroundThe Mild Behavioral Impairment Checklist (MBI-C) is a tool for detecting MBI, a neurobehavioral syndrome associated with an increased dementia risk.ObjectiveThis study aimed to evaluate the reliability and validity of the Italian version of the informant-rated MBI-C in an outpatient sample of dementia-free individuals.MethodsA cross-sectional study was conducted on 72 older people without dementia (n = 47, mild cognitive impairment; n = 25, cognitively unimpaired). During the visit, physicians administrated the MBI-C and Neuropsychiatric Inventory Questionnaire (NPI-Q) to the informant. Internal consistency of MBI-C was measured by the Cronbach's coefficient alpha and inter-domain correlation coefficients. Diagnostic performance of MBI-C for clinically identified MBI by ISTAART criteria was assessed through ROC analysis, identifying the optimal cut-off based on the Youden Index. Spearman's correlations were used to evaluate the concurrent validity of MBI-C with the NPI-Q, Mini-Mental State Examination (MMSE), Instrumental Activity of Daily Living (IADL) and 3-item UCLA Loneliness Scale.ResultsMBI-C showed high internal consistency (α = 0.867) and strong inter-domain correlation (ρ = 0.760 ∼ 0.859, p < 0.001). The Area Under the Curve (AUC) for detecting clinical MBI was 0.937 (95%CI: 0.865-0.972), with an optimal cut-off of 5.5 (sensitivity = 0.849, specificity = 0.876). The MBI-C total score strongly correlated with the NPI-Q total score (ρ = 0.820, p < 0.001). Only the MBI-C total score significantly correlated with the 3-item UCLA (ρ = 0.236, p = 0.046); no significant correlations were found with MMSE and IADL scores.ConclusionsThe Italian version of MBI-C demonstrated strong reliability, validity, and diagnostic performance. Therefore, MBI-C may be a suitable tool for assessing behavioral symptoms in dementia-free individuals.},
}

@article {pmid41042898,
year = {2025},
author = {Qadi, N and Alkhodair, Y and Alshammari, W and Aldakheel, A},
title = {Epidemiological and economic burden of dementia in the Middle East and North African region.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251378454},
doi = {10.1177/13872877251378454},
pmid = {41042898},
issn = {1875-8908},
abstract = {BackgroundDementia is a global health challenge projected to nearly triple by 2050, especially in the Middle East and North Africa (MENA). Understanding its epidemiology and economic impact is vital for public health planning.ObjectiveThis systematic review aims to synthesize evidence on dementia, particularly the prevalence of Alzheimer's disease, its economic burden, and caregiving in MENA countries, to facilitate informed policy-making and effective resource allocation.MethodsWe performed a random-effects meta-analysis to determine the pooled prevalence of dementia from studies published between 2014 and 2025 in PubMed, Scopus, and Google Scholar. Two reviewers independently selected and extracted data, assessing bias risk with the Cochrane Risk of Bias Tool. This review followed PRISMA 2020 guidelines and is registered in PROSPERO (CRD42024550935).ResultsTwelve studies met the criteria, showing dementia prevalence in MENA countries from 1.1% to 7.9%, with higher rates in Iran, Israel, and Lebanon, highlighting the need for public health campaigns. The annual estimated cost for those aged 50 and older is about USD 8.18 billion. Caregiving mainly fell to female family members, with larger socioeconomic impacts than in other regions.ConclusionsDementia is a growing public health concern in MENA, requiring improved healthcare infrastructure, increased caregiver support, and targeted research to fill knowledge gaps.},
}

@article {pmid41039568,
year = {2025},
author = {Wu, H and Qiu, Z and Mu, J and Wang, Y and Wang, J and Han, Y and Yang, R and Yuan, S and Yuan, M and Yang, R and Chen, X and Sun, Q and Li, F and Xiao, L and Zhang, M and Xu, J},
title = {Salt-sensitive hypertension promotes neuronal mitochondrial stress and neurodegenerative alterations via neuro-vascular metabolic reprogramming and local RAS signaling.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {220},
pmid = {41039568},
issn = {1742-2094},
support = {XJTU1AF-CRF-2023-021//The First Affiliated Hospital of Xi'an Jiaotong University/ ; 32271016//National Natural Science Foundation of China/ ; 81803026//National Natural Science Foundation of China/ ; 82071879//National Natural Science Foundation of China/ ; 82100454//National Natural Science Foundation of China/ ; 2023PT-09//the Health Research and Innovation Capacity Strengthening Platform Program of Shaanxi Province/ ; },
abstract = {UNLABELLED: Hypertension increases risks for cognitive impairment and Alzheimer’s disease (AD). In renal patients with both hypertension and cognitive decline, via rest-state fMRI, their cerebral cortical region showed maintained cerebral blood flow (CBF), but reduced signals of blood-oxygen-level-dependent (BOLD). In mice, although CBF was unchanged, deoxycorticosterone acetate (DOCA)-salt treatment markedly reduced cerebrovascular reactivity, with altered transcriptomic pattern in cortical endothelial cells (ECs) and astrocytes, showing downregulated expression of glucose transport 1 (GluT1) but upregulated metabolic reprogramming. Lipidomic analysis using prefrontal cortex (PFC) further revealed enhanced catabolism of glycerophospholipids and accumulation of free fatty acids. In the PFC of hypertensive mice, neurodegenerative alterations were observed, including reduced number of neuronal dendritic spines and more expression of phosphorylated Tau (p-Tau). Via both morphological and molecular tests, we identified that DOCA-salt hypertension was associated with significant mitochondrial injury and upregulated lysine succinylation in the PFC neurons. Upregulated lysine succinylation was largely mitochondria-located, and they were functionally enriched in gluconeogenesis-related energy metabolic pathways, the tricarboxylic acid (TCA) cycle, oxidative stress, and neurodegenerative diseases. In hypertensive mice, angiotensinogen (Agt) expression was markedly upregulated in most astrocytes, together with neuronal expression of Agtr1a. In cultured neuronal cells, angiotensin II (ang II) elevated mitochondrial membrane potential and ATP biosynthesis. In mice with neuronal AT1aR knockout (AT1N), DOCA-salt failed to induce cognitive impairment. Additionally, DOCA-salt-associated reduction of acetylcholine, accumulation of p-Tau, and upregulation of lysine succinylation were not observed in AT1N mice. Direct anti-hypertensive treatment did not abolish DOCA-salt-related pathological phenotypes, and enhanced lysine succinylation was not detected in hypertension models induced by norepinephrine or L-NAME. Our data provide evidence that hypertension induced metabolic rearrangement (enhanced energy metabolism from non-glucose source and upregulated mitochondrial oxidative phosphorylation) in the neuro-vascular unit, due to downregulated glucose uptake in ECs. Increased neuronal energy consumption, via local ang II/AT1R signaling, further exacerbated mitochondrial stress and neurodegenerative alterations. Together, by multi-omics analysis, this study provided novel insights regarding how hypertension increases the risk for age-related cognitive impairment.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03533-0.},
}

@article {pmid40899008,
year = {2025},
author = {Dammer, EB},
title = {Transforming tissue transcriptomes, delivering on the promise of machine learning.},
journal = {Brain : a journal of neurology},
volume = {148},
number = {10},
pages = {3433-3434},
pmid = {40899008},
issn = {1460-2156},
support = {/NH/NIH HHS/United States ; R01AG089497/AG/NIA NIH HHS/United States ; U01NS128433/NS/NINDS NIH HHS/United States ; },
abstract = {This scientific commentary refers to ‘Deep learning-based cell type profiles reveal signatures of Alzheimer’s resilience and resistance’ by Berson et al. (https://doi.org/10.1093/brain/awaf285).},
}

@article {pmid41042892,
year = {2025},
author = {Lyu, J and Zhang, W and De, J and Shan, B and Mao, G and Jiang, W and Rong, X and Li, W and Li, M and Hu, Y and Jia, D and Gao, W and Yang, D},
title = {The impact of music-based intervention on cognitive function and brain functional magnetic resonance imaging in people with mild Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251379419},
doi = {10.1177/13872877251379419},
pmid = {41042892},
issn = {1875-8908},
abstract = {BackgroundWith the accelerating global aging population, the incidence of Alzheimer's disease (AD) continues to rise, while current pharmacological treatments remain limited in efficacy. Music intervention, as a safe and feasible non-pharmacological approach, has gained increasing clinical attention, though its mechanisms of action remain unclear.ObjectiveThis study aims to evaluate the effects of music intervention on cognitive function and brain network connectivity in people with mild AD, and to elucidate its neural mechanisms and provide evidence for clinical practice.MethodsA total number of 50 AD patients with mild dementia participated in the study. Participants were randomized to music-based intervention group (music-based intervention, 20 min, 3 times/week for 6 months) or control group (standard care). Assessments included Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Geriatric Depression Scale (GDS), Neuropsychiatric Inventory (NPI), Word Fluency Test (WFT), World Health Organization-University of California, the Los Angeles Auditory Verbal Learning Test (WHO-UCLA-AVLT), and functional magnetic resonance imaging (fMRI). Data were analyzed using SPSS 20.0.Results47 participants completed the study. The music-based intervention group showed significant improvements in MoCA, GDS, NPI, WFT, and WHO-UCLA-AVLT scores (p < 0.05), with no change in MMSE. fMRI revealed enhanced frontal-temporal connectivity and increased angular gyrus activity.ConclusionsMusic-based intervention improves cognitive and neuropsychiatric outcomes in people with mild AD, likely through enhanced brain connectivity. This approach is feasible, and it supports the optimization of music-based intervention in clinical practice.},
}

@article {pmid41042852,
year = {2025},
author = {Bellaflor, S and Barfoot, MK and Boddy, J and Wallace, PJ and Baranowski, RW and Cheung, SS and Fajardo, VA and MacPherson, REK},
title = {Heat therapy increases brain HSP-70 and BDNF content in male mice.},
journal = {Journal of neurophysiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/jn.00301.2025},
pmid = {41042852},
issn = {1522-1598},
support = {2017-03904//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; 2019-05833//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; 2018-04077//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; },
abstract = {Heat shock proteins (HSPs) are molecular chaperones that play important roles in protein homeostasis, with HSP70 linked to a role in neuroprotection. HSP70 is upregulated in response to various stressors, such as heat therapy (HT), which has been shown to increase brain-derived neurotrophic factor (BDNF) content. BDNF reduces the activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the rate-limiting enzyme responsible for the generation of amyloid-β (Aβ) peptides that form the characteristic Aβ plaques observed in Alzheimer's disease brains. The current pilot study examined whether 4 weeks of HT can increase HSP70 and BDNF content (pro and mature forms) in the brain, as well as alter markers of amyloid precursor protein (APP) processing. Male mice had their core temperature maintained between 37.0-38.0° in Control (CON, n = 16) and 40.5-41.5° in Heat Therapy (HT, n = 16) for 20-minutes every 72 hours over 4-weeks. 72 hours after the last treatment, the prefrontal cortex (PFC) and hippocampus (HIP) were collected. HT significantly increased HSP70 levels in both the hippocampus and prefrontal cortex compared to controls (p = 0.0007, PFC CON=1.001 [0.314], PFC HT=1.546 [0.948], HIP CON=1.000 [0.356], HIP HT=2.207 [0.756]). In the HIP, proBDNF levels were also higher in the HT group relative to both the control group and the PFC (p < 0.05, PFC CON=1.000 [0.156], PFC HT = 0.984 [0.607], HIP CON=1.001 [0.242], HIP HT=1.575 [0.482]. There were no differences in mature BDNF in either PFC or HIP regions (p>0.05, PFC CON=1.000 [0.273], PFC HT=1.174 [0.266], HIP CON=0.999 [0.130], HIP HT=0.971 [0.207]), The findings from our pilot study suggest that HT enhances the expression of HSP70 and BDNF, indicating the potential to modulate key neuroprotective proteins. Future studies in dedicated preclinical mouse models of Alzheimer's disease using heat therapy regimen are warranted.},
}

@article {pmid41042837,
year = {2025},
author = {Boongird, C and Anothaisintawee, T and Tearneukit, W and Wongpipathpong, W and Suthutvoravut, U and Thongpan, M and Pongsettakul, N and Attia, J and McKay, GJ and Rattanasiri, S and Thakkinstian, A},
title = {Bridging the gap: Efficacy of combined therapies for cognitive, behavioral, and functional outcomes in Alzheimer's disease - results from a systematic review and network meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251378354},
doi = {10.1177/13872877251378354},
pmid = {41042837},
issn = {1875-8908},
abstract = {BackgroundEvidence regarding efficacy of combined pharmaco- and non-pharmacotherapies and their comparative effectiveness for Alzheimer's disease (AD) is limited.ObjectiveTo estimate the comparative efficacy of pharmacotherapies, non-pharmacotherapies, and combined therapies for improving cognitive, behavioral, and functional outcomes in patients with AD.MethodsRelevant studies were identified from Medline via PubMed and Scopus databases (March 2021-December 2022). Randomized-controlled trials were eligible if they assessed the efficacy of pharmacotherapies, non-pharmacotherapies, or combined therapies in patients aged 60 years or older, and measuring cognitive, behavioral, or functional outcomes. A network meta-analysis was conducted to estimate relative treatment effects, and interventions were ranked using surface under the cumulative ranking (SUCRA) curve. Confidence in the findings was evaluated using the Confidence in Network Meta-Analysis (CINeMA) framework.ResultsA total of 153 randomized-controlled trials were analyzed. Compared to placebo/usual care, donepezil plus cognitive therapy and rivastigmine plus cognitive rehabilitation significantly improved Mini-Mental State Examination scores. Behavioral outcomes were improved by rivastigmine plus cognitive stimulation, brain stimulation plus exercise, and occupational therapy. Functional status improved significantly with rivastigmine plus cognitive stimulation and exercise. Based on SUCRA ranking, rivastigmine plus cognitive rehabilitation ranked highest for cognitive improvement (92.8%), brain stimulation plus exercise ranked highest for the behavioral outcome (93.1%), and rivastigmine plus cognitive stimulation ranked highest for functional improvement (94.1%).ConclusionsDonepezil plus cognitive therapy and rivastigmine plus cognitive rehabilitation were the most effective treatments for improving cognitive outcomes. Rivastigmine plus cognitive stimulation ranked highest for both behavioral and functional outcomes, while exercise remains an important strategy for supporting daily functioning in patients with AD.},
}

@article {pmid41042700,
year = {2025},
author = {Xu, X and Tan, H and Yin, K and Xu, S and Wang, Z and Serrano, GE and Beach, TG and Wang, X and Peng, J and Wu, R},
title = {Comprehensive and Site-Specific Characterization of Protein N-Glycosylation in AD Samples Reveals Its Potential Roles in Protein Aggregation and Synaptic Dysfunction.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c02455},
pmid = {41042700},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Emerging evidence strongly suggests that protein glycosylation is strongly related to this disease. However, the extent and functional consequences of site-specific N-glycosylation alterations in AD remain to be further explored. Here, we employed a dendrimer boronic acid (DBA)-based enrichment strategy combined with multiplexed proteomics to systematically analyze protein N-glycosylation in post-mortem human brain tissues. We identified 3,105 N-glycosylation sites on 1,299 glycoproteins from nine AD cases and nine healthy controls, and performed a systematic and site-specific investigation of glycosylation alterations in AD. Glycoproteins involved in cholesterol efflux were upregulated, whereas those associated with chemical synaptic transmission and ion transport were significantly downregulated in AD compared to control brain samples. We observed widespread dysregulation of N-glycosylation across multiple protein domains, particularly in the ConA-like lectins/glucanases and Zn-dependent exopeptidases domains. Notably, we identified 161 N-glycosylation sites located within aggregation-prone regions (APRs), and reduced glycosylation at APRs on plaque-associated glycoproteins may be associated with protein aggregation and plaque formation. Additionally, downregulated N-glycosylation sites were enriched in synaptic membrane proteins, such as Ca[2+] ion channels, GABA-gated chloride channels, and glutamate receptors, implicating glycosylation loss in synaptic dysfunction. Our findings suggest that the loss of N-glycosylation may contribute to the pathogenesis of AD through impairing synaptic transmission and promoting protein aggregation. This study provides novel insights into glycosylation-dependent mechanisms of neurodegeneration, highlighting N-glycosylation as a potential therapeutic target for AD treatment.},
}

@article {pmid41042579,
year = {2025},
author = {Gunnar, J and Liu, Y and Eronen, H and Joensuu, T and Äikiä, M and Hyppönen, J and Silvennoinen, K and Mervaala, E and Hakumäki, J and Lehesjoki, AE and Kälviäinen, R},
title = {Exploring the role of apolipoprotein ε4 in progressive myoclonic epilepsy type 1.},
journal = {Epileptic disorders : international epilepsy journal with videotape},
volume = {},
number = {},
pages = {},
doi = {10.1002/epd2.70112},
pmid = {41042579},
issn = {1950-6945},
support = {//Saastamoinen Foundation/ ; //Folkhälsan Research Foundation/ ; },
abstract = {OBJECTIVE: Progressive myoclonic epilepsy type 1 (EPM1) is a neurodegenerative disease caused by biallelic variants in the cystatin B (CSTB) gene. Despite a progressive course, phenotype severity varies among patients, even within families. We studied the potential role of APOE ε4 in modifying phenotypic diversity in EPM1, given its established association with neurodegeneration, particularly in Alzheimer's disease.

METHODS: APOE genotypes were determined for 65 genetically verified EPM1 patients homozygous for the CSTB expansion mutation. The Unified Myoclonus Rating Scale (UMRS), Quality of Life in Epilepsy Inventory-31 questionnaire (QOLIE-31), intellectual ability (WAIS-R), clinical data, and quantitative neuroimaging data were compared between APOE ε4 carriers and noncarriers to assess potential correlations with EPM1 severity. Volumetric analysis was performed on MRI data, while diffusion tensor imaging (DTI) was analyzed using Tract-Based Spatial Statistics (TBSS) and atlas-based white matter (WM) tract region of interest (ROI) analysis.

RESULTS: The cohort included 20 ε4 carriers (16 ε3/ε4 and 4 ε4/ε4) and 45 ε4 noncarriers (36 ε3/ε3, 8 ε2/ε3, and 1 ε2/ε2). No significant differences were found in UMRS or disease duration. Carriers had better QOLIE-31 scores in emotional well-being (p = .047), energy/fatigue (p = .048), and medical effects (p = .024). In volumetric analysis, carriers exhibited greater preservation of bilateral hippocampal and amygdalar volumes but demonstrated more pronounced cortical thinning in the left lingual gyrus, right lateral occipital gyrus, and right posterior cingulate (p < .05). Carriers exhibited more widespread WM degeneration in DTI, characterized by reduced fractional anisotropy (FA) and increased mean diffusivity (MD).

SIGNIFICANCE: Despite greater white matter degeneration and reduced cortical thickness, APOE ε4 carriers exhibited preserved deep brain volumes and better self-reported well-being. This study highlights the complex interplay between genetic factors and neurodegenerative processes. Our future research aims to provide more natural history data of EPM1 and correlate long-term phenotypic data with additional geno-phenotypic analyses.},
}

@article {pmid41042497,
year = {2025},
author = {Schreiber, CP and Kovacik, A and Bishop, J and Helman, J},
title = {Amyloid-related Imaging Abnormalities (ARIA) in the Context of Alzheimer's Disease and Amyloid-targeting Therapies: An Introduction for Advanced Practice Providers.},
journal = {Drugs & aging},
volume = {},
number = {},
pages = {},
pmid = {41042497},
issn = {1179-1969},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the accumulation of amyloid-beta (Aβ) and neurofibrillary tangles of hyperphosphorylated tau in the brain. Amyloid-targeting therapies (ATTs) are the first available disease-modifying treatments shown to slow cognitive and functional decline for patients with mild cognitive impairment owing to AD and early symptomatic AD. Currently two ATTs are commercially available, donanemab (Kisunla™) and lecanemab (Leqembi[®]). The main potential side effect and safety concern of ATT treatment is amyloid-related imaging abnormalities (ARIA). ARIA can be categorized into two types that can co-occur: ARIA-E (edema/sulcal effusion) and ARIA-H (hemorrhage/superficial siderosis). Although both are often asymptomatic and ARIA-E typically resolves radiographically over time, both forms can be radiologically and/or clinically serious. Treating clinicians should be equipped with a comprehensive understanding of ARIA. This review aims to provide advanced practice providers, who are pivotal to patient care in AD, with critical insights into ARIA to safely identify risk factors, understand treatment guidelines, and gain familiarity with appropriate management strategies. It emphasizes the importance of understanding APOE genotype and vascular factors in ARIA risk and recognizing the clinical and radiographic manifestations of ARIA. Practical recommendations are provided for monitoring and managing ARIA, including dose management strategies and education on symptom awareness. By fostering a comprehensive understanding of ARIA and its monitoring and management, this review aims to support the safe and effective implementation of ATTs, contributing to optimized patient care for those treated with ATTs.},
}

@article {pmid41042431,
year = {2025},
author = {Shah, N and Natesan, G and Gupta, R},
title = {Uncovering Necroptosis in Alzheimer's Disease: A Systematic Review of Evidence Across Experimental Models.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {83},
pmid = {41042431},
issn = {1573-6830},
mesh = {*Necroptosis/physiology ; *Alzheimer Disease/pathology/metabolism ; Humans ; Animals ; Disease Models, Animal ; Signal Transduction ; },
abstract = {Alzheimer's disease (AD), one of the most challenging neurodegenerative disorders, with high prevalence worldwide, is characterized by progressive cognitive decline and accumulation of amyloid-β plaques and neurofibrillary tau tangles. Despite significant research, the limited efficacy of current treatments underscores the critical need to identify novel pathogenic mechanisms and therapeutic targets. Necroptosis, a regulated and highly inflammatory form of programmed cell death, has emerged as one of the key contributors to AD pathogenesis. This systematic review comprises 25 high-quality in vivo, in vitro, and autopsy studies, published between 2015 and 2025, extracted from PubMed, Scopus, and Science Direct databases. The keywords include "necroptosis", "RIPK1", "RIPK3", "MLKL", "pMLKL", "necroptosis inhibitors", "Alzheimer's disease", and "neurodegeneration". The review summarizes the multiple molecular mechanisms, including TNF-α/TNFR1 signaling, TRIF-mediated RIPK3 activation, and RHIM-dependent MLKL phosphorylation, associated with necroptosis in the pathogenesis of AD. All the studies converge on necroptosis as a central pathogenic pathway linking key molecular and cellular abnormalities observed in AD. The accumulated evidence strongly supports prioritizing the development of brain-penetrant necroptosis inhibitors and clinical validation of associated biomarkers. These insights signal a significant shift in AD therapeutics, moving from symptomatic treatment to mechanistically targeted interventions that can alter disease progression.},
}

*Necroptosis/physiology
*Alzheimer Disease/pathology/metabolism
Humans
Animals
Disease Models, Animal
Signal Transduction

@article {pmid41042139,
year = {2025},
author = {Wang, S and Dong, D and Li, X and Wang, Z},
title = {Pan-tissue transcriptome analysis reveals sex-dimorphic human aging.},
journal = {eLife},
volume = {13},
number = {},
pages = {},
doi = {10.7554/eLife.102449},
pmid = {41042139},
issn = {2050-084X},
support = {XDB38040100//Strategic Priority Research Program of CAS/ ; 91940303//National Natural Science Foundation of China/ ; 32030064//National Natural Science Foundation of China/ ; 31730110//National Natural Science Foundation of China/ ; 2018YFA0107602//National Key Research and Development Program of China/ ; 2021YFA0805200//National Key Research and Development Program of China/ ; 2019YFC1315804//National Key Research and Development Program of China/ ; 31970554//National Natural Science Foundation of China/ ; },
mesh = {Humans ; Male ; *Aging/genetics ; Female ; *Sex Characteristics ; *Gene Expression Profiling ; *Transcriptome ; Aged ; Alternative Splicing ; Middle Aged ; Adult ; Aged, 80 and over ; },
abstract = {Complex diseases often exhibit sex dimorphism in morbidity and prognosis, many of which are age-related. However, the underlying mechanisms of sex-dimorphic aging remain foggy, with limited studies across multiple tissues. We systematically analyzed ~17,000 transcriptomes from 35 human tissues to quantitatively evaluate the individual and combined contributions of sex and age to transcriptomic variations. We discovered extensive sex dimorphisms during aging with distinct patterns of change in gene expression and alternative splicing (AS). Intriguingly, the male-biased age-associated AS events have a stronger association with Alzheimer's disease, and the female-biased events are often regulated by several sex-biased splicing factors that may be controlled by estrogen receptors. Breakpoint analysis showed that sex-dimorphic aging rates are significantly associated with decline of sex hormones, with males having a larger and earlier transcriptome change. Collectively, this study uncovered an essential role of sex during aging at the molecular and multi-tissue levels, providing insight into sex-dimorphic regulatory patterns.},
}

Humans
Male
*Aging/genetics
Female
*Sex Characteristics
*Gene Expression Profiling
*Transcriptome
Aged
Alternative Splicing
Middle Aged
Adult
Aged, 80 and over

@article {pmid41041908,
year = {2025},
author = {Vaqué-Alcázar, L and Videla, L and Benejam, B and Del Hoyo Soriano, L and Barroeta, I and Fernandez, S and Rodríguez-Baz, Í and Arriola-Infante, JE and Arranz, J and Maure Blesa, L and Sanjuan-Hernández, A and Morcillo-Nieto, AO and Bejanin, A and Arenaza-Urquijo, EM and Lleó, A and Bartrés-Faz, D and Carmona-Iragui, M and Fortea, J},
title = {Generational effects in Down syndrome: Enriched environment enhances functionality without reducing Alzheimer's disease risk.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70447},
doi = {10.1002/alz.70447},
pmid = {41041908},
issn = {1552-5279},
support = {CD23/00235//Instituto de Salud Carlos III/ ; CM22/00052//Instituto de Salud Carlos III/ ; CM22/00219//Instituto de Salud Carlos III/ ; CM23/00291//Instituto de Salud Carlos III/ ; CP20/00038//Instituto de Salud Carlos III/ ; CP24/00112//Instituto de Salud Carlos III/ ; PI18/00335//European Union/ ; PI22/00785//European Union/ ; PI22/00307//European Union/ ; PI14/1561//European Union/ ; PI20/01330//European Union/ ; PI20/01473//European Union/ ; PI23/01786//European Union/ ; IIBSP-DOW-2020-151//Fundación Tatiana Pérez de Guzmán el Bueno/ ; GBHI_ALZ-18-543740//Global Brain Health Institute/ ; //ICREA Academia/ ; 2326 - GRT-2024A//Fondation Jérôme Lejeune/ ; #1913Cycle2019B//Fondation Jérôme Lejeune/ ; //BrightFocus Foundation/ ; H2020-SC1-BHC-2018-2020/GA 965422//Horizon 2020 Framework Programme/ ; AARG-22-923680/ALZ/Alzheimer's Association/United States ; AARG-22-973966/ALZ/Alzheimer's Association/United States ; 1R01AG056850-01A1//Foundation for the National Institutes of Health/ ; 3RF1AG056850-01S1//Foundation for the National Institutes of Health/ ; AG056850//Foundation for the National Institutes of Health/ ; R21AG056974//Foundation for the National Institutes of Health/ ; and R01AG061566//Foundation for the National Institutes of Health/ ; //Generalitat de Catalunya/ ; //Life Molecular Imaging (LMI)/ ; },
mesh = {Humans ; *Down Syndrome/complications/psychology/epidemiology ; *Alzheimer Disease/epidemiology/diagnosis ; Male ; Female ; Middle Aged ; Aged ; Adult ; *Intellectual Disability/etiology ; },
abstract = {INTRODUCTION: Down syndrome (DS) is the leading cause of intellectual disability (ID) and a genetic form of Alzheimer's disease (AD). We wanted to assess whether generational changes have induced (1) milder ID with greater independence and (2) delayed AD diagnosis.

METHODS: We analyzed 681 asymptomatic DS to test generational effects on ID, functionality, and cognition. In 353 DS individuals with AD, we compared clinical diagnosis age by ID using analysis of variance. In addition, dementia diagnosis age was examined through a published meta-analysis.

RESULTS: Our results indicate a generational shift toward a higher proportion of individuals with mild/moderate ID, greater intelligence, and autonomy. However, it was not paralleled by an ID-related delay in the age at AD onset in our cohort, or by generational delays reported over the past 35 years.

DISCUSSION: The findings highlight notable generational improvements in DS, but no effects on the age at AD dementia diagnosis.

HIGHLIGHTS: A generational effect has reduced the severity of intellectual disability in Down syndrome (DS). Individuals with DS have increased autonomy and improved intellectual milestones. The enriched environment has not delayed the age at Alzheimer's disease (AD) dementia in DS. Further studies should confirm if cognitive reserve might delay AD in DS.},
}

Humans
*Down Syndrome/complications/psychology/epidemiology
*Alzheimer Disease/epidemiology/diagnosis
Male
Female
Middle Aged
Aged
Adult
*Intellectual Disability/etiology

@article {pmid41041713,
year = {2025},
author = {Fahmy, NM and Fayez, S and Zengin, G and Uba, AI and Al-Sayed, E and El-Shazly, M and Eldahshan, OA and Singab, AN},
title = {Antioxidant and Amylase, Glucosidase, and Tyrosinase Enzymes Inhibitory Potential of Genistein and 11-α-Hydroxyerysotrine Supported by In Silico and Network Pharmacology Approaches.},
journal = {Chemical biology & drug design},
volume = {106},
number = {4},
pages = {e70175},
doi = {10.1111/cbdd.70175},
pmid = {41041713},
issn = {1747-0285},
support = {46667//Science and Technology Development Fund/ ; },
mesh = {*Genistein/chemistry/pharmacology ; *Monophenol Monooxygenase/antagonists & inhibitors/metabolism ; *Antioxidants/chemistry/pharmacology ; Molecular Docking Simulation ; *Enzyme Inhibitors/chemistry/pharmacology ; *Alkaloids/chemistry/pharmacology ; *Amylases/antagonists & inhibitors/metabolism ; Network Pharmacology ; *Isoflavones/chemistry/pharmacology ; Humans ; Butyrylcholinesterase/metabolism/chemistry ; Cholinesterase Inhibitors/chemistry/pharmacology ; alpha-Glucosidases/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; Plant Leaves/chemistry/metabolism ; },
abstract = {The antioxidant and enzyme inhibition properties of the isoflavone genistein (1) and the alkaloid 11-α-hydroxyerysotrine (2) isolated from the leaves of Erythrina speciosa were assessed. Both compounds exhibited notable in vitro antioxidant activities; 11-α-hydroxyerysotrine (2) demonstrated stronger effects than genistein in DPPH, ABTS, CUPRAC, and FRAP assays. On the other hand, genistein (1) demonstrated a higher metal chelating activity than 11-α-hydroxyerysotrine (2). Regarding enzyme inhibition, 11-α-hydroxyerysotrine (2) inhibited both acetyl- (AchE) and butyryl- (BchE) cholinesterases, though to a lesser extent than the standard drug galanthamine. Both compounds inhibited tyrosinase, yet a good inhibition was observed for 11-α-hydroxyerysotrine (2) as compared to genistein (1). Genistein (1) showed a lower α-amylase inhibition effect (IC50: 3.43 mg/mL, p < 0.05) compared to the standard acarbose (IC50: 0.80 mg/mL). Regarding α-glucosidase inhibition, genistein (1) (IC50: 1.02 mg/mL, p < 0.05) was more active than acarbose (IC50: 1.78 mg/mL). 11-α-Hydroxyerysotrine (2) exhibited lower α-amylase (IC50: 4.09 mg/mL) and α-glucosidase (IC50: 4.48 mg/mL) inhibition effects. The in vitro biological results were further supported by network pharmacology approaches on Alzheimer's disease and in silico studies performed on AChE, BChE, tyrosinase, α-amylase, and β-glucosidase enzymes. The results of our study suggest 11-α-hydroxyerysotrine as a potential drug candidate for further investigation in managing oxidative stress-related conditions, Alzheimer's disease, and hyperpigmentation disorders.},
}

*Genistein/chemistry/pharmacology
*Monophenol Monooxygenase/antagonists & inhibitors/metabolism
*Antioxidants/chemistry/pharmacology
Molecular Docking Simulation
*Enzyme Inhibitors/chemistry/pharmacology
*Alkaloids/chemistry/pharmacology
*Amylases/antagonists & inhibitors/metabolism
Network Pharmacology
*Isoflavones/chemistry/pharmacology
Humans
Butyrylcholinesterase/metabolism/chemistry
Cholinesterase Inhibitors/chemistry/pharmacology
alpha-Glucosidases/metabolism/chemistry
Acetylcholinesterase/metabolism/chemistry
Plant Leaves/chemistry/metabolism

@article {pmid41041706,
year = {2025},
author = {Wu, J and Zhang, Z and Rios Pulgar, IM and Jiang, S and Wang, P and Chai, K and Pathak, AP and Oishi, K and Li, Y and Bang, J and Moghekar, A and Wagandt, C and Smith, GS and Onyike, CU and Pontone, GM and Bakker, A and Zhou, J},
title = {Robust Extrapolated Semi-Solid Magnetization Transfer Reference Fitting for Quantitative Amide Proton Transfer Imaging at 3 T: Application to Patients With Mild Cognitive Impairment and Mild Dementia.},
journal = {Magnetic resonance in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/mrm.70122},
pmid = {41041706},
issn = {1522-2594},
support = {R01AG069179/NH/NIH HHS/United States ; R01CA276221/NH/NIH HHS/United States ; R37CA248077/NH/NIH HHS/United States ; },
abstract = {PURPOSE: To refine the utility of the extrapolated semi-solid magnetization transfer reference (EMR) method for amide proton transfer (APT) quantification.

METHODS: Twelve patients (7 mild cognitive impairment and 5 mild dementia; 66.3 ± 8.7 years) and 13 age-matched, cognitively normal volunteers (68.6 ± 8.0 years), as well as a 10% cross-linked bovine-serum-albumin phantom, were scanned at 3 T. A two-step, coarse-to-fine EMR fitting approach was developed, and a bias term was introduced to compensate for the discrepancy between the ideal model and practical data. The fitted model parameters and calculated APT[#] and NOE[#] (nuclear Overhauser effect) were compared across different EMR fitting methods and between the two groups. The normalized-root-mean-squared-error was used to measure the discrepancy between fitted curves and acquired Z-spectra.

RESULTS: Phantom results confirmed that the proposed EMR method had lower fitting errors and closer-to-zero APT[#] and NOE[#] signals. Human results showed the specific APT[#] signals peaked at 3.5 ppm. A noticeable APT[#] increase in the hippocampus was seen in the mild cognitive impairment/mild dementia group (mean APT[#] = 3.09%, compared to 2.41% in the cognitively normal group; p = 0.002). The APT[#] signal in the hippocampus provided higher accuracy in differentiating between cognitively normal individuals and those with mild cognitive impairment/mild dementia than APT-weighted signal (an area-under-the-curve of 0.92 compared to 0.67).

CONCLUSION: The proposed EMR method enabled more accurate quantification of APT signals and could potentially facilitate the use of APT imaging in the diagnosis and staging of Alzheimer's disease and related dementias.},
}