@article {pmid41275158,
year = {2025},
author = {Bastan, F and Saeedi-Moghaddam, F and Rashidian, M and Mirhosseini, F and Mozhgani, SH},
title = {Human herpesvirus 6 (HHV-6) infection and risk of Alzheimer's disease: a systematic review and meta-analysis.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-025-04500-1},
pmid = {41275158},
issn = {1471-2377},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia worldwide. Human Herpesvirus 6 (HHV-6), a neurotropic virus capable of establishing lifelong latency in the CNS, has been suggested as a potential risk factor in the pathogenesis of AD. However, studies investigating this association have reported inconsistent findings. This systematic review and meta-analysis aimed to explore this association further and shed light on the matter.

OBJECTIVE: This study aimed to systematically review and meta-analyze existing literature to assess the association between HHV-6 infection and the risk of Alzheimer's disease.

METHODS: A comprehensive search of MEDLINE, Web of Science, EMBASE, and grey literature was conducted following PRISMA guidelines. Case-control studies that assessed the presence of HHV-6 in patients with Alzheimer's disease were included. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS), and meta-analysis was performed using RevMan 5.3 and STATA 17.0. Subgroup and sensitivity analyses were conducted to assess heterogeneity and robustness of the results. Publication bias was evaluated using funnel plots, trim-and-fill analysis, and Begg's test.

RESULTS: Eight case-control studies comprising 1,507 participants were included. The pooled analysis revealed a significant association between HHV-6 infection and increased risk of Alzheimer's [OR = 1.81, 95% CI: 1.16-2.84, p = 0.009], with moderate heterogeneity (I² = 60%). Sensitivity analysis excluding one outlier strengthened the association [OR = 2.78, 95% CI: 1.65-4.70] and eliminated heterogeneity (I² = 0%). Subgroup analyses demonstrated stronger associations in studies using PCR detection [OR = 2.20, 95% CI: 1.22-3.98] and brain tissue samples [OR = 2.49, 95% CI: 1.22-5.11], whereas serological and blood-based studies yielded weaker, non-significant associations. Publication bias was not detected.

CONCLUSIONS: This meta-analysis suggests that HHV-6 infection is significantly associated with an increased risk of Alzheimer's disease. Nevertheless, the exact causal mechanisms remain unclear. Further longitudinal and mechanistic studies are needed to better understand the role of HHV-6 in Alzheimer's pathogenesis and to evaluate potential antiviral options for preventive or therapeutic strategies.},
}

@article {pmid41275049,
year = {2025},
author = {Xia, Z and Lin, Y and Sun, J and Wang, Y and Hu, X and Deng, C},
title = {Magnetic MXene with dual Ti-affinity sites for enhanced phosphopeptide enrichment in saliva.},
journal = {Mikrochimica acta},
volume = {192},
number = {12},
pages = {840},
pmid = {41275049},
issn = {1436-5073},
support = {22264024//National Natural Science Foundation of China/ ; 22074019, 21425518//National Natural Science Foundation of China/ ; 2024YFA1307503, 2024YFC3405402//National Key Research and Development Program of China/ ; },
mesh = {*Phosphopeptides/analysis/chemistry ; Humans ; *Titanium/chemistry ; *Saliva/chemistry ; Caseins/chemistry ; Nitrites ; Transition Elements ; },
abstract = {Saliva contains low-abundance phosphopeptides carrying important pathological information, but determining them with mass spectrometry is difficult due to matrix interference and low ionization efficiency. A well-designed nano-trapper with multiple affinity sites can help solve this problem. In this study, we developed a new dual Ti-affinity magnetic MXene (dTi-MMX). It combines the natural Ti-OH sites of MXene with additional Ti-O sites from titanium dioxide nanoparticles coated onto magnetic Ti3C2Tx MXene. This dual Ti-site approach significantly improves phosphopeptide capture, while the magnetic core allows for quick separation. Performance tests showed that dTi-MMX detects as low as 10 fmol‧µL[-1] of β-casein digests and selectively enriches phosphopeptides in mixtures of β-casein and BSA (at a 1:1000 mass ratio). When applied to human saliva, dTi-MMX successfully identified 110 unique phosphopeptides. Gene ontology analysis suggests that these peptides primarily participate in pathways such as salivary secretion and multicellular organismal processes, including several biomarkers associated with diseases, such as CST1 for cancer and LPO/CST3 for Alzheimer disease. This approach offers an effective tool for salivary phosphoproteomics research.},
}

*Phosphopeptides/analysis/chemistry
Humans
*Titanium/chemistry
*Saliva/chemistry
Caseins/chemistry
Nitrites
Transition Elements

@article {pmid41274951,
year = {2025},
author = {Bayahya, AY and Banjar, H and Talabay, O and Alamri, SH},
title = {Comparative analysis of multiple deep learning models with mitigation-driven approaches for enhanced Alzheimer's disease classification.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-27914-w},
pmid = {41274951},
issn = {2045-2322},
abstract = {Alzheimer's disease diagnosis from structural MRI remains challenging in clinical practice. While deep learning shows promise for automated dementia detection, comprehensive comparisons of different neural network approaches are lacking. It analyzed T1-weighted MRI scans comprised 14,983 2D grid images derived from 1346 unique patients. Ten coronal brain slices spaced 2mm apart were arranged in 512 × 512-pixel grids using our 2D coronal-10 slicing sMRI methodology to preserve anatomical relationships while reducing computational demands. Ten deep learning architectures were systematically compared, including traditional CNNs, Vision Transformers, and Capsule Networks. Patient-level data splitting prevented information leakage. ECAResNet269 achieved the highest balanced accuracy (63%), with mild performance across all classes: dementia (38% sensitivity/77% specificity), MCI (72% sensitivity/66% specificity), and healthy controls (44% sensitivity/90% specificity). Class imbalance mitigation strategies substantially improved model performance, with combined SMOTE, cost-sensitive learning, and focal loss approaches achieving 74% balanced accuracy and (78% CN, 76%MCI, 69% AD) sensitivity in the ECAResNet269 model. Pretrained CNNs architectures substantially outperformed advanced methods-Vision Transformer and CapsNets showed complete classification failure. The 2D grid method retained 96% of diagnostic information compared to 3D approaches while providing 4.2 × faster processing. Traditional CNNs architectures remain most effective for medical neuroimaging classification. ECAResNet269 achieved clinically relevant performance suitable for dementia screening applications. The 2D grid methodology successfully balances diagnostic accuracy with computational efficiency, enabling deployment on standard clinical hardware.},
}

@article {pmid41274899,
year = {2025},
author = {Sun, JK and Peng, AZ and Hart, RP and Herrup, K and Wu, D and Wong, GC and Chow, KH},
title = {Perimenopausal state oestradiol to progesterone imbalance drives Alzheimer's risk via ERRα dysregulation and energy dyshomeostasis.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-025-66726-4},
pmid = {41274899},
issn = {2041-1723},
support = {32022087//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32300643//National Natural Science Foundation of China (National Science Foundation of China)/ ; GRF16100219//Research Grants Council, University Grants Committee (RGC, UGC)/ ; 11410824//Research Grants Council, University Grants Committee (RGC, UGC)/ ; },
abstract = {Sex-biased differences in Alzheimer's disease (AD) are well documented, but the mechanisms underlying increased vulnerability in postmenopausal women remain unclear. This study aimed to model the effects of perimenopausal hormonal fluctuations on AD pathophysiology. Using a VCD-induced accelerated ovarian failure model in young female C57BL/6 J and 3xTg mice, we simulated a perimenopausal state with hormonal changes characterised by elevated oestradiol levels and reduced progesterone levels. Supporting human brain transcriptomic and metabolomic data from the ROSMAP study revealed that impaired oestrogen-related receptor alpha (ERRα) function was a key driver of female sex-biased vulnerability. In female mice, progesterone-guided oestrogen receptor signalling maintained ERRα activity by regulating neuronal cholesterol homoeostasis and the TCA cycle. Hormonal imbalances disrupted this mechanism, triggering an aspartate-driven "minicycle," which increased glutamate release, neuronal excitability, ATP depletion, and energy crisis susceptibility. This study demonstrates how perimenopausal hormonal imbalances exacerbate AD risk via ERRα dysfunction, linking neuronal cholesterol and energy homeostasis to disease vulnerability.},
}

@article {pmid41274321,
year = {2025},
author = {Chu, CT and Uruno, A and Suzuki, T and Taguchi, K and Baird, L and Katsuoka, F and Yamamoto, M},
title = {NRF2 Activation by CDDO-Im Regulates Inflammatory and Autophagy Pathways in Human Microglial Cells.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.11.046},
pmid = {41274321},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles, accompanied by elevated oxidative stress and inflammation. Microglia, the resident macrophages in the brain, play a key protective role by clearing plaques and damaged neurons. NRF2 (Nuclear factor erythroid 2-related factor 2) is a master regulator of cytoprotection against oxidative stress, whose activation alleviates oxidative damage, neuroinflammation, and cognitive deficits in AD models. However, direct targets of NRF2 in microglia remain unclear. In this study, we demonstrate that NRF2 activation by CDDO-Im significantly suppresses inflammation in human microglial cells (HMC3) stimulated by IFN-γ or Aβ. Through integrative RNA-sequencing and ChIP-sequencing analysis of NRF2, we identified five representative direct NRF2 target genes involved in inflammation (e.g., IL6, CDK6) and another five related to autophagy (e.g., TFE3, SQSTM1). Importantly, we also found that CDDO-Im treatment enhances autophagy as evidenced by an increased LC3-II/LC3-I ratio. Public single-cell transcriptomic data further underscored the critical role of microglia in NRF2-mediated autophagy regulation within AD brains. Together, our findings reveal new direct NRF2 target genes, highlight the dual role of NRF2 in suppressing inflammation and enhancing autophagy, and thus provide novel insights for therapeutic interventions in AD.},
}

@article {pmid41274317,
year = {2025},
author = {Anbaraki, A and Ghasemi, A and Seyedarabi, A and Yousefi, R and Saboury, AA},
title = {Dual glycation and oxidation of tau protein: Impact of methylglyoxal and hydrogen peroxide on tau structure and fibril assembly.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.11.044},
pmid = {41274317},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) indicate overlapping pathogenic mechanisms including, protein glycation and oxidative stress. Tau protein, a key player in AD pathology, undergoes various post-translational modifications, disturbing its physiological function and facilitating its aggregation/fibrillation. Nevertheless, the cumulative influence of glycation and oxidation on the structural integrity and fibrillation of tau remains inadequately elucidated. In this study, we examined the effects of methylglyoxal (MGO)-induced glycation and hydrogen peroxide (H2O2)-mediated oxidation, individually or in combination, on tau structure, fibrillation and cytotoxicity. Structural and morphological alterations were evaluated using SDS-PAGE, fluorescence spectroscopy, circular dichroism, dynamic light scattering, Fourier transform infrared spectroscopy, and atomic force microscopy. Fibrillation kinetics were monitored under two conditions: (i) pre-fibrillation modification and (ii) simultaneous modification and fibrillation. Our results indicated that the co-treatment with MGO and H2O2 synergistically altered tau structure. Moreover, the fibrillation kinetics of pre-modified tau samples with MGO indicated a reduction in fibrillation through the generation of oligomeric species. Conversely, the fibrillation kinetics of pre-modified tau samples with H2O2 and both compounds increased tau fibrillation. On the other hand, simultaneous modification and fibrillation of tau samples with MGO and H2O2 resulted in an increase in tau fibrillation and structural changes. Collectively, our results indicated that co-treatment with MGO and H2O2 synergistically enhanced tau fibrillation and produced more ordered fibril structures with increased cytotoxicity toward SH-SY5Y cells. These findings provide mechanistic insights into how glycation and oxidative stress cooperatively modulate tau fibrillation and offer a molecular basis for the pathological link between diabetes and AD.},
}

@article {pmid41274188,
year = {2025},
author = {Khan, Y and Naeem, MU and Arooj, K and Naseem, M and Adnan, R and Azmatullah, },
title = {A comprehensive computational and experimental study of novel imidazole linked thiadiazole based amide derivatives as cholinesterase duel-target inhibitor for the treatment of Alzheimer's disease.},
journal = {Computational biology and chemistry},
volume = {120},
number = {Pt 1},
pages = {108789},
doi = {10.1016/j.compbiolchem.2025.108789},
pmid = {41274188},
issn = {1476-928X},
abstract = {The thiadiazole scaffold has gained prominence in modern drug discovery due to its remarkable structural adaptability. Its unique framework enables interactions with a wide spectrum of biological targets, making it a valuable pharmacophore for therapeutic development. Reflecting its growing clinical importance, efficient synthetic access to thiadiazole derivatives has become a focal point for medicinal chemists seeking to exploit its multifunctional activity. In our study, we synthesized a streamlined and high-throughput synthetic protocol to generate a novel library of imidazole linked thiadiazole analogues. All newly imidazole linked thiadiazole analogues were spectroscopically characterized by [1]HNMR and [13]CNMR spectroscopy and high-resolution electron impact mass spectrometry (HRMS). Biological screening across a panel of key metabolic enzymes revealed potent inhibitory action against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Remarkably, a majority of tested compounds outperformed standard inhibitors donepezil exhibited compounds 1, 2, 4 and 8 showing lower IC50 values of 5.32 ± 0.87 µM (AChE), 6.09 ± 0.97 µM (BuChE), 7.40 ± 0.76 µM (AChE), 6.97 ± 0.56 µM (BuChE), 7.56 ± 0.54 µM (AChE), 7.03 ± 0.39 µM (BuChE), and 5.13 ± 0.28 µM (AChE), 5.33 ± 0.61 µM (BuChE) respectively. Detailed structure-activity relationship (SAR) analyses revealed that strategic substitution patterns modulate inhibitory efficacy and selectivity. Complementing these findings, molecular docking study illuminated key interactions within the catalytic pockets of (AChE) and (BuChE), identifying critical amino acid residues mediating ligand engagement. Hence, our integrated synthetic, biochemical, and computational approach identifies compounds 1, 2, 4 and 8 as a promising lead compound that possess favorable pharmacological attributes for further preclinical development in metabolic disease interventions.},
}

@article {pmid41273956,
year = {2025},
author = {Liu, X and Zhou, Y and Chen, M and Zhang, Y and Li, S and Fei, L},
title = {Identification and extraction of bioactive constituents from Gardenia jasminoides Ellis: Evaluation of their acetylcholinesterase inhibitory potential.},
journal = {Journal of pharmaceutical and biomedical analysis},
volume = {270},
number = {},
pages = {117240},
doi = {10.1016/j.jpba.2025.117240},
pmid = {41273956},
issn = {1873-264X},
abstract = {Research in functional foods faces two major challenges due to the complexity of natural food components: accurate and rapid identification of bioactive compounds, and their precise extraction. To address these challenges, this study developed an integrated strategy to identify and isolate acetylcholinesterase inhibitors (AChEIs) from Gardenia jasminoides Ellis (GJE)-a plant with both medicinal and edible value-while evaluating their potential against Alzheimer's disease (AD). First, affinity ultrafiltration-liquid chromatography-mass spectrometry (AUF-LC-MS) (a technique that uses AChE as a target to specifically capture binding compounds from complex extracts) was employed to screen candidate AChEIs from GJE. To verify the anti-dementia potential of these candidates and analyze their binding stability with AChE, we used molecular docking integrated with molecular dynamics simulation (a type of kinetic simulation approach that predicts static binding affinity and dynamic complex stability, respectively). Next, based on activity screening results, offline two-dimensional countercurrent chromatography (Offline 2D-CCC) (a separation technique that first groups compounds with similar polarity via 1st-dimensional separation and then purifies each group with optimized solvent systems via 2nd-dimensional separation) was used to isolate the active components. To clarify the inhibitory mechanism of the isolated compounds on AChE, we performed targeted enzymatic kinetics analysis (including determining inhibition type, calculating the half-inhibitory concentration IC50, and measuring the inhibition constant Kᵢ-parameters that characterize how compounds block AChE activity). To systematically confirm the anti-AD mechanism of GJE components and assess potential toxic effects, we applied network pharmacology-a method that constructs "compound-target-disease" interaction networks to reveal multi-component, multi-target, and multi-pathway relationships (instead of focusing on single targets). This approach helped identify cross-talk between GJE's therapeutic effects and potential toxicity. Nine potential AChEIs were finally screened from GJE: Geniposidic acid, Genipin-1-O-gentiobioside, Gardenoside, Croceic acid, Rutin, Crocin I, Crocin II, Quercetin, and Nevadensin. Their binding energies with AChE (a key parameter for evaluating binding strength) were -8.8, -8.9, -8.2, -8.7, -9.3, -10.4, -10.6, -10.2, and -10.3 kcal/mol, respectively. The terpenoids and flavonoids isolated via Offline 2D-CCC exhibited > 90 % purity (a critical standard for natural product research). Enzymatic kinetics analysis confirmed that these compounds exert reversible AChE inhibition-a property essential for developing safe therapeutic agents for cholinergic dysfunction disorders like AD. To improve the efficiency and accuracy of active compound screening, we combined computer-aided virtual screening (in this study, used to predict compound-AChE binding affinity via molecular docking) with in vitro enzyme inhibition assays. This strategy enabled rapid prioritization of candidates, reduced false-positive results (a common issue with traditional in vitro-only screening), and facilitated targeted preparation of bioactive compounds.},
}

@article {pmid41273928,
year = {2025},
author = {Li, H and Brzostek, O and Sherman, J and Ayoub, M and Chen, L and Sheng, Z and Xu, F and Dou, B and Wang, W and Zhu, X and Yan, C and Xu, Y},
title = {Cyclic nucleotide phosphodiesterase 1 and cognitive impairment: Mechanistic insights and therapeutic implications.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {193},
number = {},
pages = {118796},
doi = {10.1016/j.biopha.2025.118796},
pmid = {41273928},
issn = {1950-6007},
abstract = {Cognitive impairment is a defining feature of neurodegenerative diseases such as Alzheimer's disease (AD) and vascular dementia (VaD). However, the pathogenesis of cognitive impairment remains unclear, mainly because it involves complex pathological processes in which multiple cytokines and pathways contribute to its progression. Among key molecular regulators, cyclic nucleotide phosphodiesterase 1 (PDE1), a Calcium/calmodulin (Ca[2+]/CaM) activated enzyme that regulates intracellular levels of cAMP and cGMP by degrading them to inactive forms. PDE1 may play a critical role in influencing cognitive function through modulating these second messengers. PDE1 integrates calcium fluctuations with cyclic nucleotide metabolism, affecting a series of events including synaptic plasticity, neuronal survival, vascular tone, and neuroinflammatory responses. This review summarizes the distribution of PDE1 and its isoforms, and their regulatory mechanisms and functional roles, particularly those of PDE1A, PDE1B, and PDE1C, in the central nervous system (CNS) disorders. We also discussed the involvement of PDE1 in modulating cAMP/PKA and cGMP/PKG signaling pathways, and its impact on oxidative stress, neuroinflammation, and apoptotic cascades associated with cognitive dysfunction. In addition, this review integrates current evidence on PDE1 isoforms in both neuronal and vascular regulation of cognition, emphasizing their dual neurovascular roles in cognitive impairment. We further summarized recent progress on PDE1 target validation and the reported efficacy of PDE1A inhibitors in alleviating memory deficits associated with neurodegenerative disorders, such as AD and VaD.},
}

@article {pmid41273905,
year = {2025},
author = {Lee, SH and Kim, S and Lee, JU and Baek, SJ and Hyun, S and Jung, S and Yang, JY and Mun, C and Lee, S and Lee, CN and Park, SG and Sim, SJ},
title = {Machine learning-assisted high-performance immunoSERS platform using silk fibroin as a natural etching mask for early diagnosis of Alzheimer's disease.},
journal = {Biosensors & bioelectronics},
volume = {294},
number = {},
pages = {118222},
doi = {10.1016/j.bios.2025.118222},
pmid = {41273905},
issn = {1873-4235},
abstract = {Early and accurate diagnosis of Alzheimer's disease (AD) is a major stride toward pharmacological interventions to delay the onset or progression of the disease in patients with mild symptoms. In this study, we developed a silk fibroin-templated surface-enhanced Raman spectroscopy (SERS)-activated double-sandwich immunoassay (immunoSERS) platform that enhances plasmonic hotspot formation for the ultrasensitive detection of biomarkers. Silk fibroin, acting as a natural etching mask, facilitates the direct fabrication of Au nanocavity (AuNC) substrates and enables the immunoSERS platform to achieve attomolar-level detection (limit of detection: 35.8 aM) with high reproducibility (relative standard deviation: ∼2.5 %) due to its unique structural characteristics. This platform effectively detects four core AD biomarkers-amyloid beta 42 (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), and brain-derived neurotrophic factor (BDNF)-in human plasma. Moreover, by introducing a k-nearest neighbors (KNN)-based machine learning algorithm, the suggested platform could classify disease progression stages with 94.0 % accuracy. These results indicate that this silk fibroin-driven immunoSERS platform is a viable alternative to existing diagnostic techniques for the effective early screening of AD and are a potential therapy to delay AD incidence in clinical practice.},
}

@article {pmid41273902,
year = {2025},
author = {Guo, Y and Si, R and Li, L and Dai, X and Zhou, L and Bu, Y},
title = {Improving the performance of integrated PEC biosensors by photocarrier transfer function layers with tandem nanostructure.},
journal = {Biosensors & bioelectronics},
volume = {294},
number = {},
pages = {118211},
doi = {10.1016/j.bios.2025.118211},
pmid = {41273902},
issn = {1873-4235},
abstract = {Improving the resolution of photoelectrochemical (PEC) sensors is vital for reliable detection in complex biomedical environments. Here, we report an integrated PEC biosensor featuring a tandem nanostructured photoelectrode composed of BiVO4 (BVO), TiO2, NiCrOx, and Ti2CO2 MXene (BTNCM), designed to enhance photocarrier transfer and surface reaction kinetics thereby improving sensor resolution. This multilayered architecture acts as a photocarrier transfer function layer, where the NiCrOx cocatalyst facilitates interfacial charge transport, while TiO2 and MXene respectively contribute to efficient charge separation and aptamer immobilization. Benefiting from these synergistic effects, the BTNCM biosensor enables ultra-sensitive detection of Alzheimer's disease (AD) biomarkers, including amyloid β40 (Aβ40), amyloid β42 (Aβ42), and tau protein, achieving detection limits down to approximately 0.03 fg/mL (S/N = 3) for Aβ40 and Aβ42, together with a high signal resolution of about 40 μA cm[-2] dec[-1]. Mechanistic analysis reveals that small-molecular-weight analytes, like Aβ40 and Aβ42, enhance photocurrent through redox reactions, while larger molecules, such as tau protein, induce steric hindrance, resulting in suppressed PEC sensing responses. Notably, validation using clinical cerebrospinal fluid and plasma samples showed strong agreement with SimoA, a commercial ultra-sensitive immunoassay platform, demonstrating the sensor's reliability and clinical relevance. This work offers a scalable and cost-effective PEC biosensing strategy for early and precise AD diagnosis, offering a promising foundation for future applications in non-invasive precision medicine.},
}

@article {pmid41273627,
year = {2025},
author = {Wang, W and Tan, S and Zuo, X and Gao, X and Ma, L and Sun, R and Liang, G and Yin, L and Pu, Y and Zhang, J},
title = {Brain Organoids in Neurodegenerative Disease Modeling: Advances, Applications and Future Perspectives.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {142},
pmid = {41273627},
issn = {1559-1182},
mesh = {*Organoids/pathology ; Humans ; *Neurodegenerative Diseases/pathology ; *Brain/pathology ; Animals ; Disease Models, Animal ; *Models, Biological ; },
abstract = {Neurodegenerative diseases (NDDs) represent incurable and debilitating conditions characterized by progressive deterioration of neurological function. Investigating neurodegeneration remains a critical global challenge in aging societies. Brain organoids-self-organizing three-dimensional structures derived from human pluripotent stem cells-recapitulate cell types and cytoarchitectures of the developing human brain. This in vitro model system has advanced our bridge between conventional two-dimensional cultures and in vivo models. Brain organoids emulate early neural tube formation, neuroepithelial differentiation, and whole-brain regionalization. Furthermore, region-specific organoid models now facilitate mechanistic investigation into acquired and inherited NDDs' pathogenesis, alongside drug discovery and toxicity screening. In this review, we (i) delineate the epidemiology and pathobiology of major NDDs, (ii) analyze limitations of current animal models, (iii) critically evaluate brain organoid generation methodologies, and (iv) focus on organoid applications in modeling Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).},
}

*Organoids/pathology
Humans
*Neurodegenerative Diseases/pathology
*Brain/pathology
Animals
Disease Models, Animal
*Models, Biological

@article {pmid41273600,
year = {2025},
author = {Mohammad, SI and Hammood, YM and Vasudevan, A and Uthirapathy, S and Ballal, S and Sabarivani, A and Mishra, S and Nathiya, D and Al-Qaim, ZH and Kadhim, AJ},
title = {Mechanistic Interplay of Gut Microbiota and Blood-Brain Barrier Integrity in Neurodegenerative Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {137},
pmid = {41273600},
issn = {1559-1182},
mesh = {*Gastrointestinal Microbiome/physiology ; Humans ; *Blood-Brain Barrier/metabolism/pathology ; *Neurodegenerative Diseases/microbiology/pathology/metabolism ; Animals ; },
abstract = {The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, plays a vital role in maintaining overall health through digestion, nutrient production, and immune modulation. Factors such as diet, lifestyle, and medication use significantly influence its composition. Concurrently, the blood-brain barrier (BBB) serves as a crucial protective barrier, regulating the passage of substances between the bloodstream and the brain. Disruption of the BBB is linked to various neurological disorders and cognitive decline. Neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's, can be exacerbated by compromised BBB integrity, allowing harmful substances to penetrate the brain and accelerate neuronal degeneration. This review examines the complicated relationship between gut microbiota and BBB integrity, focusing on their collective impact on neurodegenerative diseases. Despite advancements in understanding these systems independently, there remains a critical gap in comprehending their interconnected roles in neurodegeneration. Addressing this gap is paramount for developing innovative therapeutic strategies. Specifically, this review suggests that modulating the gut microbiota offers a promising and actionable approach to preserve BBB integrity, thereby presenting a novel avenue for mitigating neurodegeneration and improving the prognosis and quality of life for affected individuals.},
}

*Gastrointestinal Microbiome/physiology
Humans
*Blood-Brain Barrier/metabolism/pathology
*Neurodegenerative Diseases/microbiology/pathology/metabolism
Animals

@article {pmid41273473,
year = {2025},
author = {Yang, Z and Peng, X and Zhang, X and Guo, H and Li, Z and Wu, X and Zhao, M and Ruganzu, JB and Zhai, C and Ji, S and Yang, W},
title = {Tanshinone IIA Promotes Hippocampal Neurogenesis in ApoE[-/-] Mice Through cAMP/PKA/CREB/BDNF Signaling Pathway.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {144},
pmid = {41273473},
issn = {1559-1182},
support = {2023-JC-YB-735//the Natural Science Basic Research Plan in Shaanxi Province of China/ ; },
mesh = {Animals ; *Neurogenesis/drug effects ; *Brain-Derived Neurotrophic Factor/metabolism ; *Hippocampus/drug effects/metabolism ; *Signal Transduction/drug effects ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Cyclic AMP/metabolism ; *Cyclic AMP-Dependent Protein Kinases/metabolism ; *Abietanes/pharmacology ; *Apolipoproteins E/deficiency ; Cell Proliferation/drug effects ; Mice ; Neural Stem Cells/drug effects/metabolism ; Mice, Knockout ; Mice, Inbred C57BL ; Male ; Phosphorylation/drug effects ; },
abstract = {New cells are generated from neural stem cells (NSCs) in the subgranular zone (SGZ) of the dentate gyrus of the hippocampus throughout life to shape brain function. Apolipoprotein E (ApoE) deficiency impairs hippocampal dentate gyrus development by affecting the neural progenitor pool over time. Impaired adult hippocampal neurogenesis has been reported in human ApoE4 and ApoE-knockout (ApoE[-/-]) mice. The ApoE gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Our previous studies indicated that tanshinone IIA (tan IIA) has a broad range of pharmacological actions on AD. Here, we aimed to investigate the effects of 2 weeks of tan IIA (15 mg/kg, intraperitoneally, once daily) treatment on hippocampal neurogenesis in 1- and 3-month-old ApoE[-/-] mice. The results showed that tan IIA treatment significantly promoted cell proliferation and increased the density of immature neurons in the hippocampus. Mechanistically, tan IIA treatment elevated the levels of cyclic adenosine monophosphate (cAMP), cAMP/protein kinase A (PKA), and cAMP response element binding protein (CREB) phosphorylation, and subsequently increasing the production of brain-derived neurotrophic factor (BDNF). Furthermore, tan IIA is capable of promoting NSCs proliferation, differentiation, and survival in vitro. Collectively, the above findings indicated that tan IIA stimulates neurogenesis in the adult hippocampus of ApoE[-/-] mice possibly through the cAMP/PKA/CREB/BDNF signaling pathway. These results suggested that tan IIA may have neuroprotective effects against neurogenesis decline in ApoE[-/-] mice.},
}

Animals
*Neurogenesis/drug effects
*Brain-Derived Neurotrophic Factor/metabolism
*Hippocampus/drug effects/metabolism
*Signal Transduction/drug effects
*Cyclic AMP Response Element-Binding Protein/metabolism
*Cyclic AMP/metabolism
*Cyclic AMP-Dependent Protein Kinases/metabolism
*Abietanes/pharmacology
*Apolipoproteins E/deficiency
Cell Proliferation/drug effects
Mice
Neural Stem Cells/drug effects/metabolism
Mice, Knockout
Mice, Inbred C57BL
Male
Phosphorylation/drug effects

@article {pmid41273462,
year = {2025},
author = {Su, Y and Zhang, D and Li, Y and Gu, H and Li, W and Zhou, W and Zhao, N and Huang, X},
title = {Caenorhabditis Elegans Ortholog of TNF Alpha-Induced Protein 1 is Upregulated by TOL-1 and Exacerbates Amyloid-Beta-Associated Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {146},
pmid = {41273462},
issn = {1559-1182},
support = {KC-23236341//Yunnan University Graduate Research Innovation Fund/ ; No. 202403AC100007//Yunnan Fundamental Research Projects/ ; No. 32170184//Natural Science Foundation Program of China/ ; },
mesh = {*Caenorhabditis elegans/metabolism/genetics ; Animals ; *Amyloid beta-Peptides/metabolism/toxicity ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Up-Regulation ; Animals, Genetically Modified ; *Toll-Like Receptors/metabolism ; Humans ; Alzheimer Disease/pathology/metabolism ; },
abstract = {Neuroinflammation has been recognized as a central pathological mechanism in Alzheimer's disease (AD), modulated by diverse molecular pathways. Among these, the tumor necrosis factor superfamily (TNFSF) pathway serves as a pivotal mediator of inflammatory responses in higher organisms, representing a potential therapeutic target for AD treatment. Notably, TNF alpha-induced protein 1 (TNFAIP1) is significantly upregulated following amyloid-beta1-42 (Aβ1-42) accumulation in the postmortem brains of patients with AD and in transgenic Caenorhabditis elegans models. However, the regulatory mechanism of its ortholog F22E5.6 in C. elegans and its role in Aβ neurotoxicity remain elusive due to the absence of the core TNFSF members in this model. Through systematic screening of TNFSF orthologs, the trf-1 gene that encodes the adapter protein, TNF receptor-associated factor (TRAF), has been identified as a critical regulator in Aβ1-42-induced F22E5.6 overexpression of C. elegans. In this genetic model, the only Toll-like receptor TOL-1 in C. elegans serves as a potential receptor to activate TRF-1 and to transmit this signal to the SRC-2/PMK-3 axis, thereby executing the effects on mitochondrial homeostasis disequilibrium. These findings reveal the regulatory mechanism on Aβ1-42-induced F22E5.6/TNFAIP1 overexpression and its involvement in AD model of C. elegans, providing a clue to resolve the paradox of TNFSF-mediated inflammation in organisms lacking the canonical TNFSF pathway.},
}

*Caenorhabditis elegans/metabolism/genetics
Animals
*Amyloid beta-Peptides/metabolism/toxicity
*Caenorhabditis elegans Proteins/metabolism/genetics
*Up-Regulation
Animals, Genetically Modified
*Toll-Like Receptors/metabolism
Humans
Alzheimer Disease/pathology/metabolism

@article {pmid41273231,
year = {2025},
author = {Kuehn, JF and Zhang, Q and Heston, MB and Kang, JW and Harding, SJ and Davenport-Sis, NJ and Peter, DC and Kerby, RL and Vemuganti, V and Schiffmann, EC and Tallon, MM and Harpt, J and Hajra, A and Wheeler, JL and Shankar, S and Mickol, A and Zemberi, J and Chow, H and Zhang, E and Clements, E and Noughani, H and Forst, A and Everitt, G and Kollmorgen, G and Quijano-Rubio, C and Christian, BT and Carlsson, CM and Johnson, SC and Asthana, S and Zetterberg, H and Blennow, K and Ulland, TK and Rey, FE and Bendlin, BB},
title = {Fecal short-chain fatty acids vary by sex and amyloid status.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70877},
pmid = {41273231},
issn = {1552-5279},
support = {//the Wisconsin Registry for Alzheimer's Prevention/ ; //the Wisconsin Alzheimer's Disease Research Center/ ; //NIH/NINDS/ ; //Wisconsin Partnership Program grant/ ; R01AG070973/AG/NIA NIH HHS/United States ; R01AG083883/AG/NIA NIH HHS/United States ; R21AG089348/AG/NIA NIH HHS/United States ; //the Swedish Research Council/ ; //Swedish Alzheimer's Foundation/ ; //Hjärnfonden, Sweden/ ; //the Swedish state under the agreement between the Swedish government and the County Councils/ ; //the ALF-agreement/ ; //the Alzheimer's Association 2021 Zenith Award/ ; //the Alzheimer's Association 2022-2025 Grant/ ; //La Fondation Recherche Alzheimer (FRA), Paris, France/ ; //the Kirsten and Freddy Johansen Foundation, Copenhagen, Denmark/ ; //Familjen Rönströms Stiftelse, Stockholm, Sweden/ ; //an anonymous philanthropist and donor/ ; //the European Union's Horizon Europe Research and Innovation Programme/ ; //Swedish State Support for Clinical Research/ ; //the European Union Joint Program for Neurodegenerative Disorders/ ; 2137424//National Science Foundation Graduate Research Fellowship Program/ ; //the Graduate School and the Office of the Vice Chancellor for Research, University of Wisconsin-Madison/ ; //the Wisconsin Alumni Research Foundation/ ; },
mesh = {Humans ; Female ; Male ; *Fatty Acids, Volatile/metabolism/analysis ; *Feces/chemistry/microbiology ; *Gastrointestinal Microbiome/physiology ; *Alzheimer Disease/metabolism ; Aged ; Sex Factors ; Biomarkers/cerebrospinal fluid ; Cognitive Dysfunction ; },
abstract = {INTRODUCTION: Short-chain fatty acids (SCFAs), produced by gut microbes, influence Alzheimer's disease (AD) pathology in animals. Less is known about SCFAs and AD in humans. We profiled feces of adults along the AD continuum to investigate gut microbiome and SCFA associations with AD pathology and cognition.

METHODS: We measured SCFAs and bacterial abundances in fecal samples from 287 participants in the Wisconsin Alzheimer's Disease Research Center and Wisconsin Registry for Alzheimer's Prevention. We performed regressions examining associations between SCFAs or gut microbes and AD pathology and cognition.

RESULTS: Fecal propionate, isovalerate, and propionate-producing bacteria are inversely associated with amyloid status. Mediation analysis found that propionate mediates sex-specific associations between SCFAs and cerebrospinal fluid biomarkers. SCFA levels are associated with slower cognitive decline.

DISCUSSION: These results link SCFAs and propionate-producing bacteria with AD. This may inform efforts to leverage diet and specific bacteria to boost SCFA production and potentially ameliorate AD progression.

HIGHLIGHTS: Fecal SCFAs link to lower amyloid burden and microglial activation, notably in females. SCFA-producing gut microbes have reduced abundance in amyloid-positive participants. Fecal propionate mediates relationships between gut microbes and amyloid status. SCFAs are associated with slower plasma pTau217 accumulation in females. SCFAs are associated with slower cognitive decline.},
}

Humans
Female
Male
*Fatty Acids, Volatile/metabolism/analysis
*Feces/chemistry/microbiology
*Gastrointestinal Microbiome/physiology
*Alzheimer Disease/metabolism
Aged
Sex Factors
Biomarkers/cerebrospinal fluid
Cognitive Dysfunction

@article {pmid41273229,
year = {2025},
author = {Nichols, E and Keller, KP and Chang, H and Chiang, YY and Gross, AL and Hayes-Larson, E and Claus Henn, B and Kezios, KL and Meijer, E and Shih, RA and Szpiro, AA and Weiss, J and Weuve, J and Adar, SD and Lee, J},
title = {Key research priorities in methodological approaches for measuring the exposome and studying its role in the development of dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70928},
pmid = {41273229},
issn = {1552-5279},
support = {/NH/NIH HHS/United States ; U24AG088894/AG/NIA NIH HHS/United States ; R01AG030153/AG/NIA NIH HHS/United States ; R00AG075317/AG/NIA NIH HHS/United States ; R00AG084769/AG/NIA NIH HHS/United States ; R01AG065359/AG/NIA NIH HHS/United States ; R01AG067497/AG/NIA NIH HHS/United States ; R13AG064971/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Dementia/etiology/epidemiology ; *Exposome ; *Environmental Exposure/adverse effects ; Research Design ; },
abstract = {There is growing recognition regarding the importance of the exposome, or the totality of exposures one experiences across the life course, in research on Alzheimer's disease and related dementias. However, the measurement of numerous exposures at once and over time, as well as modeling their effects on dementia risk, presents significant methodological challenges. Through community engagement and consensus-building processes integrating input from multidisciplinary panels of experts, we identified critical priority topics for methods used in studying links between the exposome and dementia risk, along with advances needed to address those priorities. We identified nine priority topics: high-dimensional and multimodal data, measurement error, harmonization across studies, mixtures of exposures, effect heterogeneity, exposure timing, cumulative exposures, reverse causation, and sample composition. This paper describes these priority topics and highlights areas where future research or the dissemination of existing methods could advance the state of existing science. HIGHLIGHTS: Inherent complexities central to the measurement and modeling of the exposome and its relationship to dementia pose methodological challenges. We identified nine priority topics, such as measurement error, mixtures of exposures, and cumulative exposures. Modeling approaches should consider complexity but provide useful simplifications when possible. Investments in the development and dissemination of innovative approaches and methodological guidance are needed.},
}

Humans
*Dementia/etiology/epidemiology
*Exposome
*Environmental Exposure/adverse effects
Research Design

@article {pmid41273227,
year = {2025},
author = {Kang, S and Jeon, S and Kim, Y and Jeon, SH and Choi, M and Lee, YG and Ye, BS and , },
title = {Putaminal hypermetabolism identifies Lewy body co-pathology in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70920},
pmid = {41273227},
issn = {1552-5279},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; W81XWH-12-2-0012//and DOD ADNI/ ; //the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering/ ; //groups: AbbVie, Alzheimer's Association/ ; //Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //BioClinica, Inc./ ; //Biogen/ ; //Bristol-Myers Squibb Company/ ; //CereSpir, Inc./ ; //Cogstate/ ; //Eisai Inc./ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //EuroImmun; F. Hoffmann-La Roche Ltd/ ; //Genentech, Inc./ ; //Fujirebio/ ; //GE Healthcare/ ; //IXICO Ltd./ ; //Janssen Alzheimer Immunotherapy Research & Development, LLC./ ; //Johnson & Johnson Pharmaceutical Research & Development LLC./ ; //Lumosity/ ; //Lundbeck/ ; //Merck & Co., Inc./ ; //Meso Scale Diagnostics, LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Pfizer Inc./ ; //Piramal Imaging/ ; //Servier/ ; //Takeda Pharmaceutical Company/ ; //and Transition Therapeutics./ ; /CAPMC/CIHR/Canada ; //Korea Health Technology R&D Project/ ; //Korea Health Industry Development Institute/ ; HR22C141101//Ministry of Health & Welfare, Republic of Korea/ ; //National Research Foundation of Korea/ ; //(NRF)/ ; RS-2024-00509289//Korea Government/ ; RS-2025-18362970//Korea Government/ ; //Ministry of Science and ICT, the Ministry of Trade/ ; //Industry and Energy, the Ministry of Health & Welfare/ ; 1711196790//the Ministry of Food and Drug Safety/ ; RS-2023-00247272//the Ministry of Food and Drug Safety/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/diagnostic imaging ; Male ; Female ; Positron-Emission Tomography ; *Lewy Body Disease/pathology/metabolism/diagnostic imaging ; Aged ; tau Proteins/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; *Putamen/metabolism/diagnostic imaging/pathology ; *Brain/metabolism/diagnostic imaging/pathology ; Fluorodeoxyglucose F18 ; alpha-Synuclein/cerebrospinal fluid ; Aged, 80 and over ; },
abstract = {INTRODUCTION: The clinical implications of brain hypermetabolism remain unexplored in Lewy body disease (LBD) co-pathology in Alzheimer's disease (AD).

METHODS: We investigated cognition, [18]F-fluorodeoxyglucose positron emission tomography (PET), and cerebrospinal fluid tau phosphorylated at threonine 181 (pTau181)/Aβ42 plus α-synuclein seeding amplification assays (SAA) in controls, 217 SAA-negative AD (AD[SAA-]), and 124 SAA-positive AD (AD[SAA+]). Brain metabolism was assessed using subject residual profile (SRP) and standardized uptake value ratio (SUVR).

RESULTS: Compared to AD[SAA-], AD[SAA+] showed putamen SRP hypermetabolism and middle occipital gyrus (MOG) SUVR hypometabolism. SAA positivity correlated with putamen SRP hypermetabolism independently of pTau181/amyloid beta 42 (Aβ42). Its interaction with pTau181/Aβ42 influenced MOG SUVR, showing increased MOG SUVR with higher pTau181/Aβ42 in AD[SAA+]. Putamen SRP hypermetabolism predicted faster cognitive decline and greater variability in both groups. MOG SUVR hypometabolism correlated with them only in AD[SAA-]. Adding putamen SRP hypermetabolism to models, including SAA positivity and AD signature hypometabolism, improved the prediction of cognitive decline/variability, whereas MOG SUVR did not.

DISCUSSION: Putaminal hypermetabolism may serve as a robust metabolic marker of LBD co-pathology in AD.

HIGHLIGHTS: LB co-pathology in AD alters regional brain metabolism. SRP analyses capture putaminal hypermetabolism for SAA positivity. SUVR analyses emphasize occipital hypometabolism for SAA positivity. Occipital metabolism correlates positively with AD severity in mixed AD-LB. Putaminal, not occipital, metabolism predicts cognitive change over AD-related metabolism and SAA.},
}

Humans
*Alzheimer Disease/pathology/metabolism/diagnostic imaging
Male
Female
Positron-Emission Tomography
*Lewy Body Disease/pathology/metabolism/diagnostic imaging
Aged
tau Proteins/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
*Putamen/metabolism/diagnostic imaging/pathology
*Brain/metabolism/diagnostic imaging/pathology
Fluorodeoxyglucose F18
alpha-Synuclein/cerebrospinal fluid
Aged, 80 and over

@article {pmid41273226,
year = {2025},
author = {Intzandt, B and Ramirez, J and Lam, B and Masellis, M and Einstein, G and Bherer, L and Black, SE and , and , },
title = {Exploring sex-specific risk factors in cognitive decline: Insights into modifiable and non-modifiable determinants using a network analysis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70825},
pmid = {41273226},
issn = {1552-5279},
support = {//Ontario Brain Institute/ ; CIHR CNA-137794/CAPMC/CIHR/Canada ; CNA-163902/CAPMC/CIHR/Canada ; BDO-148341/CAPMC/CIHR/Canada ; //McGill University/ ; FRQ-356162//Fonds de Recherche du Québec - Santé/ ; //Pfizer Canada/ ; //Douglas Hospital Research Centre and Foundation/ ; //Canada Foundation for Innovation/ ; //Alzheimer Society Research Program/ ; //Foundation Brain Canada/ ; //National Institute of Health of the United States/ ; //Fondation Jean-Louis Lévesque/ ; },
mesh = {Humans ; *Cognitive Dysfunction/physiopathology ; Female ; Male ; Risk Factors ; Aged ; *Alzheimer Disease ; Sex Factors ; Neuropsychological Tests ; Magnetic Resonance Imaging ; Apolipoprotein E4/genetics ; Middle Aged ; },
abstract = {BACKGROUND: How sex-specific risk factors for dementia interact remains understudied. Network analysis provides a novel approach to examine these relationships, offering insights into sex-specific risk factor connectivity in healthy controls (HCs) and individuals with mild cognitive impairment or Alzheimer's disease (cognitive decline [CD]).

METHODS: A network analysis of 896 participants examined associations among modifiable, non-modifiable, and cognitive risk factors. Network invariance and global strength tests assessed structural and connectivity differences.

RESULTS: In males, network invariance differed between HC and CD groups, but connectivity was unchanged. In females, network invariance and connectivity were significantly altered, with HC females exhibiting stronger overall connectivity. Key risk factors in females included systolic blood pressure and apolipoprotein E ε4, whereas males' networks were primarily influenced by cognitive outcomes.

DISCUSSION: Sex-specific networks suggest distinct mechanisms underlying cognitive decline. Future work differentiating mild cognitive impairment and Alzheimer's disease stages will refine our understanding of risk factor evolution and inform precision medicine approaches to dementia prevention.

HIGHLIGHTS: Sex-stratified networks of risk factors differ in healthy and cognitively impaired adults. Female networks show greater global connectivity in healthy versus cognitively decline groups. Apolipoprotein E, family history, and lifestyle factors show sex-specific centrality in networks. Network structure changes more in females across the cognitive decline spectrum. Findings support sex-specific modeling of dementia risk for precision prevention.},
}

Humans
*Cognitive Dysfunction/physiopathology
Female
Male
Risk Factors
Aged
*Alzheimer Disease
Sex Factors
Neuropsychological Tests
Magnetic Resonance Imaging
Apolipoprotein E4/genetics
Middle Aged

@article {pmid41273220,
year = {2025},
author = {Balogun, WG and Zeng, X and Triana-Baltzer, G and Saeed, A and Aigbogun, HE and Gogola, A and Lopresti, BJ and Villemagne, VL and Ganguli, M and Kolb, H and Snitz, BE and Lopez, OL and Cohen, AD and Reis, SE and Karikari, TK},
title = {Cross-cohort validation and cutpoint estimation of the Janssen plasma p-tau217+ assay in predominantly cognitively normal community studies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70916},
pmid = {41273220},
issn = {1552-5279},
support = {R37AG023651/NH/NIH HHS/United States ; R01AG072641/NH/NIH HHS/United States ; R01AG052521/NH/NIH HHS/United States ; R01HL089292/NH/NIH HHS/United States ; R01AG083874/NH/NIH HHS/United States ; U24AG082930/NH/NIH HHS/United States ; P30AG066468/NH/NIH HHS/United States ; RF1AG077474/NH/NIH HHS/United States ; R01AG083156/NH/NIH HHS/United States ; R01AG025516/NH/NIH HHS/United States ; R01AG073267/NH/NIH HHS/United States ; R01AG075336/NH/NIH HHS/United States ; U01NS141777/NH/NIH HHS/United States ; P01AG025204/NH/NIH HHS/United States ; R01MH108509/NH/NIH HHS/United States ; DAF2255207//Aging Mind Foundation/ ; //the Anbridge Charitable Fund/ ; //the Department of Psychiatry, University of Pittsburgh/ ; HT94252320064//U.S. Department of Defense/ ; },
mesh = {Humans ; *tau Proteins/blood ; Male ; Female ; Aged ; Positron-Emission Tomography ; Biomarkers/blood ; Amyloid beta-Peptides/metabolism ; Cohort Studies ; Phosphorylation ; *Alzheimer Disease/blood/diagnosis/diagnostic imaging ; Middle Aged ; *Cognition/physiology ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Cross-cohort validation studies for plasma phosphorylated tau (p-tau) 217 are limited. We evaluated the Janssen plasma p-tau217+ assay and proposed a cutpoint value in three independent community-based cohorts.

METHODS: We included n = 441 participants (age = 70.3 ± 7.3) from three independent community-based cohorts with amyloid-beta-positron emission tomography (Aβ-PET), tau-PET, clinical, and cognitive information.

RESULTS: The cohorts had low pre-test probability (%Aβ positivity = 14.9-24.7) and were predominantly cognitively normal (> 73%). Plasma p-tau217+ had high accuracy for abnormal Aβ PET (areas under the curve [AUCs] = 81-86%), good correlation with Aβ-PET burden (0.336-0.397) that was highest in the cohort with the most Aβ-PET-positive participants, and the biomarker concentrations were highest in the joint Aβ-PET and tau-PET positive group. Negative predictive value (NPV) was high across cohorts (≤93%) but positive predictive value (PPV) was consistently poor (< 57%). Sensitivity and specificity averaged 75% and 84%, respectively. A combined cohort cutpoint of 0.05pg/ml gave AUC = 84.5%, NPV = 94%, PPV = 50%, sensitivity = 75%, and specificity = 84%.

DISCUSSION: Plasma p-tau217+ can rule out Aβ pathophysiology due to Alzheimer's disease at the population level. Cohort-level %Aβ-PET positivity influences accuracies.

HIGHLIGHTS: Plasma phosphorylated tau (p-tau) 217 assays have demonstrated potential to identify older adults with brain amyloid pathology due to Alzheimer's disease. Community-based studies are crucial for accessing the clinical validity of fluid biomarkers and their real-world applicability. We evaluated the Janssen plasma p-tau217+ assay in three community-based cohorts. Janssen plasma p-tau217+ identified amyloid-beta abnormalities across three diverse cohorts of community-dwelling older adults. High NPV indicates p-tau217+ as a good tool for initial screening to enrich for high-risk individuals particularly for cohort studies and clinical trial participation.},
}

Humans
*tau Proteins/blood
Male
Female
Aged
Positron-Emission Tomography
Biomarkers/blood
Amyloid beta-Peptides/metabolism
Cohort Studies
Phosphorylation
*Alzheimer Disease/blood/diagnosis/diagnostic imaging
Middle Aged
*Cognition/physiology
Aged, 80 and over

@article {pmid41273064,
year = {2025},
author = {Zhou, J and Antic, SD and Das, B and He, W and Tran, DM and Hu, X and Fernández-Chacón, R and Yan, R},
title = {BACE1 Expression Is Required for Proper Synaptic Vesicle Dynamics in the Hippocampus.},
journal = {Journal of neurochemistry},
volume = {169},
number = {11},
pages = {e70299},
pmid = {41273064},
issn = {1471-4159},
support = {AG025493/AG/NIA NIH HHS/United States ; AG046929/AG/NIA NIH HHS/United States ; AG064554/AG/NIA NIH HHS/United States ; RF1AG058261/AG/NIA NIH HHS/United States ; 65539//Cure Alzheimer's Fund/ ; NS074256/NS/NINDS NIH HHS/United States ; NS138991/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; *Amyloid Precursor Protein Secretases/genetics/biosynthesis/metabolism ; *Synaptic Vesicles/metabolism ; *Aspartic Acid Endopeptidases/genetics/biosynthesis/metabolism ; *Hippocampus/metabolism ; Mice ; Mice, Knockout ; Exocytosis/physiology ; Mice, Inbred C57BL ; Male ; },
abstract = {BACE1 is an indispensable enzyme for the production of β-amyloid peptides by initiating the cleavage of amyloid precursor protein at the β-secretase site. Targeting BACE1 inhibition is therefore a therapeutic strategy for treating patients with Alzheimer's disease. However, several clinical trials using brain-penetrable BACE1 inhibitors have failed due to a lack of efficacy. Previous studies, including our own, have shown that both global and neuron-specific BACE1 inhibition in mice leads to impairments in synaptic strength and spine density. In this study, we investigate the effects of BACE1 inhibition on activity-dependent synaptic vesicle exocytosis and endocytosis using a synapto-pHluorin mouse model. Our results demonstrate impaired synaptic release in BACE1-deficient mice. Furthermore, transcriptomic analysis reveals a significant downregulation of genes related to synapse structure and function. Pathway analysis suggests that BACE1 deficiency significantly downregulates neurexin-neuroligin pathway, which can modulate docking and release of synaptic vesicles at the presynaptic compartment. Our findings suggest that BACE1 inhibition may lead to deficits in synaptic vesicle exocytosis due to the downregulation of key synaptic proteins.},
}

Animals
*Amyloid Precursor Protein Secretases/genetics/biosynthesis/metabolism
*Synaptic Vesicles/metabolism
*Aspartic Acid Endopeptidases/genetics/biosynthesis/metabolism
*Hippocampus/metabolism
Mice
Mice, Knockout
Exocytosis/physiology
Mice, Inbred C57BL
Male

@article {pmid41272964,
year = {2025},
author = {Sutnikiene, V and Pakulaite-Kazliene, G and Audronyte, E and Kuzmickaite, J and Kaubrys, G},
title = {McCollough and Watercolor Effects: Visual Illusions that Fade in Early Alzheimer's Disease.},
journal = {Medical science monitor : international medical journal of experimental and clinical research},
volume = {31},
number = {},
pages = {e950194},
doi = {10.12659/MSM.950194},
pmid = {41272964},
issn = {1643-3750},
mesh = {Humans ; *Alzheimer Disease/physiopathology/drug therapy/psychology ; Female ; Male ; Aged ; Cognitive Dysfunction/physiopathology ; *Visual Perception/physiology/drug effects ; Cholinesterase Inhibitors/therapeutic use/pharmacology ; *Illusions/physiology ; Neuropsychological Tests ; Cognition/physiology ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND Visual illusions provide insight into visual perception processes. We examined the McCollough effects (ME) and watercolor effects (WE) in patients with early Alzheimer disease (AD) and cognitively healthy older adults, and evaluated the influence of acetylcholinesterase inhibitors in the AD mild dementia (MD) stage. MATERIAL AND METHODS We included 28, 27, and 26 patients with MD, amnestic mild cognitive impairment (MCI), and normal cognition (control group), respectively. Participants completed the CDR, MMSE, ADAS-Cog 13, Ishihara test, and ME and WE evaluations. ME was evaluated by identifying chromatic changes in vertical, horizontal black, and white line patterns. WE was evaluated by identifying white or colored sections. RESULTS Regarding ME, white vertical lines appeared red, with no significant differences between groups (H=0.834, P=0.659). Differences were observed in perception of white horizontal lines as green (H=10.27, P=0.006). All in the control group, 25 of 27 in MCI group, and 22 of 28 in MD group reported seeing WE (Fisher exact 6.66, P=0.024). In binary logistic regression, cognitive tests and Ishihara results predicted perception of WE. Regarding MD, no significant differences were reported between patients taking or not taking acetylcholinesterase inhibitors (chi-square 0.749, P=0.38; P=0.19, P=1.00, respectively). CONCLUSIONS Perceptions of ME and WE differed significantly between cognitively normal participants and those with early AD, offering insights into the functional alterations of the visual system and ongoing neurodegeneration. The ME after-effect of red horizontal lines might represent very early AD changes, which could aid in a better understanding of AD visual perception.},
}

Humans
*Alzheimer Disease/physiopathology/drug therapy/psychology
Female
Male
Aged
Cognitive Dysfunction/physiopathology
*Visual Perception/physiology/drug effects
Cholinesterase Inhibitors/therapeutic use/pharmacology
*Illusions/physiology
Neuropsychological Tests
Cognition/physiology
Middle Aged
Aged, 80 and over

@article {pmid41272913,
year = {2025},
author = {Massa, F and Orso, B and De Cesari, F and Pelagotti, V and Garbarino, S and Raffa, S and Mattioli, P and Argenti, L and Lombardo, L and Losa, M and Bozzo, G and Kreshpa, W and Tomassini, G and Panza, A and Cirone, A and Lorenzini, L and Bozzano, F and Visigalli, D and Brugnolo, A and Girtler, N and Piana, M and Arnaldi, D and Morbelli, S and Sambuceti, G and Uccelli, A and Pardini, M},
title = {Cerebrospinal fluid NPTX2 and [[18]F]FDG PET track serotonergic vulnerability to neurodegeneration in prodromal Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01893-6},
pmid = {41272913},
issn = {1758-9193},
support = {PE0000006//Ministero dell'Università e della Ricerca/ ; },
}

@article {pmid41272902,
year = {2025},
author = {Shui, X and Zheng, X and Wu, J and Zhang, M and Kim, G and Chen, R and Peng, L and Wang, Z and Zheng, Y and Zhang, L and Li, R and Wang, L and Zhou, Y and Kim, J and Chen, D and Zhang, T and Lee, TH},
title = {Death-associated protein kinase 1-dependent SENP1 degradation increases tau SUMOylation and leads to cognitive dysfunction in a mouse model for tauopathy.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {121},
pmid = {41272902},
issn = {1750-1326},
support = {2022QH2005//Startup Fund for Scientific Research, Fujian Medical University/ ; 81901071//National Natural Science Foundation of China/ ; 82001128//National Natural Science Foundation of China/ ; 81970993//National Natural Science Foundation of China/ ; 2024J01485//Natural Science Foundation of Fujian Province/ ; 2021Y9001//Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; 2023Y9007//Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; 2024Y9094//Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; },
mesh = {Animals ; *Death-Associated Protein Kinases/metabolism ; *Sumoylation/physiology ; Mice ; Disease Models, Animal ; Humans ; *tau Proteins/metabolism ; *Tauopathies/metabolism ; *Cognitive Dysfunction/metabolism ; Phosphorylation ; *Cysteine Endopeptidases/metabolism ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Emerging evidence implicates that tau SUMOylation disrupts tau homeostasis. Death-associated protein kinase 1 (DAPK1) has been shown to affect tau phosphorylation and accumulation. The sentrin-specific protease 1 (SENP1) is important for protein SUMOylation, and is a potential substrate of DAPK1. However, whether DAPK1 regulates tau SUMOylation and proteostasis through modulating SENP1 remains elusive.

METHODS: We identified the phosphorylation of SENP1 by DAPK1 using in vitro kinase assay and mass spectrometry. The influence of DAPK1 on SENP1 expression, tau SUMOylation and phosphorylation was analyzed using a mouse model for tauopathy by overexpressing human tau in the hippocampal CA3 region, as well as using human AD brain tissues. DAPK1 genetic ablation or pharmacological inhibition was applied to assess the impact of DAPK1 on tau accumulation-related pathologies including synaptic dysfunction and gliosis. The cognitive and emotional functions were evaluated using Y-maze, novel object recognition test, Morris water maze, open field test, and elevated plus maze.

RESULTS: DAPK1 directly interacts with and phosphorylates SENP1, leading to SENP1 degradation via the ubiquitin-proteasome pathway. DAPK1 promotes tau SUMOylation by suppressing SENP1 expression in neurons. DAPK1 downregulation or pharmacological inhibition restores SENP1 level and reduces tau SUMOylation, resulting in an attenuation of aberrant tau phosphorylation and accumulation, which ultimately contributes to improved cognitive ability in vivo. We show that DAPK1 expression is negatively correlated with SENP1 level in human AD hippocampal tissues.

CONCLUSIONS: DAPK1-mediated SENP1 phosphorylation and degradation promote tau SUMOylation, exacerbating tau pathology and cognitive dysfunction in tauopathy. Our findings highlight the DAPK1-SENP1-tau SUMOylation axis as a critical regulator of tau homeostasis, and establish DAPK1 inhibition as a promising therapeutic strategy for AD and related tauopathies.},
}

Animals
*Death-Associated Protein Kinases/metabolism
*Sumoylation/physiology
Mice
Disease Models, Animal
Humans
*tau Proteins/metabolism
*Tauopathies/metabolism
*Cognitive Dysfunction/metabolism
Phosphorylation
*Cysteine Endopeptidases/metabolism
Mice, Transgenic
Male
Mice, Inbred C57BL

@article {pmid41272848,
year = {2025},
author = {Rikken, RM and Yaqub, M and Coomans, EM and Dicks, E and van der Vlies, AE and Windhorst, AD and Boellaard, R and Pijnenburg, YAL and Vijverberg, EGB and van de Giessen, E},
title = {Neuroinflammation PET and long-term cognition and survival in symptomatic Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01915-3},
pmid = {41272848},
issn = {1758-9193},
support = {WE.03-2021-04//Alzheimer Nederland/ ; },
abstract = {BACKGROUND: Neuroinflammation plays a key role in Alzheimer's disease (AD) pathophysiology, but it is not clear how neuroinflammation contributes to disease progression. We aim to investigate the role of neuroinflammation on longitudinal cognition and survival in a unique cohort with PET imaging of translocator protein (TSPO) binding tracer [[11]C]PK11195 and long-term follow-up. We hypothesized that higher [[11]C]PK11195 binding would be associated with faster cognitive decline and higher mortality.

METHODS: 19 participants with AD dementia, 9 participants with MCI due to AD, and 21 healthy controls (HC) with historical dynamic [[11]C]PK11195 PET data were included. Principal component analysis was performed to identify relevant [[11]C]PK11195 patterns. An additional AD ROI consisting of temporal and parietal regions was investigated. [[11]C]PK11195 scores in the principal components (PCs) and AD ROI were compared between groups using ANOVA. Longitudinal MMSE covering a period up to 11 years was used to measure cognitive decline. We used linear mixed models with random subject-specific intercepts and slopes corrected for age, sex and syndrome diagnosis to investigate the association of neuroinflammation with cognition in MCI and AD. Survival data were available for all MCI and AD participants, up to 15.7 years after PET. To examine the influence of neuroinflammation on survival time, we used age, sex, and syndrome diagnosis adjusted cox proportional-hazards models.

RESULTS: Two PCs were retained. PC1 explained 55.4% of the variance and was most explained by [[11]C]PK11195 binding in the thalamus and entorhinal cortex. PC2 explained 15.3% of the variance and constituted of mostly the entorhinal cortex. There was no difference in [[11]C]PK11195 PET between AD, MCI and HCs (range F(2) = 0.157-1.231, P > 0.3). [[11]C]PK11195 did not predict longitudinal MMSE (PC1: β = 0.02, P = 0.73; PC2: β = 0.1, P = 0.44; AD ROI: β = 1.3, P = 0.57) or survival (PC1: HR = 0.90[95%CI: 0.80, 1.03], P = 0.13; PC2: HR = 0.96[0.75, 1.23], P = 0.72; AD ROI: HR = 0.02[0.00, 1.33], P = 0.06).

CONCLUSIONS: Contrary to our hypothesis, we did not find evidence for [[11]C]PK11195 PET predicting long-term cognitive decline or survival. This may indicate that the level of [[11]C]PK11195 PET binding earlier in the disease trajectory is not directly linked to the long-term outcome.},
}

@article {pmid41272813,
year = {2025},
author = {Wu, YC and Lehtonen, Š and Kauppinen, R and Dhungana, H and Koistinaho, J and Rõlova, T},
title = {APPswe mutation causes functional deficits in endothelial cells generated by transient ETV2 overexpression in human iPSCs.},
journal = {Fluids and barriers of the CNS},
volume = {22},
number = {1},
pages = {118},
pmid = {41272813},
issn = {2045-8118},
}

@article {pmid41272752,
year = {2025},
author = {Saraswathi, TS and Mothilal, M and Bukke, SPN and Thalluri, C and Chettupalli, AK},
title = {Recent advances in potential drug nanocarriers for CNS disorders: a review.},
journal = {Biomedical engineering online},
volume = {24},
number = {1},
pages = {137},
pmid = {41272752},
issn = {1475-925X},
mesh = {Humans ; *Central Nervous System Diseases/drug therapy ; *Drug Carriers/chemistry ; *Nanoparticles/chemistry ; Animals ; Blood-Brain Barrier/metabolism ; },
abstract = {BACKGROUND: Neurological disorders, including Parkinson's and Alzheimer's disease, impose a significant burden on individuals and healthcare systems. Effective treatment is often hindered by the restrictive nature of the blood-brain barrier (BBB), limiting drug access to the central nervous system (CNS).

AIM: The purpose of this review is to provide an overview of existing methods to deliver therapeutics to the CNS across the BBB with an emphasis on drug delivery systems that utilize nanotechnology.

METHOD/SOURCE: We performed a thorough review of the published literature on recently emerging trends in pharmacology and nanomedicine that have attempted to deliver drugs to the CNS by addressing the challenge of delivering therapeutics across the BBB.

RESULT/FINDING: Nanoparticles and nanocarriers have shown promise for crossing the blood-brain barrier (BBB), improving drug bioavailability in the brain, and facilitating targeted delivery. Several systems applying nanomaterials, including polymeric nanoparticles, liposomes, solid-lipid nanoparticles, and quantum dots, have successfully advanced through preclinical or early clinical studies. However, demonstrated evidence of the implementation and uptake of nanoparticles in specific antitumor and neurotherapeutic indications have several significant challenges, primarily due to safety, biocompatibility, and scalability.

CONCLUSION: The combination of traditional pharmacology and nanotechnology provides valuable opportunities for drug delivery to the CNS. Gains in the design of nanocarrier systems have great potential for addressing the limits of BBBs and for improving therapeutic outcomes in neurological disease, but more research is necessary for the development of translational clinical studies.},
}

Humans
*Central Nervous System Diseases/drug therapy
*Drug Carriers/chemistry
*Nanoparticles/chemistry
Animals
Blood-Brain Barrier/metabolism

@article {pmid41272684,
year = {2025},
author = {Yinusa, G and Surr, C and Thomas, S and Fenge, LA and Howdon, D and Major, J and Heward, M and Taylor, G and Knight, H and Townson, J and Murphy, J},
title = {An intervention to provide nutritional care for people living with dementia at home receiving home care (TOMATO): study protocol for a single-arm feasibility study.},
journal = {Pilot and feasibility studies},
volume = {11},
number = {1},
pages = {146},
pmid = {41272684},
issn = {2055-5784},
support = {NIHR203110//National Institute for Health Research RfPB/ ; DEMCOMM Fellow//NIHR Applied Research Collaboration ARC Wessex and Alzheimer's Society/ ; },
abstract = {BACKGROUND: In the UK, over 980,000 people are living with dementia, and two-thirds of them live in their own homes. Up to 60% of this population is estimated to be at risk of or already experiencing malnutrition, with 45% facing significant weight loss. As dementia progresses, ensuring that people eat and drink well becomes challenging. Many families affected by dementia access home care services, with home care professionals playing a vital role in supporting and enhancing overall quality of life. Training in identifying nutritional problems and supporting family carers to prevent malnutrition is an identified research need; however, research on the contribution of home care professionals in this area is limited. This study aims to assess the feasibility and acceptability of a nutritional intervention for people living with dementia receiving home care from the perspectives of people with dementia, family carers (dyads), and home care professionals (including home care managers).

METHOD: This is a mixed-method single-arm feasibility study of a nutrition intervention with embedded process evaluation. Thirty-two participants living with dementia and their carers (dyads) will be recruited from home care organisations providing services for older adults across the South, Midlands, and North of England. The intervention comprises a nutritional awareness training session for home care workers, combined with educational resources for home care professionals, family carers, and friends. It is based on a model of person-centred nutritional care and will be delivered by trained home care professionals in the homes of participating dyads over 4 months. Outcome measures will be collected at baseline and at 4 months. Analyses will be descriptive and centred on the feasibility and acceptability of the interventions and study procedures. Key feasibility outcomes will include the rate of participant recruitment and dropout, and the percentage of home care staff who adhere to the intervention schedule (setting at least four actions in response to using the resources). Quantitative data analysis will primarily involve descriptive statistics. Acceptability of the intervention will be determined through in-depth semi-structured qualitative interviews conducted with a subsample of participants dyads and home care professionals. An embedded process evaluation will assess intervention implementation, capturing barriers and facilitators through participant interviews.

DISCUSSION: Findings from this study will help inform the development and implementation of a future RCT, should this nutrition intervention be feasible.

TRIAL REGISTRATION: NCT05866094.},
}

@article {pmid41272598,
year = {2025},
author = {Al Ghammari, A and Guo, M and Al Sinawi, H and Al Harthi, H and Yin, Y and Niu, S and Shan, E and Li, X},
title = {The moderated mediation effect of caregiving stress and social support in the relationship between behavioral and psychological symptoms of dementia and caregiver burden in oman: a cross-sectional study.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-025-06677-z},
pmid = {41272598},
issn = {1471-2318},
support = {22YJCZH089//Ministry of Education of Humanities and Social Science Project/ ; 2022SJYB0298//Philosophy and Social Science Research Projects of Jiangsu Universities/ ; BK20240527//Natural Science Foundation of Jiangsu Province/ ; Jiangsu Education Department [2023] No.11//Project of "Nursing Science" Funded by the 4th Priority Discipline Development Program of Jiangsu Higher Education Institutions/ ; },
abstract = {BACKGROUND: Caregivers of individuals presenting behavioral and psychological symptoms of dementia (BPSD) experience substantial emotional, physical, and psychological distress, potentially compromising their health status and caregiving capacity. This burden manifests through a complex interplay of factors, including symptom severity, caregiving-related stress levels, and social support accessibility. Our study investigated the moderated mediation effects of caregiving stress and social support on the BPSD-caregiver burden relationship within the Omani context.

METHODS: This cross-sectional study included 100 caregivers of patients with BPSD from Al Masarra Hospital and Sultan Qaboos University Hospital in Oman. Validated instruments were used: Zarit Burden Interview (ZBI-22) for caregiver burden, Abe's BPSD Score (ABS) for neuropsychiatric symptoms, Caregiver Reaction Scale (CRS) for caregiving stress, and Multidimensional Scale of Perceived Social Support (MSPSS) for social support.

RESULTS: The proposed model demonstrated a sound fit (PCMIN/DF = 2.612). Statistical analysis revealed a significant positive correlation between BPSD severity and caregiver burden (p < 0.01). Caregiving stress emerged as a significant mediator in this relationship, with its effect moderated by social support availability. Furthermore, caregiver burden showed significant associations with dementia progression stage (β = 0.42, p < 0.001) and intensity of care requirements (β = 0.38, p < 0.01).

CONCLUSIONS: The research highlights the complex nature of caregiver burden in BPSD, indicating that caregiver stress increases the connection between BPSD and burden, while social support moderates this association. Specific interventions must incorporate stress reduction approaches, address patient-specific care needs, and enhance caregiver support systems to effectively reduce burden.},
}

@article {pmid41272481,
year = {2025},
author = {Li, Q and Degan, S and Galeffi, F and Colton, CA and Turner, DA},
title = {Dysregulated microvascular reactivity in hippocampus and cortex in CVN Alzheimer's disease mouse model.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X251383112},
doi = {10.1177/0271678X251383112},
pmid = {41272481},
issn = {1559-7016},
abstract = {Microvascular reactivity in acute cortical and hippocampal brain slices and hippocampal synaptic- evoked cerebral blood flow (CBF) in vivo were analyzed in a mouse model of Alzheimer's disease (AD, CVN). Microvessels underwent initial vasoconstriction (2 µM noradrenaline) then treatment with either 0.5 mM glutamate or 100 µM NMDA. In acute brain slices from young mice (<20 weeks) the glutamate and NMDA treatment led to dilation of capillaries in cortex and hippocampus, but not in aged CVN mice (>30 weeks, with AD pathology). Furthermore, 1 mM adenosine restored pre-constricted capillaries to control levels in WT but not in aged CVN brain slices. Stimulation of endothelial ET-1 receptors (10 nM ET-1) showed enhanced vasoconstriction in hippocampal capillaries of aged CVN slices, but blockade of both ET-1A/1B receptors did not alter basal capillary tone in aged CVN slices. Stimulation-evoked hippocampal CBF in vivo was significantly reduced in aged CVN mice. These results provide evidence for a progressive, complex age- and AD pathology-related impairment of vascular reactivity and vasodilation in the CVN model. The dysregulation of NVC function and reduced functional hyperemia in aged CVN AD mice may underscore dynamic hypoperfusion and metabolic insufficiency, which could accelerate progression in AD.},
}

@article {pmid41272422,
year = {2025},
author = {Wilson, RF and Harrison, DD and Amoakohene, E and Lyons, BH},
title = {Homicides among people with disabilities, United States, 2003-2022.},
journal = {Injury epidemiology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40621-025-00640-7},
pmid = {41272422},
issn = {2197-1714},
abstract = {BACKGROUND: People with disabilities (PwD) are at an increased risk of experiencing nonfatal violence; however, the risk of fatal violence victimization (i.e., homicide) among this population is less well established.

METHODS: We used National Violent Death Reporting System (NVDRS) data for homicide victims with disabilities for 2003 to 2022 in 50 states, the District of Columbia, and Puerto Rico. NVDRS is a surveillance system that collects data on violent deaths, linking information from death certificates, coroner or medical examiner records, and law enforcement reports. NVDRS does not currently include standard variables on disability status or disability type; these decedent characteristics were identified using a literal text search of textual data. Descriptive statistics were used to characterize homicides among PwD.

RESULTS: From 2003 to 2022, NVDRS collected 1,498 homicides among people with disabilities. The largest proportion of victims had a neurological disability (36.7%), followed by cognitive disability (35.5%), physical disability (22.4%), or unspecified disability type (5.4%); 18.2% had multiple disability types. Those aged ≥ 65 years accounted for 45.1% of all victims; the largest proportion of victims were ≥ 75 years old (29.7%). A firearm was used in 38.5% of these homicides. The top three precipitating circumstances of these homicides were: caregiver abuse and neglect (27.0%), argument (26.0%), and intimate partner violence (IPV; 24.0%). Caregiver abuse or neglect precipitated 38.1% of homicides among female victims, versus 19.1% of male victims. IPV precipitated 43.7% of female homicides, versus 9.1% of male homicides. Half (49.5%) of all victims had a mental health problem at the time of death; 23.3% had a history of ever being treated for a mental health problem; 17.8% were receiving mental health treatment at the time of death.

CONCLUSION: This study characterized homicides among PwD. Older adults accounted for nearly half of all victims, and mental health conditions such as dementia and Alzheimer's disease were frequently present among decedents, especially female victims. Among older adults and child victims, caregiver abuse/neglect was common. Our results underscore the importance of supporting caregivers of PwD, creating protective environments for PwD, systematically collecting data on violence against PwD, and tailoring prevention strategies to address the needs of PwD.},
}

@article {pmid41272400,
year = {2025},
author = {Shao, S and Lu, H and Zu, R and Chen, Y and Peng, Z and Peng, Q and Ma, H and Sun, Y},
title = {Pharmacological Regulation of Mitophagy by Natural Plant Products as a Therapeutic Target for Alzheimer's Disease.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70131},
pmid = {41272400},
issn = {1099-1573},
support = {CMC 2021//Horizontal research project of Chengdu Medical College/ ; 242102311258//Scientific and Technological Project of Henan Province/ ; 2021LHPG-08//Joint Fund of Chengdu Medical College and Chengdu Pidu District People's Hospital/ ; 231111312900//Henan Province key research and development project/ ; No. 2022M711080//Postdoctoral Foundation of China/ ; No. 32301030//The National Natural Science Foundation of China/ ; No. 82274612//The National Natural Science Foundation of China/ ; No. 82305087//The National Natural Science Foundation of China/ ; 2024KYCX003//Henan University of Chinese Medicine/ ; },
abstract = {Alzheimer's disease (AD), a prevalent senile dementia, is characterized by the progressive decline in cognitive function, accumulation of tau tangles and Aβ plaques. Despite significant research efforts in the field of AD, effective therapeutic drugs for its prevention and treatment remain elusive. Consequently, a more comprehensive understanding of the molecular mechanisms underlying the pathological processes of AD is crucial for novel therapeutic strategies. Mitophagy, the selective degradation of mitochondria through autophagy, is an essential mechanism for maintaining mitochondrial homeostasis in terms of both quantity and quality. Mitophagy plays a crucial role in numerous cellular processes, including inflammation, differentiation, and apoptosis. Recent studies have increasingly demonstrated that mitophagy is extensively characterized in AD and may represent a novel therapeutic strategy for its treatment. Notably, a number of natural plant products (NPPs) have been demonstrated to modulate mitophagy and intervene in the pathological process of AD. For instance, NPPs such as urolithin A and β-asarone have been reported to enhance mitophagy by activating the PINK1/Parkin pathway, thereby alleviating Aβ-induced neurotoxicity. The distinctive multi-target properties and favorable safety profiles of NPPs endow them with significant research potential and developmental value, establishing them as a vital resource for novel drug discovery. This review explores the mechanistic hypotheses linking mitophagy to AD pathology and provides a systematic overview of recent advances in representative NPPs that regulate mitophagy to alleviate AD-related impairments, offering new perspectives for the development of therapeutic strategies against AD.},
}

@article {pmid41272336,
year = {2025},
author = {Tang, C and Ding, Y and Yang, S and Lei, X and Zhang, M and Xu, B and He, D},
title = {Dual Mechanisms of Cognitive Function and Pathological Improvements by the Selective S1PR1/5 Modulator Siponimod in 3xTg-AD Mice.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {133},
pmid = {41272336},
issn = {1559-1182},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism/physiopathology ; *Cognition/drug effects ; Microglia/drug effects/metabolism/pathology ; *Benzyl Compounds/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; *Azetidines/pharmacology/therapeutic use ; *Sphingosine-1-Phosphate Receptors/metabolism ; Disease Models, Animal ; Molecular Docking Simulation ; Signal Transduction/drug effects ; Male ; Cell Line ; Myelin Sheath/metabolism/drug effects ; *Sphingosine 1 Phosphate Receptor Modulators/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, with neuroinflammation and myelin dysfunction as crucial pathological mechanisms. Siponimod, a selective S1PR1/5 modulator, shows promising therapeutic potential through enhanced brain penetration and improved pharmacokinetic properties compared to first-generation modulators. Network pharmacology and molecular docking analyses were utilized to comprehensively elucidate the underlying mechanisms of Siponimod in the context of AD. Specifically, network pharmacology identified key targets and pathways associated with Siponimod, while molecular docking facilitated predictions of binding affinities to these targets. For in vitro assessments, BV2 microglia cells were used to investigate the effects of Siponimod after stimulation with LPS, focusing on inflammatory responses and cellular signaling pathways. Concurrently, in vivo studies employed the 3xTg-AD mouse model to investigate behavioral outcomes related to cognitive function, alongside evaluations of neuroinflammation and the integrity of myelin sheaths. Siponimod treatment resulted in a significant reduction in pro-inflammatory cytokines and ROS production in BV2 microglia cells, thereby indicating its robust anti-inflammatory and antioxidant properties. In the 3xTg-AD mouse model, administration of Siponimod led to marked improvements in cognitive performance as assessed through various behavioral tests. Additionally, there was a noteworthy decrease in Aβ plaque deposition, coupled with evidence of myelin repair, which was reflected in the increased expression of myelination-related proteins, namely OLIG2 and MBP. Furthermore, Siponimod was found to activate the PI3K-AKT signaling pathway, which plays a crucial role in promoting neuroprotection and enhancing cellular resilience against neurodegenerative processes. This study demonstrates that Siponimod effectively treats AD through dual mechanisms: reducing neuroinflammation and promoting myelin repair via the S1PR1/5 and PI3K-AKT signaling pathway. These findings suggest Siponimod's potential as a promising therapeutic agent for AD treatment.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism/physiopathology
*Cognition/drug effects
Microglia/drug effects/metabolism/pathology
*Benzyl Compounds/pharmacology/therapeutic use
Mice
Mice, Transgenic
*Azetidines/pharmacology/therapeutic use
*Sphingosine-1-Phosphate Receptors/metabolism
Disease Models, Animal
Molecular Docking Simulation
Signal Transduction/drug effects
Male
Cell Line
Myelin Sheath/metabolism/drug effects
*Sphingosine 1 Phosphate Receptor Modulators/pharmacology/therapeutic use

@article {pmid41272323,
year = {2025},
author = {Choi, DJ and Murali, S and Kwon, W and Woo, J and Song, EC and Ko, Y and Sardar, D and Lozzi, B and Cheng, YT and Williamson, MR and Huang, TW and Sanchez, K and Jankowsky, J and Deneen, B},
title = {Astrocytic Sox9 overexpression in Alzheimer's disease mouse models promotes Aβ plaque phagocytosis and preserves cognitive function.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41272323},
issn = {1546-1726},
support = {R35-NS132230//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01-AG071687//U.S. Department of Health & Human Services | NIH | Center for Information Technology (Center for Information Technology, National Institutes of Health)/ ; K01-AG08128//U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/ ; R56-MH133822//U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/ ; },
abstract = {Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer's disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aβ) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aβ plaques by astrocytes through the regulation of the phagocytic receptor MEGF10, which is sufficient to preserve cognitive function in AD models. Collectively, these studies highlight a role for astrocytic Sox9 during aging and AD while identifying Sox9-MEGF10 signaling as a prospective astrocyte-based therapeutic approach to ameliorate cognitive decline in neurodegenerative disease.},
}

@article {pmid41272186,
year = {2025},
author = {Rabee, AR and Abdel-Hamid, H and Soliman, SM and Ashraf, S and Sobhy, AA and Ghareeb, DA and Saad, AK and Hagar, M},
title = {Design and synthesis of 1,2,3-triazole thiadiazole hybrids with in vitro and in silico evaluation of their anti-inflammatory and anti-alzheimer activities.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {41157},
pmid = {41272186},
issn = {2045-2322},
mesh = {*Thiadiazoles/chemistry/pharmacology/chemical synthesis ; Molecular Docking Simulation ; *Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry ; *Triazoles/chemistry/pharmacology/chemical synthesis ; *Alzheimer Disease/drug therapy ; Drug Design ; Humans ; Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Nanoparticles/chemistry ; Acetylcholinesterase/metabolism/chemistry ; },
abstract = {Nano technology possesses a role in the enhancement of anti-inflammatory and anti-Alzheimer activities of the synthesized triazole/thiadiazole hybrids 3a-c. Selective propargylation of 5-amino-1,3,4-thiadiazole-2-thiol with propargyl bromide and triethyl amine followed by Click reaction with different azides to afford 1,2,3-triazole/thiadiazole hybrids 3a-c. The structure of the synthesized compounds was confirmed using different spectroscopic analysis such as FT-IR, [1]H NMR,[13]C NMR and elemental analysis. Moreover, the synthesized compounds were prepared in nano scale via chitosan to enhance their solubility and compatibility, and their size was evaluated via transmission electron microscope (TEM). The formulated nanoparticles are found to be relatively stable with higher positive zeta potential 22.5-29.5 mV and particle size 29-80 nm. The studied compounds were further subjected to molecular docking in the active site of four particular proteins AChE, BuChE, LOX-5 and COX-2.The synthesized compounds and their nanoformulations were tested as anti-inflammatory and anti-Alzheimer as acetylcholinesterase inhibitors. The result revealed that nanoformulations N-(3a-c) exhibited superior inhibitory activity compared to their synthesized counterparts 3a-c, demonstrating enhanced potency against AChE, BuChE, NO formation, iNOS, LOX-5, and RBC lysis. N-3a showed the strongest iNOS inhibition, while N-3b was the most effective BuChE inhibitor. Notably, all nanoformulations matched the reference drug in LOX-5 inhibition and outperformed diclofenac K in protecting against RBC lysis. These results highlight the potential of these hybrids as anti-inflammatory and anti-Alzheimer agents.},
}

*Thiadiazoles/chemistry/pharmacology/chemical synthesis
Molecular Docking Simulation
*Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry
*Triazoles/chemistry/pharmacology/chemical synthesis
*Alzheimer Disease/drug therapy
Drug Design
Humans
Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry
Nanoparticles/chemistry
Acetylcholinesterase/metabolism/chemistry

@article {pmid41271757,
year = {2025},
author = {Rabiei, K and Petrella, JR and Lenhart, S and Liu, C and Hao, W and , },
title = {Data-driven modeling of amyloid-β targeted antibodies for Alzheimer's disease.},
journal = {NPJ systems biology and applications},
volume = {11},
number = {1},
pages = {134},
pmid = {41271757},
issn = {2056-7189},
support = {1R35GM146894/GM/NIGMS NIH HHS/United States ; 1R35GM146894/GM/NIGMS NIH HHS/United States ; DMS-2052676//National Science Foundation/ ; P30AG072958/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism/immunology/chemistry/antagonists & inhibitors ; Humans ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; Kinetics ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta, which is strongly associated with disease progression and cognitive decline. Despite the approval of monoclonal antibodies targeting Aβ, optimizing treatment strategies while minimizing side effects remains a challenge. This study develops a mathematical framework to model Aβ aggregation dynamics, capturing the transition from monomers to higher-order aggregates, including protofibrils, toxic oligomers, and fibrils, using mass-action kinetics and coarse-grained modeling. Parameter estimation, sensitivity analysis, and data-driven calibration ensure model robustness. An optimal control framework is introduced to identify the optimal dose of the drug as a control function that reduces toxic oligomers and fibrils while minimizing adverse effects, such as amyloid-related imaging abnormalities (ARIA). The results indicate that Donanemab achieves the most significant reduction in fibrils. These findings provide a quantitative basis for optimizing AD treatments, providing valuable insight into the balance between therapeutic efficacy and safety.},
}

*Alzheimer Disease/drug therapy/metabolism
*Amyloid beta-Peptides/metabolism/immunology/chemistry/antagonists & inhibitors
Humans
*Antibodies, Monoclonal/therapeutic use/pharmacology
Kinetics

@article {pmid41271752,
year = {2025},
author = {Vidal-Piñeiro, D and Sørensen, Ø and Strømstad, M and Amlien, IK and Baaré, W and Bartrés-Faz, D and Brandmaier, AM and Cattaneo, G and Düzel, S and Ghisletta, P and Henson, RN and Kühn, S and Lindenberger, U and Mowinckel, AM and Nyberg, L and Pascual-Leone, A and Roe, JM and Solana-Sánchez, J and Solé-Padullés, C and Watne, LO and Wolfers, T and , and Walhovd, KB and Fjell, AM},
title = {Vulnerability to memory decline in aging revealed by a mega-analysis of structural brain change.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-025-66354-y},
pmid = {41271752},
issn = {2041-1723},
support = {SUAG/046/G101400//RCUK | Medical Research Council (MRC)/ ; AN-NC-AB-Research-01169072//Simons Foundation/ ; AN-NC-AB-Research-01169072//Simons Foundation/ ; AN-NC-AB-Research-01169072//Simons Foundation/ ; R01AG076708//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 325001, 301395, 239889//Norges Forskningsråd (Research Council of Norway)/ ; 725025//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; },
abstract = {Brain atrophy is a key factor behind episodic memory loss in aging, but the nature and ubiquity of this relationship remains poorly understood. This study leverages 13 longitudinal datasets, including 3737 cognitively healthy adults (10,343 MRI scans; 13,460 memory assessments), to determine whether brain change-memory change associations are more pronounced with age and genetic risk for Alzheimer's Disease. Both factors are associated with accelerated brain decline, yet it remains unclear whether memory loss is exacerbated beyond what atrophy alone would predict. Additionally, we assess whether memory decline aligns with a global pattern of atrophy or stems from distinct regional contributions. Our mega-analysis reveals a nonlinear relationship between memory decline and brain atrophy, primarily affecting individuals with above-average brain structural decline. The associations are stronger in the hippocampus but also spread across diverse cortical and subcortical regions. The associations strengthen with age, reaching moderate associations in participants in their eighties. While APOE ε4 carriers exhibit steeper brain and memory loss, genetic risk has no effect on the change-change associations. These findings support the presence of common biological macrostructural substrates underlying memory function in older age which are vulnerable to multiple age-related factors, even in the absence of overt pathological changes.},
}

@article {pmid41271735,
year = {2025},
author = {Sun, X and Saha, D and Wang, X and Mörman, C and Sternke-Hoffmann, R and Gerez, JA and Herranz-Trillo, F and Riek, R and Zheng, W and Luo, J},
title = {Spermine modulation of Alzheimer's Tau and Parkinson's α-synuclein: implications for biomolecular condensation and neurodegeneration.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {10239},
pmid = {41271735},
issn = {2041-1723},
support = {10002967//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; },
mesh = {*Spermine/pharmacology/metabolism ; *alpha-Synuclein/metabolism/genetics/chemistry ; Animals ; Caenorhabditis elegans/metabolism/genetics ; Humans ; *Alzheimer Disease/metabolism/genetics ; *tau Proteins/metabolism/genetics/chemistry ; *Parkinson Disease/metabolism ; Autophagy/drug effects ; Mitochondria/metabolism/drug effects ; Scattering, Small Angle ; },
abstract = {Spermine, a pivotal player in biomolecular condensation and diverse cellular processes, has emerged as a focus of investigation in aging, neurodegeneration, and other diseases. Despite its significance, the mechanistic details of spermine remain incompletely understood. Here, we describe the distinct modulation by spermine on Alzheimer's Tau and Parkinson's α-synuclein, elucidating their condensation behaviors in vitro and in vivo. Using biophysical techniques including time-resolved SAXS and NMR, we trace electrostatically driven transitions from atomic-scale conformational changes to mesoscopic structures. Notably, spermine extends lifespan, ameliorates movement deficits, and restores mitochondrial function in C. elegans models expressing Tau and α-synuclein. Acting as a molecular glue, spermine orchestrates in vivo condensation of α-synuclein, influences condensate mobility, and promotes degradation via autophagy, specifically through autophagosome expansion. This study unveils the interplay between spermine, protein condensation, and functional outcomes, advancing our understanding of neurodegenerative diseases and paving the way for therapeutic development.},
}

*Spermine/pharmacology/metabolism
*alpha-Synuclein/metabolism/genetics/chemistry
Animals
Caenorhabditis elegans/metabolism/genetics
Humans
*Alzheimer Disease/metabolism/genetics
*tau Proteins/metabolism/genetics/chemistry
*Parkinson Disease/metabolism
Autophagy/drug effects
Mitochondria/metabolism/drug effects
Scattering, Small Angle

@article {pmid41271684,
year = {2025},
author = {Brown, JA and Lee, AJ and Fernhoff, K and Pistone, T and Pasquini, L and Wise, AB and Staffaroni, AM and Mandelli, ML and Lee, SE and Boxer, AL and Rankin, KP and Rabinovici, GD and Gorno Tempini, ML and Rosen, HJ and Kramer, JH and Miller, BL and Seeley, WW},
title = {Functional network collapse in neurodegenerative disease.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {10273},
pmid = {41271684},
issn = {2041-1723},
support = {K01AG055698//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P50AG023501//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; P01AG019724//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
mesh = {Humans ; Magnetic Resonance Imaging ; Male ; Female ; Aged ; Middle Aged ; Frontotemporal Dementia/physiopathology/diagnostic imaging/pathology ; *Alzheimer Disease/physiopathology/diagnostic imaging/pathology ; *Neurodegenerative Diseases/physiopathology/diagnostic imaging/pathology ; Atrophy ; *Brain/physiopathology/diagnostic imaging/pathology ; Gray Matter/pathology/diagnostic imaging/physiopathology ; *Nerve Net/physiopathology/diagnostic imaging/pathology ; Aphasia, Primary Progressive/physiopathology/diagnostic imaging/pathology ; },
abstract = {Cognitive and behavioral deficits in Alzheimer's disease (AD) and frontotemporal dementia (FTD) arise alongside gray matter atrophy and altered functional connectivity, yet the structure-function relationship across the dementia spectrum remains unclear. Here we combine structural and functional MRI from 221 patients-AD (n = 82), behavioral variant FTD (n = 41), corticobasal syndrome (n = 27), and nonfluent (n = 34) or semantic (n = 37) variant primary progressive aphasia-and 100 cognitively normal individuals. Partial least-squares regression reveals three structure-function components. Component 1 links cumulative atrophy to sensorimotor hypo-connectivity and hyper-connectivity in association cortical and subcortical brain regions. Components 2 and 3 tie focal, syndrome-specific atrophy to peri-lesional hypo-connectivity and distal hyper-connectivity. Structural and functional component scores explain 34% of the variance in global and domain-specific cognitive deficits on average. The functional connectivity changes reflect alterations of intrinsic activity gradients. Eigenmode analysis shows that atrophy relates to reduced gradient amplitudes and narrowed phase angles between gradients, offering a mechanistic account of network collapse in neurodegeneration.},
}

Humans
Magnetic Resonance Imaging
Male
Female
Aged
Middle Aged
Frontotemporal Dementia/physiopathology/diagnostic imaging/pathology
*Alzheimer Disease/physiopathology/diagnostic imaging/pathology
*Neurodegenerative Diseases/physiopathology/diagnostic imaging/pathology
Atrophy
*Brain/physiopathology/diagnostic imaging/pathology
Gray Matter/pathology/diagnostic imaging/physiopathology
*Nerve Net/physiopathology/diagnostic imaging/pathology
Aphasia, Primary Progressive/physiopathology/diagnostic imaging/pathology

@article {pmid41271423,
year = {2025},
author = {Crook, H and Swann, P and Fye, H and Kigar, S and Savulich, G and Mckeever, A and Herrero, E and Turner, L and Aimola, L and Grey, GD and Blackburn, D and Matthews, PM and Su, L and Chouliaras, L and Rowe, JB and Malhotra, P and O'Brien, JT},
title = {Immune Profiling in Early Cognitive Disorders (IMPRINT) study protocol: a longitudinal cohort study exploring biomarkers of inflammation in early dementia with Lewy bodies and Alzheimer's disease, as part of the Dementias Platform UK.},
journal = {BMJ open},
volume = {15},
number = {11},
pages = {e107399},
doi = {10.1136/bmjopen-2025-107399},
pmid = {41271423},
issn = {2044-6055},
mesh = {Humans ; *Lewy Body Disease/immunology ; *Alzheimer Disease/immunology ; Biomarkers/blood ; Longitudinal Studies ; *Inflammation/immunology ; *Cognitive Dysfunction/immunology ; United Kingdom ; Disease Progression ; Male ; Female ; Aged ; },
abstract = {INTRODUCTION: Growing evidence points towards the integral role of both central and peripheral inflammation across all neurodegenerative diseases, including dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). The immune alterations observed in these diseases may occur long before the onset of clinical and cognitive symptoms; however, the exact timing and role of inflammation in the pathogenesis of neurodegenerative disease remains unclear. Findings to date are conflicting, with most work focused on AD rather than other dementias and most studies from single sites and cross-sectional. Through longitudinally examining detailed phenotypes of the peripheral immune system using mass cytometry, the Immune Profiling in Early Cognitive Disorders study aims to uncover specific immune signatures in early AD and DLB, how these signatures change over time and how they relate to disease progression and cognitive changes.

METHODS AND ANALYSIS: Blood, cerebrospinal fluid, saliva and urine samples will be collected from a cohort of participants with either prodromal (mild cognitive impairment) or early dementia due to Lewy bodies or AD (MCI-LB and DLB; and MCI-AD and AD), alongside healthy controls. Through immunophenotyping with mass cytometry, detailed immune fingerprints will be identified for these groups. We will assess which key combinations of immune cell clusters are predictive of disease phenotype, cognitive decline and progression to dementia. Samples will also be evaluated with novel techniques to measure markers of degenerative pathology and inflammation.

ETHICS AND DISSEMINATION: This study was approved by the Preston North West Research Ethics committee (21/NW/0314) and is registered with the ISRCTN registry (ISRCTN62392656). The study is ongoing (since June 2022). Baseline visits are being undertaken, and follow-up visits have started for some participants. Full data analyses will be completed and submitted for publication upon conclusion of the study.},
}

Humans
*Lewy Body Disease/immunology
*Alzheimer Disease/immunology
Biomarkers/blood
Longitudinal Studies
*Inflammation/immunology
*Cognitive Dysfunction/immunology
United Kingdom
Disease Progression
Male
Female
Aged

@article {pmid41271328,
year = {2025},
author = {Jia, L and Xiao, L and Song, X and Zhang, X and Han, X and Liang, W and Fu, T and Xie, Y and Wang, Y and Geng, W},
title = {Postbiotics alleviate cognitive impairment and neuroinflammation via gut-brain axis and TLR4/MyD88/NLRP3 pathway.},
journal = {Food research international (Ottawa, Ont.)},
volume = {222},
number = {Pt 2},
pages = {117708},
doi = {10.1016/j.foodres.2025.117708},
pmid = {41271328},
issn = {1873-7145},
mesh = {Animals ; Toll-Like Receptor 4/metabolism ; *Gastrointestinal Microbiome ; *Cognitive Dysfunction ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Male ; Rats ; Signal Transduction ; Myeloid Differentiation Factor 88/metabolism ; *Probiotics/administration & dosage ; *Brain/metabolism ; *Neuroinflammatory Diseases ; *Brain-Gut Axis ; *Alzheimer Disease ; Rats, Sprague-Dawley ; Disease Models, Animal ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cerebral amyloid-β deposition, neurofibrillary tangles of hyperphosphorylated tau, and chronic neuroinflammation. Growing evidence underscores the role of the gut-brain axis in mediating bidirectional communication between the gut and the central nervous system. Postbiotics, non-viable microorganisms and/or ingredients that are beneficial to the host's health, have emerged as promising modulators of brain function via this axis. Herein, we evaluated the neuroprotective effects of three postbiotics derived from Bifidobacterium animalis subsp. lactis IOBL07, Lactiplantibacillus plantarum IOB602 and Lactobacillus paracasei IOB413 in a D-galactose/AlCl3-induced AD rats. These postbiotics ameliorated cognitive deficits and anxiety-like behaviors, reduced neuronal degeneration and Aβ accumulation, and suppressed microglial activation and neuroinflammation via the TLR4/MyD88/NLRP3 signaling pathway. 16S rDNA sequencing revealed that postbiotics intervention induced substantial gut microbiota remodeling, selectively enriching Lachnospiraceae, Ruminococcus and Lactobacillus, while depleting Muribaculaceae. Postbiotic administration also elevated fecal short-chain fatty acid levels. Metabolomics analysis identified 11 metabolites, including indole derivatives, cholinergics and niacinamides, that were uniquely enriched in the IOB602 group. These metabolites may underlie its anti-AD effects by attenuating oxidative stress, modulating neuroinflammation, and enhancing mitochondrial function. Together, these findings provide a foundation for developing postbiotic-based adjuvant therapies against AD pathogenesis.},
}

Animals
Toll-Like Receptor 4/metabolism
*Gastrointestinal Microbiome
*Cognitive Dysfunction
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
Male
Rats
Signal Transduction
Myeloid Differentiation Factor 88/metabolism
*Probiotics/administration & dosage
*Brain/metabolism
*Neuroinflammatory Diseases
*Brain-Gut Axis
*Alzheimer Disease
Rats, Sprague-Dawley
Disease Models, Animal

@article {pmid41271117,
year = {2025},
author = {Yin, C and Tang, X and Zeng, J and Wang, Z and Mi, J and Liang, Y and Qin, D and Feng, Q and Wu, A},
title = {Next-Generation Biosensor Technologies for Alzheimer's Disease: Innovations in Diagnosis, Monitoring, and Treatment.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102954},
doi = {10.1016/j.arr.2025.102954},
pmid = {41271117},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, remains a global health crisis due to the lack of early diagnostic tools, dynamic monitoring strategies, and effective therapies. Current diagnostic methods such as cerebrospinal fluid (CSF) analysis and neuroimaging, while accurate, are invasive, expensive, and unsuitable for routine screening, highlighting the pressing need for alternative approaches. This review comprehensively examines the transformative role of next-generation biosensors in revolutionizing AD management. By leveraging breakthroughs in nanotechnology, materials science, and artificial intelligence (AI), modern biosensors enable ultrasensitive, non-invasive detection of AD biomarkers-including amyloid-β (Aβ), Tau proteins, and neurofilament light chain (NfL)-across diverse biofluids such as blood, saliva, and tears. We critically evaluate electrochemical, optical, and acoustic biosensing platforms, highlighting their integration into wearable and portable devices for real-time disease monitoring and personalized therapeutic interventions. Emerging trends such as AI-driven analytics, CRISPR-based diagnostics, and closed-loop neuromodulation systems are explored for their potential to decode disease progression and optimize treatment responses. Challenges in clinical translation, including sensor stability, regulatory hurdles, and ethical considerations, are addressed to pave the way for scalable, patient-centric solutions. By synthesizing cutting-edge advancements and interdisciplinary insights, this review charts a roadmap for biosensor technologies to shift AD care from reactive to proactive, ultimately improving quality of life for patients and caregivers.},
}

@article {pmid41271115,
year = {2025},
author = {Su, L and Wang, Y},
title = {From Genes to Lifestyle: A Multi-Dimensional Framework for Alzheimer's Disease Prevention and Therapy.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102947},
doi = {10.1016/j.arr.2025.102947},
pmid = {41271115},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder driven by multilayered molecular and cellular mechanisms that cannot be fully elucidated through single-omics approaches. Consequently, large-scale multi-omics integration-encompassing transcriptomics, epigenomics (e.g., methylation), and genetic association studies (GWAS/eQTL/mQTL)-has uncovered critical genetic and epigenetic networks underlying disease risk and progression.Based on these integrative insights, this review emphasized several genes-including KLHL21, SCN2B, ZNF415, and PITRM1-as potential contributors to AD pathogenesis. Notably, single-cell and spatial transcriptomics analyses revealed specific enrichment of thesegenes in astrocytes, underscoring the pivotal role of this cell type in Aβ clearance, tau propagation, and neuroinflammation. Exercise interventions were shown to selectively modulate the expression of these genes, providing molecular support for the preventive and therapeutic potential of non-pharmacological lifestyle strategies. Drug repurposing analyses using DrugBank have identified promising therapeutic candidates, including FDA-approved agents (e.g., valproic acid, raloxifene, and clomipramine) and naturally derived compounds (e.g., quercetin and fisetin), which may modulate key AD-related pathways. Furthermore, emerging evidence of miRNA-gene regulatory networks suggested an additional layer of post-transcriptional control that may regulate responses to pathological stimuli. Collectively, these integrative insights advocated for a multidimensional precision medicine framework that spans genetic, cellular,network, and lifestyle levels of regulation. This shift from single-target therapeutics to an integrated "gene-cell-network-lifestyle" paradigm open new theoretical and translational avenues for delaying or mitigating AD progression.},
}

@article {pmid41271114,
year = {2025},
author = {Yin, H and Lu, Z and Deng, Y and Tian, X and Gong, Q},
title = {Decoding Blood-Brain Barrier Dysfunction in Alzheimer's Disease: Innovations and Challenges in Multimodal MRI and PET Imaging Biomarkers.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102952},
doi = {10.1016/j.arr.2025.102952},
pmid = {41271114},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD), a leading neurodegenerative disorder, involves blood-brain barrier (BBB) dysfunction as a critical contributor to its pathogenesis. This review synthesizes current advancements in in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques for imaging BBB breakdown in AD. The BBB, a dynamic neurovascular interface, regulates amyloid-beta (Aβ) and tau clearance through specialized transporters and cellular interactions. BBB dysfunction, driven by tight junction disruption, transporter deficits, and pericyte degeneration, exacerbates Aβaccumulation and neuroinflammation. Dynamic contrast-enhanced MRI quantifies subtle leakage via gadolinium kinetics, while water-exchange MRI probes trans-BBB water dynamics without contrast agents. Dynamic glucose-enhanced MRI maps glucose transport anomalies linked to glucose transporter- 1 dysfunction. PET imaging with tracers like [[18]F]-fluorodeoxyglucose and [[11]C]-verapamil evaluates glucose metabolism and efflux transporter activity, revealing early metabolic deficits and impaired Aβ clearance. Challenges include low sensitivity for subtle leakage, model-dependent quantification, and spatial-temporal resolution trade-offs. Emerging strategies emphasize multimodal integration, ultrahigh-field systems, and artificial intelligence-driven analytics to decode region-specific BBB pathology. Longitudinal studies correlating imaging biomarkers with clinical progression and novel PET tracer development are pivotal for early diagnosis and personalized therapies. These innovations promise to elucidate BBB's role and promote a paradigm shift in diagnostic and therapeutic strategies from solely targeting amyloid proteins to multi-target interventions in AD.},
}

@article {pmid41270999,
year = {2025},
author = {Parveen, N and Qais, FA and Faheem, M},
title = {Molecular insights into diosgenin's role in preventing protein aggregation in neurodegenerative diseases.},
journal = {Biochimica et biophysica acta. Proteins and proteomics},
volume = {1874},
number = {1},
pages = {141116},
doi = {10.1016/j.bbapap.2025.141116},
pmid = {41270999},
issn = {1878-1454},
abstract = {Neurodegenerative disorders (ND) such as Parkinson's and Alzheimer's progressively impair the nervous system, leading to cognitive deterioration and motor dysfunction. A primary factor in these diseases is the accumulation of misfolded protein aggregates, which interfere with cellular processes and ultimately result in neuronal death. Preventing the formation of these toxic aggregates has the potential to protect neurons and slow the advancement of disease. This study examined the impact of diosgenin on protein aggregation, utilizing human serum albumin (HSA) as model protein. Diosgenin reduced ThT fluorescence by 64.35 % and decreased turbidity by 62.61 %, indicating a notable suppression of protein aggregation. The % α-helix in HSA experienced a decline from 57.68 % to 8.82 %, but diosgenin treatment restored it to 43.89 %. Binding studies demonstrated that diosgenin interacts with HSA with -11.0 kcal/mol binding energy, facilitated by van der Waals, hydrophobic and hydrogen bonding interactions, and stability of HSA-diosgenin complex was also validated using molecular simulations. To further elucidate the aggregation inhibition mechanism by diosgenin, advanced molecular dynamics simulations were employed. Diosgenin increased the solvent accessibility of the HSA282-292 oligomers, reduced β-sheet formation, and prevented H-bond interactions, key factors in aggregate formation. Molecular simulation of Aβ oligomers (Aβ16-22) also showed the diosgenin prevents oligomerization and β-sheet formation. We show that diosgenin presents a promising alternative due to its ability to stabilize protein structures and inhibit protein aggregation, making it a potential therapeutic candidate for NDs. However, further experimental validation in animal models is necessary to confirm diosgenin's anti-aggregation effects, particularly of amyloid-forming proteins.},
}

@article {pmid41270820,
year = {2025},
author = {Mayr, D and Preishuber-Pflügl, J and Koller, A and Migschitz, SM and Michael, J and Altendorfer, B and Rabl, R and Amschl, D and Hitzl, W and Aigner, L and Reitsamer, HA and Trost, A},
title = {The effect of CysLTR1 inhibition on cells of the retinal neurovascular unit in 5xFAD Alzheimer mice.},
journal = {Experimental eye research},
volume = {262},
number = {},
pages = {110763},
doi = {10.1016/j.exer.2025.110763},
pmid = {41270820},
issn = {1096-0007},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that affects both the brain and the retina. Many cerebral-associated AD pathologies, including neuroinflammation and vascular changes, have been reported to manifest in the retina. Furthermore, the neurovascular unit (NVU), composed of vascular cells, glia and neurons, regulates blood flow and neuronal metabolic activity and has been described to be dysfunctional in AD brains and retinas. As leukotrienes are modulators of both neuroinflammation and the vasculature, their receptors have been recognized as potential targets for ameliorating AD pathology. Therefore, the present study investigated the effects of the cysteinyl leukotriene receptor 1 (CysLTR1) antagonist montelukast (MTK) on retinal NVU cells in the 5xFAD mouse model of AD. Retinal analyses were performed in male and female 8-month-old 5xFAD mice and after 13-weeks of treatment with low and high doses of MTK or vehicle, and in age-matched controls. The retinal pericyte (PC) coverage was unchanged in AD, but CysLTR1 inhibition resulted in increased PC coverage in AD mice. Furthermore, an AD-associated decrease in capillary diameter was observed, which was not affected by CysLTR1 inhibition. The number of retinal microglial cells was increased in AD, independent of treatment. In addition, the astrocyte area and retinal ganglion cell density were not affected by either AD or CysLTR1 inhibition. In conclusion, the present study revealed minor AD-associated changes in retinal NVU cells in the 5xFAD mouse model. MTK treatment increased dose-independently PC coverage, but it remains to be clarified whether this affects the vessel tightness and blood flow.},
}

@article {pmid41270792,
year = {2025},
author = {Yu, K and Gatchel, JR and Ho, EH and Hajjar, I and Arnold, SE and Marshall, GA and Dodge, HH},
title = {The NIH Toolbox Emotion Battery and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease: Findings from the Multisite ARMADA Study.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbaf236},
pmid = {41270792},
issn = {1758-5368},
abstract = {OBJECTIVES: Investigating the relationships between socioemotional functioning and Alzheimer's Disease (AD) pathology can contribute to screening and early detection of AD. This study explored the associations between socioemotional functioning and cerebrospinal fluid (CSF) AD biomarkers in older adults.

METHODS: We used baseline data from the Advancing Reliable Measurement in Alzheimer's Disease and Cognitive Aging (ARMADA) study. ARMADA is a multisite study with independent protocols for CSF assays at each site. The available sample size with comparable CSF assays had 31 participants with normal cognition (NC, mean age 72.6) and 28 with amnestic mild cognitive impairment (aMCI) or early-stage AD dementia (mean age 72.2). CSF-derived AD biomarkers included were: phosphorylated-tau 181 (p-Tau181), total tau (t-Tau), Aβ42, Aβ42/40 ratio, and p-Tau181/Aβ42 ratio. Socioemotional functioning (negative affect, psychological well-being, and social satisfaction) was measured with the self-reported NIH Toolbox Emotion Battery (NIHTB-EB). We ran linear regressions by cognitive subgroups (NC and aMCI/early-stage AD).

RESULTS: Among participants with NC, lower social satisfaction was associated with higher p-Tau181 and t-Tau; higher t-Tau was additionally associated with more negative affect. None of the CSF AD biomarkers were associated with the NIHTB-EB outcomes among participants with aMCI or early-stage AD.

DISCUSSION: These findings suggest that socioemotional functioning may be associated with tau pathology. Amyloid markers were not associated with socioemotional functioning in either cognitive group. Future studies with larger, more diverse samples and harmonized CSF assay protocols are needed to further investigate the role of socioemotional changes in the early detection and prevention of dementia.},
}

@article {pmid41270732,
year = {2025},
author = {Wang, JL and Sha, XY and Shao, Y and Zhang, ZH and Huang, SM and Lin, H and Gan, SY and Zhang, N and Xia, XY and Sun, YN and Ding, JH and Zhao, RQ and Cheng, J and Shang, P and Wang, JP and Liu, YJ and Yang, F and Xiao, P and Wang, LW and Zhao, DY and Tang, Y and Tie, L and Du, Y and Zhang, Y and He, JF and Sun, JP},
title = {Elucidating pathway-selective biased CCKBR agonism for Alzheimer's disease treatment.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2025.10.034},
pmid = {41270732},
issn = {1097-4172},
abstract = {Expressed in the entorhinal cortex (EC), the cholecystokinin (CCK) B receptor (CCKBR) plays an important role in memory and learning. Here, we identify that CCKBR-Gs and -Gq signaling, rather than CCKBR-Gi signaling, are beneficial for Alzheimer's disease (AD) treatment. Clinically, patients with more severe AD associated with lower CCKBR-Gq activity. The cryo-electron microscopy (cryo-EM) structures of CCKBR in complex with the endogenous agonist sulfated CCK8 (CCK8s) and 3 different G protein subtypes revealed that distinct receptor conformations contribute to selective G protein bias. Leveraging these structural insights, we rationally develop synthetic CCKBR agonists, including a Gi-biased agonist (z-44) and a Gq-biased agonist (3r1). Notably, 3r1 demonstrates therapeutic potential by ameliorating cognitive decline in 5×FAD mice, reducing the number of amyloid-β plaques, and promoting long-term potentiation (LTP) via upregulation of the α-secretase (ADAM10) and the calcium signaling molecule PLCB4. Our findings suggest that synthetic biased agonists targeting CCKBR-Gq signaling have therapeutic potential for AD.},
}

@article {pmid41270680,
year = {2025},
author = {Pieperhoff, L and Lorenzini, L and Mastenbroek, S and Tranfa, M and Shekari, M and Wink, AM and Wolz, R and Grootoonk, S and Ritchie, C and Boada, M and Marquié, M and van der Flier, W and Vandenberghe, R and Hanseeuw, BJ and Martínez-Lage, P and Payoux, P and Visser, PJ and Schöll, M and Frisoni, GB and Stephens, A and Buckley, C and Farrar, G and Jessen, F and Grau-Rivera, O and Gispert, JD and García, DV and Mutsaerts, H and Barkhof, F and Collij, LE and , },
title = {Amyloid PET predicts atrophy in older adults without dementia: Results from the AMYPAD Prognostic & Natural History study.},
journal = {NeuroImage. Clinical},
volume = {48},
number = {},
pages = {103912},
doi = {10.1016/j.nicl.2025.103912},
pmid = {41270680},
issn = {2213-1582},
abstract = {The impact of amyloid-β (Aβ) accumulation on regional brain atrophy in preclinical Alzheimer's disease (AD), and its interaction with risk factors like sex and APOE-ε4 carriership, remains unclear. In this study, we examined these associations in a population of older adults without dementia and evaluated the potential of Aβ-PET for risk stratification. We included 1329 participants (56 % female) with an age of 68.2 ± 8.78 years from the prospective multi-center AMYPAD Prognostic and Natural History Study who underwent [[18]F]Flutemetamol or [[18]F]Florbetaben Aβ-PET and T1-weighted MRI, with longitudinal data for 684 participants (median follow-up = 3.4 years). Linear mixed models assessed the effect of baseline Aβ burden through the Centiloid approach on longitudinal changes in regional gray matter volume and thickness. Sensitivity analyses were performed in cognitively normal only (CDR = 0) individuals and while correcting for CSF p-tau181 and t-tau. A second model investigated the effects of sex or APOE-ε4 carriership. Baseline global Aβ was predictive of widespread atrophy in several brain regions, most strongly in the fusiform (βVolume = -0.006, βThickness = -0.009), hippocampus (βVolume = -0.005), posterior cingulate (βVolume = -0.006), and precuneus (βVolume = -0.004, βThickness = -0.007), also when investigating only in cognitively normal individuals. Only fusiform atrophy (βp-tau = -0.011; βt-tau = -0.011) remained predicted by Aβ when correcting for p-tau181 or t-tau. Temporal atrophy was exacerbated in women, while frontal, lateral-temporal and hippocampal atrophy was exacerbated by carriership of at least one APOE-ε4 allele, with volumetric loss more sensitive to sex effects and thinning more sensitive to APOE-ε4 effects. Our findings suggest that in older adults with mostly preserved cognition, baseline Aβ-PET predicts future brain atrophy, with fusiform atrophy showing independence from tau pathology and Aβ-dependent atrophy being exacerbated in region-dependent manners in females and APOE-ε4 carriers. Regional cortical volume and thickness may serve as sensitive markers for early Aβ-related neurodegeneration and aid in stratifying risk in AD prevention trials.},
}

@article {pmid41270541,
year = {2025},
author = {Zhang, M and Liu, X and Ren, Y and Li, L and Wang, R and Sun, L and Ma, Q},
title = {Decoding alzheimer's: The role of EEG rhythms and aperiodic components in cognitive decline.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {181},
number = {},
pages = {2111437},
doi = {10.1016/j.clinph.2025.2111437},
pmid = {41270541},
issn = {1872-8952},
abstract = {OBJECTIVE: To investigate detailed alterations in brain electrical activity and their relationship with cognitive decline in Alzheimer's disease (AD) using electroencephalogram (EEG) power spectrum analysis.

METHODS: EEG data from 80 AD patients and 80 healthy control (HC) were analyzed, focusing on theta and alpha band powers, aperiodic offset, and exponent. Topographic and gender-specific analyses were conducted to explore associations with disease progression and cognitive impairment.

RESULTS: AD patients showed increased theta and alpha band powers, with theta band power exhibiting statistically significant differences. Globally elevated theta band power correlated with cognitive impairment severity. Higher aperiodic offsets and exponents were observed in AD patients, exhibiting upward trends with disease progression. Male AD patients displayed more pronounced EEG abnormalities and unique Montreal Cognitive Assessment (MOCA) score patterns.

CONCLUSIONS: Our findings highlight the critical role of theta band power in AD pathology and suggest potential EEG biomarkers for neurodegenerative changes. Gender-specific differences emphasize the importance of personalized approaches in AD diagnosis and treatment.

SIGNIFICANCE: This study provides novel neurophysiological insights into AD, underscoring the clinical utility of EEG markers and the necessity for gender-specific considerations in precision medicine for AD.},
}

@article {pmid41270343,
year = {2025},
author = {Britt, KC and Xiao, X and Sun, K and Ge, S and Buck, H and Huang, B},
title = {A qualitative study with primary care providers: Barriers and facilitators in cognitive care planning.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {67},
number = {},
pages = {103726},
doi = {10.1016/j.gerinurse.2025.103726},
pmid = {41270343},
issn = {1528-3984},
abstract = {Cognitive care planning (CCP) is an effective service that supports aging adults with cognitive impairment and dementia and is reimbursable by Medicare; however, CCP remains underutilized by providers. We explored the experiences and perceptions of U.S. primary care providers regarding the implementation of CCP with older adults. Using a qualitative descriptive design, we conducted semi-structured teleconferencing interviews with nine primary care providers (work experience ranged from 8 to 38 years) actively providing care to older adults, including those with cognitive impairment and dementia. Conventional content analysis was used to analyze the data. Three categories of CCP barriers and facilitators emerged: (a) person-level factors, (b) condition factors, and (c) system-level factors. In addition to supporting previous dementia care in primary care studies, our study adds perceived facilitators and additional barriers to CCP implementation, expanding our understanding of ways to improve CCP in the older adult population.},
}

@article {pmid41270077,
year = {2025},
author = {Kuzio, NJ and Tonelli, M and Fejzo, J and Hardy, JA},
title = {An NMR sample preparation case study: Considerations for the self-destructive protease caspase-6.},
journal = {PloS one},
volume = {20},
number = {11},
pages = {e0337291},
pmid = {41270077},
issn = {1932-6203},
mesh = {*Caspase 6/chemistry/metabolism/isolation & purification ; Humans ; *Nuclear Magnetic Resonance, Biomolecular/methods ; Protein Conformation ; },
abstract = {Proteases represent a difficult family of proteins to purify, concentrate and store at homogeneity due to their toxicity during overexpression and their propensity to self-cleave, leading to the loss of sample stability and function. A protease of interest, caspase-6, is a member of the apoptotic family of caspases, and has been shown to be involved in human neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Previous studies have elucidated key structural aspects and potential inhibition mechanisms of caspase-6 through various structural biology techniques such as x-ray crystallography and hydrogen-deuterium exchange mass spectrometry. However, caspase-6 undergoes a structural transition that requires atomic-resolution insight in solution to understand the conformational transitions and ensemble. This can be most optimally achieved using multi-dimensional biomolecular NMR. Prior attempts to study caspase-6 by NMR have failed due to challenges in sample preparation and insufficient protein concentration. Here, we document our exploratory strategy, which ultimately led to the refinement of crucial sample preparation steps and enabled us to obtain isotopically-labeled caspase-6 in yields suitable for heteronuclear NMR studies. We present this work in the hope that it will assist others in the preparation of difficult protein samples, particularly proteases.},
}

*Caspase 6/chemistry/metabolism/isolation & purification
Humans
*Nuclear Magnetic Resonance, Biomolecular/methods
Protein Conformation

@article {pmid41269883,
year = {2025},
author = {van Adrichem, JJ and van der Loo, RJ and Ambrosini Defendi, R and Smit, AB and van den Oever, MC and van Kesteren, RE},
title = {Progressive remote memory decline coincides with parvalbumin interneuron hyperexcitability and enhanced inhibition of cortical engram cells in a mouse model of Alzheimer's disease.},
journal = {eLife},
volume = {14},
number = {},
pages = {},
pmid = {41269883},
issn = {2050-084X},
support = {WE.03-2020-05//Alzheimer Nederland/ ; },
mesh = {Animals ; *Interneurons/physiology/metabolism ; *Alzheimer Disease/physiopathology/pathology ; *Parvalbumins/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; *Prefrontal Cortex/physiopathology/pathology ; *Memory, Long-Term/physiology ; Male ; },
abstract = {Patients with Alzheimer's disease (AD) initially show temporally graded retrograde amnesia, which gradually progresses into more severe retrograde amnesia. Although mouse models of AD have provided insight into neurobiological mechanisms contributing to impaired formation and retrieval of new memories, the process underlying the progressive loss of remote memories in AD has remained elusive. Here, we demonstrate age-dependent remote memory decline in APP/PS1 mice, which coincides with progressive hyperexcitability of parvalbumin (PV) interneurons in the medial prefrontal cortex (mPFC). Analysis of Fos expression showed that the remote memory deficit is not mirrored by changes in reactivation of memory-encoding neurons, so-called engram cells, nor PV interneuron (re)activation, in the mPFC. However, inhibitory input is enhanced onto engram cells compared to non-engram cells specifically in APP/PS1 mice. Our data indicate that age-dependent remote memory impairment in APP/PS1 mice is due to increased innervation of cortical engram cells by hyperexcitable PV interneurons, suggesting that dysfunctional inhibitory microcircuits in the neocortex mediate progressive retrograde amnesia in AD.},
}

Animals
*Interneurons/physiology/metabolism
*Alzheimer Disease/physiopathology/pathology
*Parvalbumins/metabolism
Disease Models, Animal
Mice
Mice, Transgenic
*Prefrontal Cortex/physiopathology/pathology
*Memory, Long-Term/physiology
Male

@article {pmid41269712,
year = {2025},
author = {Lin, RSY and Su, JJ and Chan, TW and Kwan, RYC},
title = {Adaptation and validation of the Chinese version of the Fear of Alzheimer's Disease Scale.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/13607863.2025.2585493},
pmid = {41269712},
issn = {1364-6915},
abstract = {OBJECTIVES: Despite emerging evidence suggesting the importance of alleviating dementia fear in improving psychological wellbeing and effective coping strategies, a major barrier to the evaluation and management of dementia fear is the lack of a valid tool to measure it, especially among the Chinese ethnic group. This study aims to evaluate the validity and reliability of the Chinese version of the Fear of Alzheimer's Disease Scale (FADS).

METHOD: 196 community-dwelling older adults aged over 50 years completed the survey. Reliability was assessed by internal consistency and two-week test-retest reliability. Validity was assessed by content validity, concurrent validity, known group comparison, and exploratory factor analysis (EFA).

RESULTS: Reliability was supported by Cronbach's alpha of 0.912, and the intra-class correlation coefficient among 32 participants is 0.793. EFA model confirms its three-factor structure. Content validity was deemed acceptable. Concurrent validity was demonstrated by significant correlations between FADS scores and both perceived susceptibility and severity of dementia. Divergent validity was evident from significant score differences between participants with and without prior interaction with individuals with dementia.

CONCLUSION: This study confirms the FADS as a valid and reliable instrument to assess dementia-related fear among middle-aged and older adults in the Chinese population.},
}

@article {pmid41269690,
year = {2025},
author = {Brickman, AM and Muller, C and Warren, JR and Grodsky, E and Kim, S and Culbertson, MJ and Thyagarajan, B and Manly, JJ},
title = {Alzheimer Disease Blood Biomarker Concentrations Across Race and Ethnicity Groups in Middle-Aged Adults.},
journal = {JAMA network open},
volume = {8},
number = {11},
pages = {e2545046},
doi = {10.1001/jamanetworkopen.2025.45046},
pmid = {41269690},
issn = {2574-3805},
mesh = {Humans ; Biomarkers/blood ; Female ; Male ; *Alzheimer Disease/blood/ethnology ; Middle Aged ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Cohort Studies ; Neurofilament Proteins/blood ; Hispanic or Latino/statistics & numerical data ; United States/epidemiology ; Glial Fibrillary Acidic Protein/blood ; *Ethnicity/statistics & numerical data ; Black or African American/statistics & numerical data ; White People/statistics & numerical data ; White ; },
abstract = {IMPORTANCE: The incidence and prevalence of clinical Alzheimer disease (AD) are higher among Black and Latinx older adults than among White older adults. Past studies that compared plasma AD biomarker concentrations among groups minoritized by their race and ethnicity yielded inconsistent findings; however, these efforts did not include population representative samples or statistical procedures to ensure population representation.

OBJECTIVE: To examine race and ethnicity differences in plasma AD biomarker concentrations and in the association between biomarkers and medical conditions in a US population-representative cohort of middle-aged adults (approximately 58 years of age).

Data for this cohort study came from the High School and Beyond sample, a nationally representative cohort of high school sophomores and seniors who were recruited in 1980. In 2021, a subset of participants provided blood samples that were assayed for amyloid-β (Aβ42/Aβ40 ratio), phosphorylated tau-181 (pTau-181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). The analyses for the present study were conducted between July 2, 2024, and August 26, 2025, using data collected during the 2021 follow-up study.

EXPOSURES: Race and ethnicity groups and common medical conditions.

MAIN OUTCOMES AND MEASURES: General linear models with Wald tests were used to compare biomarker concentrations between race and ethnicity groups and to test interactions with common medical conditions using unadjusted biomarker values and models adjusted to ensure population representation with inverse probability weighting and multiple imputation.

RESULTS: The sample included 4340 adults (mean [SD; range] age, 58.1 [1.1; 56-63] years; 2400 [55.3%] women); 630 (14.4%) were Black, 900 (20.7%) were Latinx, and 2610 (60.1%) were White. Black participants had a lower Aβ42/Aβ40 ratio (d = -0.002; 95% CI, -0.004 to -0.000; P = .04) and lower NfL concentrations (d = -1.16; 95% CI, -2.15 to -0.16; P = .02) than White participants, but these differences were attenuated when models were adjusted for population representation (d = 0.000; 95% CI, -0.002 to 0.002; P = .85 for Aβ ratio; d = -0.88; 95% CI, -1.78 to 0.02; P = .05 for NfL). Latinx participants had lower GFAP concentrations than White participants (d = -3.87; 95% CI, -7.30 to -0.45; P = .03), but these differences were also attenuated when models were adjusted for population representation (d = 3.36; 95% CI, -3.13 to 9.86; P = .31). In general, estimated biomarker means were similar between race and ethnicity groups. History of type 2 diabetes was associated with increased NfL concentration (d = 0.19; 95% CI, 0.07 to 0.30; P = .04), and high body mass index was associated with lower Aβ42/Aβ40 ratio (d = -0.13; 95% CI, -0.21 to -0.06; P = .02); whereas high cholesterol was associated with lower pTau-181 concentration (d = -0.18; 95% CI, -0.25 to -0.10; P = .01) and high BMI was associated with lower GFAP concentration (d = -0.30; 95% CI -0.44 to -0.16; P = .01). No differences in associations between morbidities and AD biomarker concentrations were detected across race and ethnicity groups.

CONCLUSIONS AND RELEVANCE: In this cohort of middle-aged adults, the use of appropriate statistical estimation to ensure population representation indicated that blood-based AD biomarker concentrations were not distinguishable among race and ethnicity groups. Common medical conditions were associated with plasma biomarker concentrations similarly across race and ethnicity groups. These results highlight the importance of considering population representation and comorbid conditions in AD research to ensure accurate characterization of disease pathophysiology and improve precision of diagnostic and treatment strategies for populations that experience AD disparities.},
}

Humans
Biomarkers/blood
Female
Male
*Alzheimer Disease/blood/ethnology
Middle Aged
Amyloid beta-Peptides/blood
tau Proteins/blood
Cohort Studies
Neurofilament Proteins/blood
Hispanic or Latino/statistics & numerical data
United States/epidemiology
Glial Fibrillary Acidic Protein/blood
*Ethnicity/statistics & numerical data
Black or African American/statistics & numerical data
White People/statistics & numerical data
White

@article {pmid41269421,
year = {2025},
author = {Asadinejad, H and Taherkhani, S and Golboos, SM and Azizi, Y and Mohammadkhanizadeh, A},
title = {Targeting Neurodegeneration with SGLT2is: From Molecular Mechanisms to Clinical Implications.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {119},
pmid = {41269421},
issn = {1559-1182},
mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; },
abstract = {Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a class of antidiabetic drugs that have demonstrated significant cardiovascular and renal benefits. Accumulating evidence suggests that SGLT2is also exert neuroprotective effects and may influence the progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). SGLT2is modulate glucose metabolism, reduce oxidative stress, suppress inflammation, and enhance mitochondrial function. Beyond glycemic control, they show potential therapeutic effects in ameliorating the metabolic dysregulation associated with neurodegenerative pathologies. Current preclinical and clinical evidence including metabolic regulation, anti-inflammatory actions, and neuroprotective effects mediated through SGLT2is associated molecular pathways have been critically evaluated to delineate their therapeutic potential in neurodegenerative disorders. Although preclinical studies have shown promising results, more clinical trials are needed. This review highlights key research gaps and proposes future translational applications.},
}

Humans
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology
Animals
*Neurodegenerative Diseases/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology

@article {pmid41267097,
year = {2025},
author = {Tang, C and Sun, Q and Zeng, X and Li, G and Yang, X and Liu, F and Zhao, J and Shen, Y and Liu, B and Wen, J and Li, Y},
title = {Cell type-specific inference from bulk RNA-sequencing data by integrating single-cell reference profiles via EPIC-unmix.},
journal = {Genome biology},
volume = {26},
number = {1},
pages = {395},
pmid = {41267097},
issn = {1474-760X},
support = {75N92021F00229//NHLBI TOPMed Fellowship/ ; T32ES007018/ES/NIEHS NIH HHS/United States ; P50HD103573//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; U24AR076730/AR/NIAMS NIH HHS/United States ; R01HL146500/HL/NHLBI NIH HHS/United States ; },
abstract = {UNLABELLED: Cell type-specific analysis is crucial for uncovering biological insights hidden in bulk tissue data, yet single-cell or single-nuclei approaches are often cost-prohibitive for large samples. We introduce EPIC-unmix, a novel two-step empirical Bayesian method combining reference single-cell/single-nuclei and bulk RNA-seq data to improve cell type-specific inference, accounting for the difference between reference and target datasets. Under comprehensive simulations, we demonstrate that EPIC-unmix outperforms alternative methods in accuracy. Applied to Alzheimer’s disease brain RNA-seq data, EPIC-unmix identifies multiple differentially expressed genes in a cell type-specific manner, and empowers cell type-specific eQTL analysis.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-025-03847-5.},
}

@article {pmid41269417,
year = {2025},
author = {Yuan, M and Han, XJ and Luo, CQ and Pan, HL and Zhou, HY},
title = {PSMD4 Alleviates Aβ1-42-Induced Mitochondrial Dysfunction and Oxidative Stress via the PGC-1α/Nrf Axis in Alzheimer's Disease Models.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {117},
pmid = {41269417},
issn = {1559-1182},
support = {2024SSY06081//the Jiangxi Province Key Laboratory of Neurology/ ; 2023ZD001//The Key Science and Technology Innovation Project of Jiangxi Provincial Health Commission/ ; 82071245, 82360238//the National Natural Science Foundation of China/ ; 20202ACB215003, 20232ACB205008//Jiangxi Province Natural Science Foundation/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Oxidative Stress/drug effects ; *Mitochondria/metabolism/drug effects/pathology ; *Amyloid beta-Peptides/toxicity ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Disease Models, Animal ; Mice, Transgenic ; *Peptide Fragments/toxicity ; Reactive Oxygen Species/metabolism ; *Nuclear Respiratory Factor 1/metabolism ; *Proteasome Endopeptidase Complex/metabolism ; Mice ; Membrane Potential, Mitochondrial/drug effects ; Signal Transduction/drug effects ; Hippocampus/pathology/metabolism ; },
abstract = {This study aimed to investigate the role of 26S proteasome non-ATPase regulatory subunit 4 (PSMD4) in regulating mitochondrial function and oxidative stress in Alzheimer's disease (AD) and to explore its potential molecular mechanism in Aβ-induced neurotoxicity. An in vitro AD model was established by treating Neuro-2a cells with Aβ1-42, and PSMD4 was overexpressed using a lentiviral vector. Flow cytometry was employed to assess reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm). Quantitative PCR and Western blotting were utilized to examine the expression of mitochondrial biogenesis-associated regulators, including PGC-1α, Nrf1, Nrf2, and TFAM. For the in vivo study, APP/PS1 double-transgenic mice served as the AD model. Histological analyses (HE and Nissl staining), immunofluorescence, and Western blotting were performed to evaluate hippocampal neuronal morphology and the expression of PSMD4 and mitochondrial marker TOM20. Aβ1-42 significantly increased ROS levels, reduced ΔΨm, and downregulated the expression of PGC-1α, Nrf1, Nrf2, and TFAM in Neuro-2a cells. PSMD4 overexpression attenuated these changes, suggesting a protective role against mitochondrial dysfunction and oxidative stress. In APP/PS1 mice, hippocampal neurons showed morphological damage with reduced Nissl substance and decreased PSMD4 and TOM20 expression. Immunofluorescence revealed cytoplasmic PSMD4 localization and enhanced co-localization with MAP2, TOM20, and Aβ1-42 in transgenic mice. PSMD4 is downregulated in AD models, and its overexpression ameliorates Aβ-induced oxidative stress and mitochondrial impairment, potentially by promoting mitochondrial biogenesis. These findings suggest that PSMD4 may serve as a novel therapeutic target for AD intervention.},
}

Animals
*Alzheimer Disease/metabolism/pathology
*Oxidative Stress/drug effects
*Mitochondria/metabolism/drug effects/pathology
*Amyloid beta-Peptides/toxicity
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
Disease Models, Animal
Mice, Transgenic
*Peptide Fragments/toxicity
Reactive Oxygen Species/metabolism
*Nuclear Respiratory Factor 1/metabolism
*Proteasome Endopeptidase Complex/metabolism
Mice
Membrane Potential, Mitochondrial/drug effects
Signal Transduction/drug effects
Hippocampus/pathology/metabolism

@article {pmid41269410,
year = {2025},
author = {Chen, M and Ning, Y and Yang, H and Jia, J},
title = {Trofinetide Improves Cognitive Function in APP/PS1 Mice by Suppressing Inflammation and Apoptosis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {129},
pmid = {41269410},
issn = {1559-1182},
support = {No.2021ZD0201802//the STI2030-Major Projects/ ; U20A20354//the Key Project of the National Natural Science Foundation of China/ ; Z201100005520016, Z201100005520017//Beijing Brain Initiative from Beijing Municipal Science & Technology Commission/ ; CX23YZ15//the grant from the Chinese Institutes for Medical Research/ ; 31627803//the National Key Scientific Instrument and Equipment Development Project/ ; },
mesh = {Animals ; *Apoptosis/drug effects ; Mice, Transgenic ; *Inflammation/drug therapy/pathology ; *Cognition/drug effects ; Mice ; Microglia/drug effects/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; *Amyloid beta-Protein Precursor/metabolism/genetics ; Alzheimer Disease/drug therapy/pathology ; Neurons/drug effects/metabolism/pathology ; *Presenilin-1/metabolism ; Hippocampus/pathology/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Amyloid Precursor Protein Secretases/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment, neuroinflammation, and neuronal apoptosis. Trofinetide, an analog of insulin-like growth factor 1 (IGF-1), has shown neuroprotective effects in various neurological disorders, but its role in AD remains unclear. Six-month-old APP/PS1 transgenic mice received intraperitoneal trofinetide for 2 months. Cognitive function was assessed using the Morris water maze (MWM) test. Immunohistochemistry (IHC) and immunofluorescence (IF) evaluated β-amyloid (Aβ) pathology, microglial activation, and neuronal loss. In vitro, BV2 microglial cells and HT22 hippocampal neurons were treated with trofinetide against AβO-induced cytotoxicity. Western blot (WB) was used to analyze inflammation and apoptosis-related proteins. Trofinetide significantly improved cognitive deficits, reduced Aβ plaque deposition, and decreased microglial activation and neuronal loss in APP/PS1 mice. In vitro, it rescued AβO-induced cytotoxicity, suppressed inflammatory cytokines (TNF-α, IL-6, IL-1) in BV2 cells, and inhibited apoptosis in HT22 cells. Mechanistically, trofinetide upregulated PPAR-γ, reduced BACE1, suppressed NF-κB phosphorylation, inhibited caspase-3 activation, and restored Bax/Bcl-2 balance, alleviating neuroinflammation and apoptosis. This study provides the first evidence that trofinetide improves cognitive function and mitigates Aβ pathology, neuroinflammation, and apoptosis in APP/PS1 mice and AβO-treated cells, highlighting its therapeutic potential for AD.},
}

Animals
*Apoptosis/drug effects
Mice, Transgenic
*Inflammation/drug therapy/pathology
*Cognition/drug effects
Mice
Microglia/drug effects/metabolism/pathology
Amyloid beta-Peptides/metabolism
*Amyloid beta-Protein Precursor/metabolism/genetics
Alzheimer Disease/drug therapy/pathology
Neurons/drug effects/metabolism/pathology
*Presenilin-1/metabolism
Hippocampus/pathology/drug effects
Neuroprotective Agents/pharmacology/therapeutic use
Male
Amyloid Precursor Protein Secretases/metabolism

@article {pmid41269403,
year = {2025},
author = {Jin, J and Hand, R and Meltzer, M and Abate, C and Geva, M and Hayden, MR and Ross, CA},
title = {Sigma-2 Receptor Antagonism Enhances the Neuroprotective Effects of Pridopidine, a Sigma-1 Receptor Agonist, in Huntington's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {121},
pmid = {41269403},
issn = {1559-1182},
mesh = {*Receptors, sigma/antagonists & inhibitors/agonists/metabolism ; *Huntington Disease/drug therapy/pathology/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; Sigma-1 Receptor ; *Piperidines/pharmacology/therapeutic use ; Mice ; Humans ; Neurons/drug effects/metabolism/pathology ; Huntingtin Protein/metabolism ; },
abstract = {Pridopidine is a selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Activation of the S1R by pridopidine is neuroprotective in multiple preclinical models of neurodegenerative disease. The sigma-2 receptor (S2R) is evolutionarily and structurally unique from the S1R. Nevertheless, the S1R and S2R share an overlapping yet distinct ligand binding profile. Inhibition of the S2R is neuroprotective and S2R antagonists are in clinical development for Alzheimer's Disease (AD), ⍺-synucleinopathies, and dry age-related macular degeneration. In this study, we hypothesized that simultaneous activation of the S1R by pridopidine and inhibition of the S2R by the selective S2R antagonist FA10 might provide enhanced protection against mutant huntingtin (mHTT) expression in an in vitro model of neurodegeneration. Consistent with previous studies, pridopidine reduced neuronal cell death in a mouse primary neuron mHTT model. Similarly, we found that inhibition of the S2R by FA10 was also sufficient to protect against mHTT induced neurodegeneration in this model. The combination treatment of pridopidine and FA10 achieved greater efficacy than either compound alone, even at lower concentrations. The combination of these compounds may allow for lower efficacious doses leading to improved safety profiles and reduced off-target effects. This novel combinatorial approach, in which the S1R is activated while simultaneously inhibiting the S2R may prove to be a highly effective therapeutic strategy for HD and other neurodegenerative diseases.},
}

*Receptors, sigma/antagonists & inhibitors/agonists/metabolism
*Huntington Disease/drug therapy/pathology/metabolism
Animals
*Neuroprotective Agents/pharmacology/therapeutic use
Sigma-1 Receptor
*Piperidines/pharmacology/therapeutic use
Mice
Humans
Neurons/drug effects/metabolism/pathology
Huntingtin Protein/metabolism

@article {pmid41269384,
year = {2025},
author = {Di Domenico, F and Greco, V and Tramutola, A and Rataj-Baniowska, M and Barone, E and Lanzillotta, C and Pieroni, L and Butterfield, DA and Herault, Y and Pagnotta, S and Cassano, T and Head, E and Urbani, A and Perluigi, M},
title = {Proteome Signature of Alzheimer-Like Phenotypes in Frontal Cortices From Young and Old Individuals With Down Syndrome.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {126},
pmid = {41269384},
issn = {1559-1182},
support = {RM11916B78D5711A//Sapienza Università di Roma/ ; RG12117A75C98BE3//Sapienza Università di Roma/ ; 2022KP5LKS//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; M4C2-I1.3 Project PE_00000019 "HEAL ITALIA" CUP: D73C22001230006//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; #2280-2023b//Fondation Jérôme Lejeune/ ; APAFIS#15187- 201805221519333v3//Ministère de l'Enseignement supérieur et de la Recherche/ ; R01HD064993/NH/NIH HHS/United States ; BFF17_0008//BrightFocus Foundation/ ; 2022-23 Anna Tramontano//Istituto Pasteur-Fondazione Cenci Bolognetti/ ; },
mesh = {Humans ; *Down Syndrome/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; *Frontal Lobe/metabolism/pathology ; *Proteome/metabolism ; Phenotype ; Male ; Female ; Middle Aged ; *Aging/metabolism/pathology ; Aged ; Adult ; Proteomics/methods ; Young Adult ; Aged, 80 and over ; },
abstract = {Down syndrome (DS) stands out as the most prevalent genetic contributor to intellectual disability, marked by the presence of an extra copy of chromosome 21 (HSA21). Notably, individuals with DS exhibit significant neuropathological changes for a diagnosis of Alzheimer's disease (AD), typically by the age of 50 years. To search for and identify biomarkers crucial for detecting and understanding the mechanisms involved in DS neuropathology, we conducted a protein expression analysis of post-mortem brain samples. We evaluated the frontal cortex of post-mortem brain samples from patients with DS both before and after the onset of AD pathology (DSAD), in comparison with age-matched healthy patients (CTRY and CTRO). Employing a comprehensive label-free shotgun proteomics approach, we sought to gain a deeper understanding of the intricate protein profiles associated with DS and its progression into DSAD. Collected results have been analyzed using specific databases and bioinformatics analysis software to understand relevant pathways, networks, and functions related to the experimental data. Our data support a genotype effect in DS at young and old ages that promotes specific proteome signatures associated with AD development. Notably, the affected signalling pathways encompass energy-related processes, synaptic transmission, and stress response. With aging, the dynamic shift in protein expression contributes to accelerating the neurodegenerative process, culminating in the manifestation of the AD phenotype.},
}

Humans
*Down Syndrome/metabolism/pathology
*Alzheimer Disease/metabolism/pathology
*Frontal Lobe/metabolism/pathology
*Proteome/metabolism
Phenotype
Male
Female
Middle Aged
*Aging/metabolism/pathology
Aged
Adult
Proteomics/methods
Young Adult
Aged, 80 and over

@article {pmid41269303,
year = {2025},
author = {Xin, H and He, L and Zhu, B},
title = {Ecological Insights into Gut Microbiota Networks Across Cognitive States in Alzheimer's Disease.},
journal = {Microbial ecology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00248-025-02662-6},
pmid = {41269303},
issn = {1432-184X},
support = {No. 202212691//Jiangxi Provincial Health Commission/ ; },
abstract = {The ecological mechanisms governing gut microbial community stability during Alzheimer's disease (AD) progression remain poorly understood. This study employed an ecological network to investigate microbial interactions and stability across cognitively normal controls (CK), individuals with mild cognitive impairment (MCI), and AD patients. We observed a stepwise decline in network complexity across groups, characterized by reduced clustering coefficients and average degree, from CK to AD. While the MCI group exhibited intermediate structural complexity, it displayed the highest vulnerability and lowest robustness, indicating a critical transitional state. Keystone taxa analysis revealed a significant shift in microbial community, with the CK network was enriched with diverse, potentially beneficial keystone taxa, whereas the AD network retained only connector species, and the MCI network showed a complete absence of keystone taxa. Cohesion analysis revealed a non-linear trajectory of microbial interactions, with negative cohesion peaking in MCI. Our findings demonstrate that cognitive decline is associated with a fundamental reorganization of the gut microbial ecosystem. This reorganization pattern reveals a resilient state in health, a vulnerable phase in MCI, and a stable yet dysbiotic configuration in AD, with keystone taxa serving as pivotal regulators of community stability. Community assembly analysis showed a shift from deterministic to stochastic processes during cognitive decline, with weakened host regulatory mechanisms. These findings advance our understanding of the gut microbial ecology in neurodegenerative disease and reveal the mechanism by which microbial communities reorganize network to maintain stability in different cognitive states.},
}

@article {pmid41269248,
year = {2025},
author = {Maggi, S and Fulöp, T and De Vita, E and Limongi, F and Pizzol, D and Di Gennaro, F and Veronese, N},
title = {Association between vaccinations and risk of dementia: a systematic review and meta-analysis.},
journal = {Age and ageing},
volume = {54},
number = {11},
pages = {},
doi = {10.1093/ageing/afaf331},
pmid = {41269248},
issn = {1468-2834},
mesh = {Humans ; *Dementia/epidemiology/prevention & control/diagnosis ; *Vaccination ; Aged ; Incidence ; Risk Factors ; Middle Aged ; Risk Assessment ; Cognitive Dysfunction/epidemiology/prevention & control ; Pneumococcal Vaccines ; Influenza Vaccines/administration & dosage ; },
abstract = {IMPORTANCE: Dementia is a highly prevalent issue in older people. Whilst the prevention of dementia is a public health priority, the role of vaccinations is still largely unexplored.

OBJECTIVE: The aim of this systematic review is to evaluate whether common adult vaccinations are associated with a reduced risk of dementia.

DATA SOURCES: PubMed, Embase and Web of Science were searched from inception to 1 January 2025.

STUDY SELECTION: Observational studies comparing dementia and mild cognitive impairment incidence between vaccinated and unvaccinated adults aged ≥50 years.

DATA EXTRACTION AND SYNTHESIS: Four reviewers independently extracted data and assessed study quality using the Newcastle-Ottawa Scale. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model.

MAIN OUTCOMES AND MEASURES: Incidence of dementia, including its subtypes.

RESULTS: Twenty-one studies (n = 104 031 186 participants) were included. Vaccination against herpes zoster was associated with a reduced risk of any dementia (RR 0.76, 95% CI 0.69-0.83) and Alzheimer's disease (RR 0.53, 95% CI 0.44-0.64). Influenza vaccination was linked to a reduction in dementia risk (RR 0.87, 95% CI 0.77-0.99), as was pneumococcal vaccination (RR 0.64, 95% CI 0.47-0.87) for Alzheimer's disease. Tetanus, diphtheria, pertussis (Tdap) vaccination was also associated with a significant reduction for any dementia (RR 0.67, 95% CI 0.54-0.83).

CONCLUSIONS AND RELEVANCE: Adult vaccinations, particularly against herpes zoster, influenza, pneumococcus and Tdap, are associated with a lower risk of dementia. Vaccination strategies should be incorporated into public health initiatives for dementia prevention.

REGISTRATION: https://osf.io/x3d4f/.},
}

Humans
*Dementia/epidemiology/prevention & control/diagnosis
*Vaccination
Aged
Incidence
Risk Factors
Middle Aged
Risk Assessment
Cognitive Dysfunction/epidemiology/prevention & control
Pneumococcal Vaccines
Influenza Vaccines/administration & dosage

@article {pmid41269127,
year = {2025},
author = {Linton, KF},
title = {A Quasi-Experimental Study Comparing a VR, Computer-Based, and Face-to-Face Alzheimer's Embodiment Education Scenario, "Beatriz.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnaf251},
pmid = {41269127},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Effective education on Alzheimer's disease (AD) requires methods fostering empathy, confidence, and knowledge. Artificial intelligence (AI)-enhanced virtual reality (VR) provides immersive experiences potentially superior to traditional modalities. No previous studies have compared VR immersive learning experiences to analogous computer-based or in-person embodiment exercises. This quasi-experimental study compared the efficacy of an AI-enhanced VR scenario, "Beatriz," with computer-based and face-to-face methods in improving students' confidence, empathy, and knowledge of AD.

RESEARCH DESIGN AND METHODS: A quasi-experimental design included 173 undergraduate health science students assigned to AI-enhanced VR, computer-based, or face-to-face modalities depicting early, middle, and late AD stages. Confidence, empathy, and knowledge were measured via pre-post surveys. Repeated measures ANOVAs determined significant differences.

RESULTS: All groups significantly improved confidence across AD stages post-intervention. The VR group showed greater improvement specifically in early-stage confidence. VR also significantly increased empathy compared to other modalities. No modality significantly improved factual knowledge of AD symptoms.

DISCUSSION AND IMPLICATIONS: AI-enhanced VR effectively improved empathy and early-stage confidence, suggesting strong benefits for dementia education. However, it did not surpass traditional methods in improving factual knowledge. AI-driven VR has promising implications for enhancing therapeutic and caregiving practices for aging populations. Further research should explore long-term impacts and direct older adult care applications.},
}

@article {pmid41269125,
year = {2025},
author = {Singh, RK and Bekena, S and Zhu, Y and Adkins-Jackson, PB and Ances, BM and Babulal, GM},
title = {Sleep Quality as a Modifier of Plasma pTau217 and GFAP Associations with Cognitive Function.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glaf259},
pmid = {41269125},
issn = {1758-535X},
abstract = {BACKGROUND: Plasma biomarkers, such as neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau (pTau217), and total tau (tTau), are associated with cognitive decline. However, the role of sleep quality in modifying these associations remains unclear. This study examines whether subjective sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI), modifies the associations between plasma biomarkers and cognitive performance.

METHODS: We analyzed cross-sectional data from 491 adults aged 36 years or older in the Aging Adult Brain Connectome study. Plasma levels of NfL, GFAP, pTau217, and total tTau were measured. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA) and the Preclinical Alzheimer's Cognitive Composite (PACC). Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI). Generalized linear models were used to test main and moderation effects while adjusting for demographics. Sensitivity analyses included APOE ε4 status and body mass index.

RESULTS: Higher plasma levels of NfL, GFAP, and pTau217 were associated with lower cognitive performance on both MoCA and PACC (all P < 0.05). Poorer sleep quality was independently associated with worse PACC outcomes. Critically, significant moderation effects were observed: PSQI moderated the negative associations between GFAP and both PACC (β = 0.0003, P = 0.039) and MoCA (β = 0.0019, P = 0.021), and between pTau217 and MoCA (β = 0.0299, P = 0.004), indicating a synergistic relationship between sleep quality and glial/amyloid-related pathology in cognitive aging.

CONCLUSION: Sleep quality modifies biomarker-cognition associations, highlighting its potential as a behavioral target to support brain health.},
}

@article {pmid41268975,
year = {2025},
author = {Saxena, V and Garg, S},
title = {Engineered Commensals as Next-Generation Drug Delivery Agents for Nose-to-Brain Therapeutics in Neurological Disorders.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00874},
pmid = {41268975},
issn = {1948-7193},
abstract = {Central nervous system (CNS) disorders such as Alzheimer's diseases, Parkinson's diseases, stroke, and glioma remain among the most challenging to treat, largely due to the restrictive nature of the blood-brain barrier (BBB). In recent years, intranasal administration has emerged as a noninvasive route for CNS drug delivery. Due to its anatomical advantage over the traditional route, the nose-to-brain route can easily bypass the BBB and deliver drugs directly to the brain. Parallel advances in the interface of synthetic biology and materials engineering have led to the development of engineered living materials (ELMs) dynamic structures that embed mammalian cells, bacteria, or viruses within self-renewing or engineered matrices. These bioengineered systems have been developed as next-generation therapeutic platforms for various biomedical applications, utilizing intrinsic or engineered capabilities such as disease-targeted migration, localized therapeutic production, adaptive delivery, immune activation, and metabolic regulation. Therefore, developing a bioengineered commensal based delivery system that uses the intranasal route to effectively deliver drug across the BBB could represent a transformative strategy for treating CNS disorder and advancing neurotherapeutic research.},
}

@article {pmid41268926,
year = {2025},
author = {},
title = {Cyrus A. Raji, MD, PhD, is the recipient of the 2025 Mark A. Smith Alzheimer Award.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {106},
number = {4},
pages = {1217-1218},
doi = {10.1177/13872877251361092},
pmid = {41268926},
issn = {1875-8908},
}

@article {pmid41268856,
year = {2025},
author = {Andrews, SJ and Tolosa-Tort, P and Jonson, C and Fulton-Howard, B and Renton, AE and Yokoyama, JS and Yaffe, K and , },
title = {The role of genomic-informed risk assessments in predicting dementia outcomes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70826},
doi = {10.1002/alz.70826},
pmid = {41268856},
issn = {1552-5279},
support = {5U24AG072122//National Alzheimer's Coordinating Center New Investigator Award/ ; R35AG071916/NH/NIH HHS/United States ; U19AG069701/NH/NIH HHS/United States ; /AG/NIA NIH HHS/United States ; Z01ZIAAG000534/HH/HHS/United States ; /NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Dementia/genetics/epidemiology/diagnosis ; Risk Assessment ; Aged ; Apolipoproteins E/genetics ; *Genomics ; Risk Factors ; Disease Progression ; Alzheimer Disease/genetics ; Aged, 80 and over ; Genetic Predisposition to Disease ; Middle Aged ; },
abstract = {INTRODUCTION: By integrating genetic and clinical risk factors into genomic-informed dementia risk reports, healthcare providers can offer patients detailed risk profiles to facilitate understanding of individual risk and support the implementation of personalized strategies for promoting brain health.

METHODS: We constructed an additive score comprising the modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score (mCAIDE), family history of dementia, apolipoprotein E (APOE) genotype, and an Alzheimer's disease (AD) polygenic risk score in National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Iniative (ADNI), and assessed its association with progression to all-cause dementia.

RESULTS: A total of 81% of participants had at least one high-risk indicator for dementia, with each additional risk indicator linked to a 34% increase in the hazard of dementia onset.

DISCUSSION: We found that most participants in memory and aging clinics had at least one high-risk indicator for dementia. Furthermore, we observed a dose-response relationship where a greater number of risk indicators was associated with an increased risk of incident dementia.

HIGHLIGHTS: Compiled genomic-informed dementia risk report of genetic and clinical risk factors. Most memory clinic patients have at least one high-risk indicator for dementia. A higher risk indicator burden is associated with a greater dementia risk.},
}

Humans
Male
Female
*Dementia/genetics/epidemiology/diagnosis
Risk Assessment
Aged
Apolipoproteins E/genetics
*Genomics
Risk Factors
Disease Progression
Alzheimer Disease/genetics
Aged, 80 and over
Genetic Predisposition to Disease
Middle Aged

@article {pmid41268805,
year = {2025},
author = {Suemoto, CK and Paradela, R and Leite, REP and Paes, VR and Pasqualucci, CA and Ferriolli, E and Zatz, M and do Nascimento Santos, G and de Alexandria, MALS and Pereira, AC and Fortea, J and Naslavsky, M and Grinberg, LT},
title = {Apolipoprotein E and Alzheimer's disease pathology in a diverse autopsy study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70927},
doi = {10.1002/alz.70927},
pmid = {41268805},
issn = {1552-5279},
support = {2020/14339-3//the Sao Paulo Research Foundation/FAPESP/ ; 2024/03917-7//the Sao Paulo Research Foundation/FAPESP/ ; INT21/00073 PI20/01473//the Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España/ ; PI23/01786//the Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España/ ; //the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas CIBERNED Program 1/ ; //by Fondo Europeo de Desarrollo Regional, Unión Europea, Una Manera de Hacer Europa/ ; R01 AG056850//the National Institutes of Health/ ; R21 AG056974/AG/NIA NIH HHS/United States ; R01 AG061566//the National Institutes of Health/ ; R01 AG081394/AG/NIA NIH HHS/United States ; R61AG066543//the National Institutes of Health/ ; 1RF1AG080769-01//the National Institutes of Health/ ; IIBSP-DOW-2020-151//the Departament de Salut de la Generalitat de Catalunya, Fundación Tatiana Pérez de Guzmán el Bueno/ ; H2020-SC1-BHC-2018-2020//the Horizon 2020-Research and Innovation Framework Programme from the European Union/ ; //BrightFocus/ ; //and Life Molecular Imaging/ ; 24CBIDR-1185483//the Alzheimer's Association/ ; AARG-20-678884//the Alzheimer's Association/ ; AARGD-22-972378//the Alzheimer's Association/ ; 24CBIDR-1185483//the Alzheimer's Association/ ; AARG-20-678884//the Alzheimer's Association/ ; AARGD-22-972378//the Alzheimer's Association/ ; //the Sanford J. Grossman Charitable Trust/ ; //the Brian and Tania Higgins Charitable Foundation/ ; //Carolyn and Eugene Mercy Research Gift/ ; //the Karen Strauss Cook Research Scholar Award/ ; //Alzheimer's New Jersey/ ; //the Robert J. and Claire Pasarow Foundation/ ; //the Marvin and Judith Herb Family/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; Female ; Male ; Aged ; Autopsy ; Cross-Sectional Studies ; Brazil ; Aged, 80 and over ; *Brain/pathology ; *Apolipoprotein E4/genetics ; *Apolipoproteins E/genetics ; Genotype ; },
abstract = {INTRODUCTION: Apolipoprotein E allele 4 (APOE ε4) is the main genetic risk factor for late-onset Alzheimer's disease (AD), but most evidence comes from White populations in high-income countries. We investigated APOE and AD pathology in an ethnically diverse Brazilian autopsy cohort.

METHODS: This cross-sectional study used Biobank for Aging Studies (BAS) data. AD pathology was evaluated with Braak, Consortium to Establish a Registry for Alzheimer's Disease, and Thal criteria. APOE genotypes were obtained from blood or brain tissue. Regression models were adjusted for age, sex, race, and education; interaction with race was tested.

RESULTS: Among 1391 participants (mean age 75.1 ± 12.4 years, 50% women, 64% White), APOE ε4showed a dose response with greater AD pathological burden and higher odds of AD diagnosis, while APOE ε2/X was protective. APOE ε4/ε4 did not show full penetrance across age groups. Associations were similar in White and Black individuals.

DISCUSSION: APOE ε4was strongly associated with AD pathology, with consistent associations across racial groups.

HIGHLIGHTS: APOE ε4 increased AD neuropathological burden in Brazilians. APOE ε2/εX was protective against AD pathology. APOE ε4/ε4did not show full penetrance across age groups. Associations between APOE and AD pathology were similar by race. Large multiethnic autopsy study expands evidence beyond high-income country studies.},
}

Humans
*Alzheimer Disease/genetics/pathology
Female
Male
Aged
Autopsy
Cross-Sectional Studies
Brazil
Aged, 80 and over
*Brain/pathology
*Apolipoprotein E4/genetics
*Apolipoproteins E/genetics
Genotype

@article {pmid41268794,
year = {2025},
author = {Zhang, H and Ya, J and Liao, X and Du, X and Zhao, C and Ren, J and Qu, X},
title = {In Situ Activatable Hydrogen-Bonded Organic Framework-Based Nanozyme as NADH Peroxidase Mimic Restoring Homeostasis for Treatment of Alzheimer's Disease.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e09547},
doi = {10.1002/smll.202509547},
pmid = {41268794},
issn = {1613-6829},
support = {2022YFA1205804//National Key R&D Program of China/ ; T249526//National Natural Science Foundation of China/ ; 22437006//National Natural Science Foundation of China/ ; 22237006//National Natural Science Foundation of China/ ; },
abstract = {Nicotinamide adenine dinucleotide (NAD) serves as a vital regulator in metabolic networks, and the decrease in the level of its oxidized form, NAD+, is closely related to Alzheimer's disease (AD). However, unsatisfactory efficacy, non-targeted and imprecise treatment, along with interconnected pathogenic factors in AD, constrain the therapeutic efficacy of current AD therapeutic strategies. Herein, in lieu of complex multi-module treatments for pathogenesis, a bespoke in situ activatable hydrogen-bonded organic framework (HOF)-based nanozyme (denoted as NADH@Pre-Cu-HOF@KD8) has been constructed to modulate multiple interconnected homeostatic imbalances in AD. Benefiting from the specific organic monomers, 2,2'-bipyridine-5,5'-dicarboxylic acid, NADH@Pre-Cu-HOF@KD8 can sequester neurotoxic Cu[2+] from amyloid-β (Aβ)-Cu[2+] by competitive binding. The segregation of Cu[2+] from Aβ mitigated the generation of reactive oxygen species, Aβ toxicity, and alleviated the activation of microglia cells. Moreover, HOF-based nanozyme possessed NADH peroxidase (NPX)-like catalytic activity after binding Cu[2+], which can reduce oxidative stress and elevate compromised NAD+ levels, thereby restoring mitochondrial impairment and adenosine triphosphate (ATP) production. Spatiotemporally precise intervention is enabled through targeted delivery mediated by peptide modification and lesion-specific activation. Notably, cognitive deficits, neuropathology, and homeostatic markers in a 3xTg-AD mouse model are ameliorated upon treatment. By employing a facile HOF platform to modulate multiple interconnected pathological homeostatic imbalances in AD-copper toxicity, NAD[+] depletion, oxidative stress, and Aβ toxicity-this strategy offers a paradigm for ameliorating AD-associated homeostatic imbalances.},
}

@article {pmid41268793,
year = {2025},
author = {Morgan, A and Durkin, C and Tari, B and Squires, E and Young, S and Bauermeister, J and Bauermeister, S and Gallacher, J},
title = {Dementia Data Landscape 1. Cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70901},
doi = {10.1002/alz.70901},
pmid = {41268793},
issn = {1552-5279},
support = {//Alzheimer's Disease Data Enablement Fund/ ; //Gates Ventures/ ; },
mesh = {Humans ; *Dementia/epidemiology ; Cohort Studies ; *Metadata ; },
abstract = {INTRODUCTION: Understanding and maximizing complex health data is crucial for accelerating discovery, translational research, funding priorities, and improving data management. Rapid, cost-effective progress can be made by repurposing datasets. This work explores the dementia cohort landscape, identifies cohorts relevant to dementia translation, and highlights areas to strengthen health cohort infrastructure.

METHOD: PubMed was searched for publications utilizing dementia-related cohorts (1970-2024), supplemented by international dementia data platforms. A template aligned with the C-Surv data model was used to summarize administrative details and the presence of measurements across 17 themes.

RESULTS: From 4596 publications and 11 data platforms, 883 cohorts were identified (558 population and 325 clinical). Of these, 74% indicated data availability for future research, though metadata reporting varied. Cohort metadata are accessible via the landscape tool.

DISCUSSION: This work reveals extensive global dementia-related data for repurposing and identifies priority areas for improvement, including metadata transparency, data accessibility, and locations to prioritize for future research.

HIGHLIGHTS: A total of 883 cohorts were identified globally (1970 to 2024): 558 population and 325 clinical The Global South is substantially underrepresented Seventy-four percent of cohorts offer data access, but protocols and metadata quality vary widely Only 45% of cohorts were discoverable via existing data platforms The online landscape tool enables strategic discovery and reuse of dementia data.},
}

Humans
*Dementia/epidemiology
Cohort Studies
*Metadata

@article {pmid41268790,
year = {2025},
author = {Coburn, MA and Eskandari-Sedighi, G and Hasselmann, J and England, W and Shabestari, SK and Mansour, K and McQuade, A and Mgerian, MA and Chadarevian, JP and Tu, C and Silva, J and Beck, J and Keulen, Z and Spitale, RC and Davtyan, H and Blurton-Jones, M},
title = {Human microglia differentially respond to β-amyloid, tau, and combined Alzheimer's disease pathologies in vivo.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70930},
doi = {10.1002/alz.70930},
pmid = {41268790},
issn = {1552-5279},
support = {//Cure Alzheimer's Fund/ ; Discovery23-10//Alzheimer Society of Canada/ ; //The Larry L. Hillblom Foundation : 2024-A-023-FEL and 2025-A-175-FEL/ ; A2025007F//BrightFocus Postdoctoral Fellowship Program in Alzheimer's/ ; P30CA-062203//NIH / ; 1S10RR025496-01//NIH / ; 1S10OD010794-01//NIH / ; 1S10OD021718-01//NIH / ; 2024-A-023-FEL//NIH / ; NS082174//NIH Training Grant/ ; AG000096//NIH Training Grant/ ; //Susan Scott Foundation/ ; ADSF-21-829655-C/ALZ/Alzheimer's Association/United States ; },
mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/pathology/metabolism ; Animals ; Humans ; Mice ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *tau Proteins/metabolism ; Plaque, Amyloid/pathology/metabolism ; Mice, Transgenic ; Neurofibrillary Tangles/pathology/metabolism ; },
abstract = {INTRODUCTION: Recent studies have identified important species-dependent differences in the response of microglia to β-amyloid (Aβ) pathology. Yet, whether human microglia also interact differently with the pathognomonic combination of amyloid and tau pathologies that occur in Alzheimer's disease (AD) remains unclear.

METHODS: We generated a xenotolerant mouse model of AD that develops both plaque and tangle pathologies, transplanted stem cell-derived microglial progenitors and examined the interactions between human microglia and AD pathologies with scRNA sequencing, immunohistochemistry, and in vitro modeling.

RESULTS: The combined amyloid and tau pathologies induced robust type-I interferon and proinflammatory cytokine responses, as well as an increased adoption of a distinct "rod" morphology in human microglia. The rod morphology could be induced with type-I interferon treatment in vitro.

DISCUSSION: We provide new insights into human microglial responses to combined AD pathologies and a novel platform to investigate and manipulate human microglia in vivo.

HIGHLIGHTS: Amyloid pathology promotes the rapid development of neurofibrillary tangles and neuronal loss in a novel chimeric model of AD. Combined Alzheimer's disease pathologies lead to an expansion of disease-associated microglia (DAM) and exacerbate Interferon-responsive and cytokine/chemokine-enriched states in xenotransplanted human microglia. The combination of amyloid and tau promotes the development of a distinctive rod microglial phenotype that closely correlates with tau pathology and neurodegeneration. Rod morphology and transcriptional changes can be modeled in vitro by treatment of induced pluripotent stem cells (iPSC) -microglia with type-I interferons.},
}

*Microglia/metabolism/pathology
*Alzheimer Disease/pathology/metabolism
Animals
Humans
Mice
*Amyloid beta-Peptides/metabolism
Disease Models, Animal
*tau Proteins/metabolism
Plaque, Amyloid/pathology/metabolism
Mice, Transgenic
Neurofibrillary Tangles/pathology/metabolism

@article {pmid41268784,
year = {2025},
author = {Ghanbarian, E and Qian, T and Khorsand, B and Zheng, L and Sajjadi, SA and Grill, JD and Rabin, LA and Lipton, RB and Sperling, RA and Ezzati, A},
title = {Prognostic value of plasma glial fibrillary acidic protein in cognitively unimpaired older adults: Results from the A4 study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70948},
doi = {10.1002/alz.70948},
pmid = {41268784},
issn = {1552-5279},
support = {NIA K23 AG063993/NH/NIH HHS/United States ; R01 AG080635/NH/NIH HHS/United States ; R01AG095017/NH/NIH HHS/United States ; SG-24-988292(ISAVRAD)/ALZ/Alzheimer's Association/United States ; //Cure Alzheimer's Fund/ ; },
mesh = {Humans ; *Glial Fibrillary Acidic Protein/blood ; Female ; Male ; Aged ; Biomarkers/blood ; Prognosis ; *Alzheimer Disease/blood/diagnosis ; *Cognitive Dysfunction/blood/diagnosis ; Cross-Sectional Studies ; Disease Progression ; Aged, 80 and over ; Cognition ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Plasma glial fibrillary acidic protein (GFAP), a marker of astrocytic activation, has been linked to Alzheimer's disease; however, its prognostic value in cognitively unimpaired (CU) individuals remains unclear.

METHODS: We included 949 CU older adults from the A4 preclinical AD trial and its companion LEARN cohort. Baseline plasma GFAP was measured, and associations with cognitive decline (Preclinical Alzheimer's Cognitive Composite [PACC]), Clinical Dementia Rating (CDR) progression, and imaging biomarkers were assessed over 240 weeks.

RESULTS: Baseline plasma GFAP was higher in females and in A4 (amyloid-positive) versus LEARN (amyloid-negative) participants. Cross-sectionally, elevated GFAP was associated with lower cognitive performance and greater amyloid burden. Longitudinally, higher GFAP predicted faster cognitive decline, increased risk of CDR progression, AD-related cortical atrophy, and amyloid conversion, with stronger effects in females.

DISCUSSION: Plasma GFAP is a prognostic biomarker in CU older adults, predicting cognitive and biological changes, with stronger associations observed in females, highlighting a possible sex-specific vulnerability.

HIGHLIGHTS: Elevated plasma glial fibrillary acidic protein (GFAP) predicted faster cognitive decline measured by Preclinical Alzheimer's Cognitive Composite (PACC). GFAP was associated with increased risk of progression to mild cognitive impairment. GFAP predicted conversion to amyloid positivity in amyloid-negative subjects. Higher baseline GFAP was associated with cortical atrophy in Alzheimer's disease (AD) -signature areas. Associations of GFAP with cognition and AD biomarkers were stronger in females.},
}

Humans
*Glial Fibrillary Acidic Protein/blood
Female
Male
Aged
Biomarkers/blood
Prognosis
*Alzheimer Disease/blood/diagnosis
*Cognitive Dysfunction/blood/diagnosis
Cross-Sectional Studies
Disease Progression
Aged, 80 and over
Cognition
Neuropsychological Tests

@article {pmid41268768,
year = {2025},
author = {Dacey, R and Hou, L and Gurnani, A and Han, X and Paller-Moore, MR and Chung, J and Durape, S and Rosenthaler, M and Uretsky, M and Abdolmohammadi, B and Lee, AJ and Brickman, AM and Hohman, TJ and Cuccaro, ML and Bennett, DA and Crane, PK and Kamboh, MI and Kukull, WA and Jun, G and Stein, TD and McKee, AC and Haines, JL and Pericak-Vance, MA and Wang, LS and Schellenberg, GD and Mayeux, R and Lunetta, KL and Farrer, LA and Mez, J},
title = {Alzheimer's disease multi-ancestry genome-wide interaction and stratified study with smoking.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70922},
doi = {10.1002/alz.70922},
pmid = {41268768},
issn = {1552-5279},
support = {U24-AG021886/AG/NIA NIH HHS/United States ; U01-AG016976/AG/NIA NIH HHS/United States ; U24-AG041689/AG/NIA NIH HHS/United States ; U24-AG074855/AG/NIA NIH HHS/United States ; U01-AG068057/AG/NIA NIH HHS/United States ; R01-AG059716/AG/NIA NIH HHS/United States ; U19-AG068753/AG/NIA NIH HHS/United States ; R01-AG048927/AG/NIA NIH HHS/United States ; U54-AG052427/AG/NIA NIH HHS/United States ; U01-AG058654/AG/NIA NIH HHS/United States ; U01-AG032984/AG/NIA NIH HHS/United States ; RF1-AG057519/AG/NIA NIH HHS/United States ; U01-AG062602/AG/NIA NIH HHS/United States ; P30-AG072978/AG/NIA NIH HHS/United States ; U24-AG074855/AG/NIA NIH HHS/United States ; U01-AG068057/AG/NIA NIH HHS/United States ; R01-AG059716/AG/NIA NIH HHS/United States ; U19-AG066567/AG/NIA NIH HHS/United States ; P30-AG066468/AG/NIA NIH HHS/United States ; P30-AG10161/AG/NIA NIH HHS/United States ; P30-AG72975/AG/NIA NIH HHS/United States ; R01-AG17917/AG/NIA NIH HHS/United States ; R01-AG015819/AG/NIA NIH HHS/United States ; U01-AG072572/AG/NIA NIH HHS/United States ; U01-AG046152/AG/NIA NIH HHS/United States ; U01-AG046152/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; *Genome-Wide Association Study ; Polymorphism, Single Nucleotide/genetics ; Male ; Female ; *Smoking/genetics ; White People/genetics ; Aged ; *Gene-Environment Interaction ; Genetic Predisposition to Disease ; Quantitative Trait Loci ; Middle Aged ; Brain/metabolism ; Black or African American/genetics ; White ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) has genetic and environmental risk factors, including cigarette smoking. Gene-environment interactions may explain AD missing heritability.

METHODS: Lifetime smoking data from 22,032 European ancestry and 3126 African ancestry participants from the Alzheimer's Disease Genetic Consortium and the Framingham Heart Study were used to conduct genome-wide single nucleotide polymorphism (SNP)-by-smoking interaction and smoking-stratified association studies. For top-ranked loci, brain-derived bulk and single nuclei RNA-sequencing were used for differential expression and colocalization analyses.

RESULTS: Among smokers only, there was a genome-wide significant association in the APAF1/ANKS1B region (rs12368451; odds ratio = 1.19, 95% confidence interval: [1.12, 1.27], p = 3.0 × 10[-8]). Rs12368451 had expression quantitative trait locus (eQTL) activity that differed by smoking status and brain cell types but showed the most significant posterior probability (PP = 0.15) for being causal via ANKS1B expression in oligodendrocytes among smokers.

DISCUSSION: Potentially causal in smokers via eQTL activity, the top SNP may alter expression of ANKS1B, which encodes amyloid beta precursor protein intracellular domain associated-1, known to regulate amyloid beta plaques.

HIGHLIGHTS: Among smokers only, a novel chromosome 12 single nucleotide polymorphism (SNP) near ANKS1B was associated with Alzheimer's disease. Evidence came from European and African ancestry cohorts. RNA-sequencing analyses implicated the top SNP as causal via ANKS1B expression in oligodendrocytes. A genome-wide African ancestry-specific significant SNP-smoking interaction was observed on chromosome 6 in SLC22A23.},
}

Humans
*Alzheimer Disease/genetics
*Genome-Wide Association Study
Polymorphism, Single Nucleotide/genetics
Male
Female
*Smoking/genetics
White People/genetics
Aged
*Gene-Environment Interaction
Genetic Predisposition to Disease
Quantitative Trait Loci
Middle Aged
Brain/metabolism
Black or African American/genetics
White

@article {pmid41268764,
year = {2025},
author = {Valipour, MA and Abdollahi, E and Yadegar, A and Morad, H and Sheibani, M and Noori, M and Valipour, M},
title = {Therapeutic Potential of Trolox and Its Synthetic Derivatives as Multifunctional Bioactive Molecules in Periodontal Disease Management.},
journal = {Drug development research},
volume = {86},
number = {8},
pages = {e70200},
doi = {10.1002/ddr.70200},
pmid = {41268764},
issn = {1098-2299},
support = {//The authors received no specific funding for this work./ ; },
mesh = {Humans ; *Periodontal Diseases/drug therapy ; *Chromans/therapeutic use/pharmacology/chemistry ; *Antioxidants/therapeutic use/pharmacology/chemistry ; Animals ; Anti-Inflammatory Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {Periodontal disease is a chronic inflammatory problem that has destructive effects on the tooth-supporting tissues. This disease affects a large portion of the population, influencing overall health and quality of life, and significant socioeconomic burden. Therefore, efforts to more effectively manage the problems caused by this disease are a necessity. This review describes the therapeutic potential of Trolox (a water-soluble analogue of vitamin E) and its modified derivatives as potential candidates for managing periodontal disease, highlighting their multifaceted pharmacological properties. Unlike the lipophilic molecule vitamin E, Trolox can be formulated into aqueous solutions, gels, mouthwashes, or rinses, ensuring optimal bioavailability at sites of inflammation and infection in the oral cavity. This compound can also help treat periodontal disease by combating oxidative stress, where its antioxidant properties neutralize harmful reactive oxygen species (ROS), reducing tissue damage and bone loss caused by undesired conditions such as bacterial imbalance. In addition to antioxidant and anti-inflammatory properties, Trolox and its derivatives exhibit various pharmacological activities against diabetes, Alzheimer's disease, Plasmodium falciparum malaria infection, and periodontopathogens, all of which are associated with the development of periodontal disease. In conclusion, this review suggests that Trolox and some of its derivatives with favorable activity/toxicity profiles have significant potential to be considered as new drug candidates for combating periodontal diseases.},
}

Humans
*Periodontal Diseases/drug therapy
*Chromans/therapeutic use/pharmacology/chemistry
*Antioxidants/therapeutic use/pharmacology/chemistry
Animals
Anti-Inflammatory Agents/therapeutic use/pharmacology
Oxidative Stress/drug effects

@article {pmid41268707,
year = {2025},
author = {Xu, K and Wang, L and Lv, T and Jin, C and Wu, Q and Zhou, Y and Xu, G and Duan, Z and Luo, K and Yang, J},
title = {Nanomedicines Against Mitochondrial Dysfunction-Induced Metabolic Diseases.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e14522},
doi = {10.1002/advs.202514522},
pmid = {41268707},
issn = {2198-3844},
support = {2023YFB3810004//National Key Research and Development Program of China/ ; 32271445//National Natural Science Foundation of China/ ; 52203182//National Natural Science Foundation of China/ ; 82300663//National Natural Science Foundation of China/ ; 82370624//National Natural Science Foundation of China/ ; 23ZDYF2182//the Key R&D Projects of Sichuan Province/ ; ZYGD23026//1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University/ ; ZYGD24002//1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University/ ; },
abstract = {Mitochondrial dysfunction is a common pathology for metabolic diseases such as obesity, diabetes, non-alcoholic fatty liver disease, atherosclerosis, Alzheimer's disease (AD), and Parkinson's disease (PD). Nanomedicines provide a revolutionary strategy for mitochondrial function repair. They can realize targeted delivery, responsive release, and integration of multimodal therapies through nanotechnology and engineering and overcome limitations of traditional therapeutic methods, such as insufficient targeting, low bioavailability, and toxic side effects. In this article, the pathological characteristics of mitochondria are first introduced, and the relationship between mitochondrial dysfunction and metabolic diseases are illustrated. Structural features and design strategies of nanomedicines targeting mitochondrial dysfunction are summarized, with particular elaboration on targeting strategies and response mechanisms for diseased organs and subcellular organelles such as the liver, adipose tissue, atherosclerotic plaques, the brain, and mitochondria. The application and clinical translation of nanomedicines in obesity, atherosclerosis, diabetes, non-alcoholic fatty liver disease (NAFLD), and brain metabolic disorders are detailed. This article is concluded with a summary and outlook of the current research status, challenges, and future development directions.},
}

@article {pmid41268687,
year = {2025},
author = {Chen, J and Liu, B and Yao, X and Yang, X and Sun, J and Yi, J and Xue, F and Zhang, J and Shen, Y and Chen, B and Sun, H},
title = {AMPK/SIRT1/PGC-1α Signaling Pathway: Molecular Mechanisms and Targeted Strategies From Energy Homeostasis Regulation to Disease Therapy.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {11},
pages = {e70657},
doi = {10.1111/cns.70657},
pmid = {41268687},
issn = {1755-5949},
support = {32130060//National Natural Science Foundation of China/ ; 82401633//National Natural Science Foundation of China/ ; BK20232023//Natural Science Foundation of Jiangsu Province/ ; 24KJA310007//Natural Science Research Projects in Universities of Jiangsu Province/ ; 24KJB310013//Natural Science Research Projects in Universities of Jiangsu Province/ ; SYW2024048//Suzhou Science and Technology Development Program/ ; },
mesh = {Humans ; *Sirtuin 1/metabolism ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Animals ; *Signal Transduction/physiology ; *AMP-Activated Protein Kinases/metabolism ; *Homeostasis/physiology ; *Energy Metabolism/physiology ; },
abstract = {BACKGROUND: The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunction is implicated in the pathogenesis of a wide spectrum of complex modern diseases, spanning neurodegeneration, metabolic syndromes, and chronic inflammatory conditions. This review examines the pathway's role as an integrative hub and its potential as a therapeutic target.

METHODS: We synthesize current mechanistic evidence from molecular, cellular, and preclinical studies to elucidate the pathway's operational logic and the consequences of its dysregulation. The analysis is structured around key disease paradigms-including Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular injury, stroke, and chronic kidney disease-to dissect its tissue-specific pathophysiological impacts.

RESULTS: The AMPK/SIRT1/PGC-1α axis operates through a core positive feedback loop: AMPK activation elevates NAD+, thereby activating SIRT1, which in turn deacetylates and activates PGC-1α to drive mitochondrial biogenesis and function, further reinforcing SIRT1 activity. Disruption of this cascade manifests in disease-specific mechanisms: promoting Aβ production via BACE1/γ-secretase in Alzheimer's; impairing α-synuclein clearance in Parkinson's; disrupting GLUT4 translocation and insulin signaling in diabetes; exacerbating oxidative damage and mitochondrial dysfunction in cardiovascular and neuronal injury; and accelerating fibrosis and sustained inflammation in renal and pulmonary diseases via NLRP3 and TGF-β/Smad3 signaling.

CONCLUSIONS: The AMPK/SIRT1/PGC-1α pathway represents a cornerstone target at the intersection of metabolism, aging, and disease. Current therapeutic strategies-including pharmacological activators (e.g., metformin, SRT1720), natural compounds (e.g., resveratrol), lifestyle interventions (e.g., exercise, caloric restriction), and emerging technologies (e.g., gene editing, exosomal miRNAs)-offer multidimensional avenues for intervention. Future research must prioritize elucidating tissue-specific regulatory mechanisms, such as AMPK isoform diversity and PGC-1α interactome dynamics, to enable precision therapeutics and successful clinical translation for a range of complex disorders.},
}

Humans
*Sirtuin 1/metabolism
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
Animals
*Signal Transduction/physiology
*AMP-Activated Protein Kinases/metabolism
*Homeostasis/physiology
*Energy Metabolism/physiology

@article {pmid41268645,
year = {2025},
author = {Kang, K and Wu, Z and Qian, X and Song, X and Zhu, H},
title = {Federated double machine learning for high-dimensional semiparametric models.},
journal = {Biometrics},
volume = {81},
number = {4},
pages = {},
doi = {10.1093/biomtc/ujaf150},
pmid = {41268645},
issn = {1541-0420},
support = {12301368//National Natural Science Foundation of China/ ; 2024A04J4505//Guangzhou Science and Technology Programme/ ; },
mesh = {*Machine Learning ; Humans ; *Models, Statistical ; Alzheimer Disease/diagnostic imaging ; Computer Simulation ; Neuroimaging/statistics & numerical data ; Biometry/methods ; Multicenter Studies as Topic/statistics & numerical data ; },
abstract = {Federated learning enables the training of a global model while keeping data localized; however, current methods face challenges with high-dimensional semiparametric models that involve complex nuisance parameters. This paper proposes a federated double machine learning framework designed to address high-dimensional nuisance parameters of semiparametric models in multicenter studies. Our approach leverages double machine learning (Chernozhukov et al., 2018a) to estimate center-specific parameters, extends the surrogate efficient score method within a Neyman-orthogonal framework, and applies density ratio tilting to create a federated estimator that combines local individual-level data with summary statistics from other centers. This methodology mitigates regularization bias and overfitting in high-dimensional nuisance parameter estimation. We establish the estimator's limiting distribution under minimal assumptions, validate its performance through extensive simulations, and demonstrate its effectiveness in analyzing multiphase data from the Alzheimer's Disease Neuroimaging Initiative study.},
}

*Machine Learning
Humans
*Models, Statistical
Alzheimer Disease/diagnostic imaging
Computer Simulation
Neuroimaging/statistics & numerical data
Biometry/methods
Multicenter Studies as Topic/statistics & numerical data

@article {pmid41268620,
year = {2025},
author = {Sun, L and Wang, J and Zhang, L},
title = {The Role of Sphingomyelin Synthase 2 in Lipid Metabolism and Its Implications in Diseases.},
journal = {Cell biology international},
volume = {},
number = {},
pages = {},
doi = {10.1002/cbin.70103},
pmid = {41268620},
issn = {1095-8355},
support = {//This study was supported by National Natural Science Foundation of China (82272306), Taishan Scholars Program (tstp20221142), and Joint Innovation Team for Clinical & Basic Research [202409]./ ; },
abstract = {Sphingomyelin synthase 2 (SMS2) is a crucial enzyme predominantly localized to the plasma membrane, playing an essential role in sphingomyelin metabolism and signaling. SMS2 catalyzes the final step in the biosynthesis of sphingomyelin by transferring phosphocholine from phosphatidylcholine to ceramide, resulting in the production of sphingomyelin and diacylglycerol. This enzymatic activity dynamically regulates the intracellular levels of ceramide, diacylglycerol, and phosphatidylcholine, thereby influencing several critical cellular processes. SMS2 is integral to multiple signaling pathways, including TGF-β/Smad, NF-κB, and CXCL12/CXCR4, which are involved in cancer progression and platelet activation. SMS2 displays versatile enzymatic activities, including phospholipase C activity and ceramide phosphoethanolamine synthesis. Dysregulation of SMS2 is associated with various pathological conditions, such as skin barrier dysfunction, skeletal disorders, inflammatory diseases, and different types of cancer. Targeting SMS2 through inhibition or modulation demonstrates therapeutic potential in treating multiple conditions, including pancreatic cancer, Alzheimer's disease, and atherosclerosis, by impacting tumor growth dynamics and cellular migration. Given its multifaceted role in diverse pathological processes and its promise as a therapeutic target, further research on SMS2 is essential for the development of innovative treatment strategies aimed at cancer therapy, inflammation regulation, and overcoming drug resistance.},
}

@article {pmid41268476,
year = {2025},
author = {Villaman, C and Cartas-Espinel, I and Saez, M and Martin, AJM},
title = {Gaining insights into Alzheimer's disease by predicting chromatin spatial organization.},
journal = {Bioinformatics advances},
volume = {5},
number = {1},
pages = {vbaf268},
pmid = {41268476},
issn = {2635-0041},
abstract = {MOTIVATION: CTCF is a conserved protein involved in the establishment and maintenance of topologically associating domains (TADs) and loops. Alzheimer's disease (AD) represents the most common form of dementia, affecting over 50 million elderly individuals. Epigenetic alterations are a hallmark of AD, and epigenetic disruptions are able to affect CTCF binding and looping. Understanding the dynamics of CTCF loops behind AD may lead to new, undiscovered contributions of CTCF to the etiology of AD. To understand the dynamics behind CTCF loops, we developed a CTCF loop predictor using different genomic and epigenomic features, such as CTCF motif information, CTCF protein binding information, and different histone marks.

RESULTS: We obtained F-scores of over 0.9 in GM12878 and K562 cell lines. We reported the importance of each feature in classification, and compared the results with other loop predictors. After testing the predictor, we predicted loops in control and AD data, reported a score of loop disruption and selected the top disrupted loops on AD which were all previously linked with AD in bibliography. Our study contributes to a better understanding of the role of CTCF binding and CTCF loops in gene regulation, and highlights new clues about CTCF in the etiology and development of AD.

The method can be found in https://github.com/networkbiolab/jalpy.},
}

@article {pmid41268324,
year = {2025},
author = {Thakur, DK and Padole, S and Sarkar, T and Arumugam, S and Chattopadhyay, S},
title = {Liquid-Liquid Phase Separation: Mechanisms, Roles, and Implications in Cellular Function and Disease.},
journal = {FASEB bioAdvances},
volume = {7},
number = {11},
pages = {e70054},
pmid = {41268324},
issn = {2573-9832},
abstract = {Liquid-liquid phase separation is a basic biophysical process that creates essential membraneless organelles that support different cellular activities, including chromatin organization and gene expression. The malfunction of liquid-liquid phase separation (LLPS) plays a critical role in numerous diseases, such as neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), which involve TDP-43 and Tau, various cancers that utilize SPOP and YAP/TAZ proteins, and viral infections where pathogens use LLPS to replicate and avoid immune detection. This review brings together the fast-growing knowledge about LLPS across multiple scientific fields. The paper examines the physiological functions of LLPS along with its disease pathogenesis mechanisms and presents various experimental techniques (e.g., advanced microscopy, FRAP, FCS) for its investigation. It introduces new therapeutic approaches such as PTM modulation, small molecules like 1,6-hexanediol and Lipoamide, and advanced genetic tools including CRISPR and PROTACs like PSETAC, which also explores diagnostic applications. The thorough integration of knowledge presented here is essential to connect separate scientific findings while propelling research forward and turning LLPS discoveries into new biomedical developments.},
}

@article {pmid41268269,
year = {2025},
author = {Benavides, ED and Fuentes, MDM and Bell, L and Benedicenti, L and Galban, EM and Niggel, JK and Murgiano, L and Lenz, JA and Miska, JM and Amankulor, NM and Panek, WK},
title = {The role of regulatory T cells in central nervous system diseases in dogs: fighting with a double-edged sword toward translational discoveries.},
journal = {American journal of translational research},
volume = {17},
number = {10},
pages = {8222-8242},
pmid = {41268269},
issn = {1943-8141},
abstract = {Regulatory T cells (Tregs) are a recently discovered subpopulation of immunosuppressive T cells critical for sustaining immune homeostasis and self-tolerance. Depending on the disease, Tregs can alter immune responses by exerting their effects on various immunological functions. Evidence reveals that altered Treg homeostasis plays an important role in the development and progression of several central nervous system (CNS) diseases in humans. There have been positive outcomes in trials aimed at restoring Treg balance, but their clinical success has been limited. This could partly be due to a lack of an animal model to recapitulate the complex immune alterations that occur as the disease progresses. Therefore, there is a need for naturally occurring, immune-competent disease models to serve as the next critical step in translating therapy from murine models to human clinical trials. Several CNS diseases have canine analogs due to high inter-species homology of molecular signatures and clinicopathologic features. Human multiple sclerosis, Alzheimer's disease, glioblastoma, and meningioma parallel canine granulomatous meningoencephalomyelitis (GME), canine cognitive dysfunction (CCD), high-grade glioma (HGG), and canine meningioma, respectively. In addition, pet dogs share the same living environment and therefore may offer a compelling model faithfully recapitulating these diseases. This review discusses the current knowledge of Treg homeostasis and dysregulation mechanisms within canine CNS diseases, their analogous diseases in humans, and the ongoing clinical trials aimed at restoring normal Treg function. Collectively, comparative translational research investigating Treg homeostasis is needed to bridge well-designed pre-clinical canine studies with early-phase human clinical trials, ultimately benefiting the health of both species.},
}

@article {pmid41268264,
year = {2025},
author = {Chen, J and Zhao, J and Fan, Y and Jin, Y and Mi, R and Wang, H and Yu, S and Feng, X and Zhang, Y and Ren, G},
title = {Predictive value of beta amyloid, phosphorylated Tau, neurofilament light chain, and glial fibrillary acidic protein for depression in Alzheimer's disease.},
journal = {American journal of translational research},
volume = {17},
number = {10},
pages = {7789-7802},
pmid = {41268264},
issn = {1943-8141},
abstract = {OBJECTIVES: To investigate differences in biochemical markers and their association with depressive symptoms in patients with Alzheimer's disease (AD) with and without concurrent depression.

METHODS: In this retrospective case-control study, 329 AD patients admitted to Beijing Panjiayuan TCM-Western Integrated Hospital between May 2019 and May 2022 were included. Patients were categorized into a comorbid depression group (n=167) and a non-depression group (n=162) based on Cornell Scale for Depression in Dementia (CSDD) scores. Biochemical markers, including β-amyloid proteins (Aβ1-42, Aβ1-40), phosphorylated Tau proteins (p-Tau181, p-Tau217), neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP), and inflammatory cytokines, were measured and statistically analyzed.

RESULTS: High-density lipoprotein cholesterol (HDL-C) was significantly lower in the comorbid depression group (P<0.001). Levels of Aβ1-42 (P=0.012), Aβ1-40 (P=0.006), p-Tau181 (P=0.003), p-Tau217 (P=0.003), NfL (P<0.001), and GFAP (P=0.008) were significantly elevated in the depression group compared to the non-depression group. Additionally, interleukin-10 (P=0.004) and interleukin-6 (P=0.047) levels were higher, while interleukin-1β (P<0.001) was lower in the comorbid depression group. Receiver operating characteristic curve identified HDL-C (area under the curve [AUC]=0.602), p-Tau217 (AUC=0.595), NfL (AUC=0.692), GFAP (AUC=0.580), and IL-1β (AUC=0.600) as significant predictors of depression severity.

CONCLUSIONS: Specific biochemical markers, including HDL-C, Aβ42/40, p-Tau217, NfL, GFAP, and IL-1β, are independently associated with depression in AD patients. A combined biomarker model may improve prediction of comorbid depression in AD and provide guidance for personalized treatment.},
}

@article {pmid41268178,
year = {2025},
author = {Zhu, N and Altuna, M and Arranz, J and Rodriguez-Baz, Í and Sanchez-Saudinós, MB and Videla, L and Valldeneu, S and Carrera-Vega, M and Romero, S and Fortea, J and Lleó, A and Giménez, S and Alcolea, D},
title = {Sleep-related changes in astrocytic biomarkers are modulated by APOE ε4 genotype in cognitively unimpaired adults.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf437},
pmid = {41268178},
issn = {2632-1297},
abstract = {Astrocytes are key regulators of sleep and neuroinflammatory responses. However, the relationship between objective sleep parameters and astrocytic fluid biomarkers in cognitively unimpaired individuals remains unclear. We examined how sleep architecture relates to astrocytic, neuroaxonal and Alzheimer's disease-related fluid biomarkers in cognitively unimpaired adults and whether age, sex and APOE ε4 moderate these associations. This cross-sectional study included 51 cognitively unimpaired participants from the Sant Pau Initiative on Neurodegeneration cohort. One-night in-lab polysomnography was used to quantify sleep architecture, fragmentation, slow-wave activity and respiratory parameters. CSF biomarkers included glial fibrillary acidic protein (GFAP), chitinase-like-3 protein 1 (YKL-40), Aβ42, Aβ40, pTau181 and tTau; plasma biomarkers included GFAP and neurofilament light chain (NfL). Associations were analysed using Spearman correlations, multiple linear regression, and moderation models, adjusting for age, sex, body mass index, APOE ε4 status and sleep apnoea. Lighter and more fragmented sleep, characterized by longer N1 duration, increased wake after sleep onset, frequent stage transitions and elevated cortical arousal, was associated with higher CSF YKL-40, Aβ40, pTau181 and tTau (ρ = 0.32-0.62, all P < 0.05). In contrast, deeper, more consolidated sleep, indicated by longer total time of sleep, greater N3 duration and higher slow-wave activity, was associated with lower CSF GFAP and YKL-40 (ρ = -0.35 to -0.44, all P < 0.05). These associations remained significant in adjusted regression models. Plasma GFAP and NfL exhibited an inverse profile, with positive associations with deeper sleep (β: 0.16-0.18, P < 0.05) and negative associations with lighter sleep stages (β: -0.23 to -0.29, P < 0.01). Rapid eye movement (REM) sleep was also associated with astrocytic fluid biomarkers, with negative correlations for CSF and plasma GFAP (ρ = -0.49 and ρ = -0.28, respectively, all P < 0.05), while in regression models, REM duration remained a negative predictor of plasma GFAP (β = -0.23, P = 0.003) and a positive predictor of CSF YKL-40 (β = 0.12, P = 0.037). Notably, APOE ε4 consistently moderated associations between sleep and CSF YKL-40 and GFAP, while age and sex influenced plasma GFAP and CSF YKL-40, respectively (all P < 0.05). In cognitively unimpaired adults, sleep architecture is differentially associated with central and peripheral biomarkers of astrocytic activation, neuroaxonal integrity and Alzheimer's disease-related proteins. These findings support the importance of considering sleep as a key factor in the early pathophysiology of neurodegenerative disease.},
}

@article {pmid41268140,
year = {2025},
author = {Doza, A and Lin, P and Rodriguez, GM and Cigolle, C and Mahmoudi, E},
title = {Identifying Likely Incidents of Traumatic Spinal Cord Injury and Elevated Risk of Alzheimer's Disease and Related Dementia: Health Care Cost Institute Data.},
journal = {Topics in spinal cord injury rehabilitation},
volume = {31},
number = {4},
pages = {188-198},
pmid = {41268140},
issn = {1945-5763},
mesh = {Humans ; *Alzheimer Disease/epidemiology/etiology ; Male ; Female ; *Spinal Cord Injuries/epidemiology/complications ; Case-Control Studies ; Middle Aged ; *Dementia/epidemiology/etiology ; Aged ; Longitudinal Studies ; Adult ; Incidence ; Risk Factors ; },
abstract = {OBJECTIVES: To examine the association between incident traumatic spinal cord injury (TSCI) and the risk of Alzheimer's disease and related dementia (ADRD).

METHODS: This is a longitudinal case-control study. We used 2012-2019 commercial insurance claims data from the Health Care Cost Institute (HCCI) and applied semi-parametric Cox survival models to compute hazard ratio (HR) for ADRD diagnosis comparing cases with incident TSCI with their controls without TSCI, adjusting for age, sex, a set of comorbid conditions, and any use of 6 classes of prescription medications. To reduce potential selection bias, we conducted a probability matching between cases (n = 251) and controls (n = 2480) using a 1:10 ratio without replacement based on age, sex, diagnosed chronic conditions, and index year of the TSCI diagnosis.

RESULTS: Cases with incident TSCI had a higher HR of 2.39 (95% CI 1.19-4.80) for ADRD compared to their matched controls. Our sensitivity analysis of removing cases with traumatic brain injury at the index TSCI date or afterward did not change the results (HR 2.21, 95% CI 1.06-4.62).

CONCLUSION: Incident TSCI is associated with an increased risk of ADRD. Clinical guidelines for people with TSCI should consider the early and regular use of cognitive screening.},
}

Humans
*Alzheimer Disease/epidemiology/etiology
Male
Female
*Spinal Cord Injuries/epidemiology/complications
Case-Control Studies
Middle Aged
*Dementia/epidemiology/etiology
Aged
Longitudinal Studies
Adult
Incidence
Risk Factors

@article {pmid41268048,
year = {2025},
author = {Moczygemba, W and Bradley, D and Carmona, R and Celano, V and Farley, L and Valverde, S and Sampley, A and Stratton, L},
title = {Perspectives on meaningful dementia treatment and care from those with lived experience.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70175},
doi = {10.1002/trc2.70175},
pmid = {41268048},
issn = {2352-8737},
abstract = {UNLABELLED: The ongoing conversations surrounding the importance of minimal clinically important differences and descriptions of meaningful impacts must include the voices of those living with Alzheimer's disease and related dementias. To provide this perspective, members of the Alzheimer's Association Early Stage Advisory Group were asked to describe what matters most to them, their experiences with treatment, how they define meaningful care, and what would provide them with feelings of progress and hope. Responses offer differing yet complementary definitions of a quality life, ways in which clinicians and providers can recognize and support the person behind the diagnosis, and how participating in clinical trials can bring hope - both now and for the future. By centering on the lived experiences and perspectives of those people living with dementia, this article provides insight for those seeking to develop novel treatments and provide care and support, both now and in the future.

HIGHLIGHTS: Maintaining independence, purposeful living, and social connection are among what matter most to those living with dementia.Meaningful treatment and care are person-centered and responsive to the needs and wants of the person living with dementia.Participating in clinical trials can have meaningful physical, cognitive, and psychosocial impacts for those living with dementia.},
}

@article {pmid41267917,
year = {2025},
author = {Kim, S and Jang, EH and Lee, S},
title = {Effects of the MIND Diet on the Cognitive Function of Older Adults: A Systematic Review.},
journal = {Clinical nutrition research},
volume = {14},
number = {4},
pages = {318-328},
pmid = {41267917},
issn = {2287-3732},
abstract = {The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet is a brain-focused dietary pattern designed to prevent cognitive decline in older adults. This systematic review, conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, aimed to examine the association between the MIND diet and cognitive function in older adults. Relevant studies published between 2015 and 2024 were identified through comprehensive searches of PubMed and the Cochrane Library using keywords including "MIND diet," "cognitive performance," and "older adults." From a total of 138 records screened, 11 studies met the inclusion criteria after excluding reviews, meta-analyses, editorials, and those incorporating other lifestyle interventions such as physical activity or education. These studies included 7 prospective cohort studies, 2 cross-sectional studies, 1 randomized controlled trial (RCT), and 1 case-control study, comprising a total of 17,201 participants aged 57-91 years. Across studies, at least 57% of participants were women, and in the 5 studies reporting race, more than 75% were White. Dietary intake and MIND adherence were assessed primarily via food frequency questionnaires, while cognitive outcomes were evaluated using validated instruments including the Montreal Cognitive Assessment, global cognition scores, Consortium to Establish a Registry for Alzheimer's Disease tests, and magnetic resonance imaging. Six cohort and two cross-sectional studies reported significant associations between higher MIND adherence and better cognitive outcomes. One cohort study and the single RCT showed no effect. Excluding 2 studies with short durations (≤ 3 years), the remaining nine studies suggest consistent cognitive benefits of MIND adherence. Future studies should include systematic reviews and large-scale RCTs focusing on Asian populations.},
}

@article {pmid41267905,
year = {2025},
author = {Valdevila Figueira, JA and Ramírez, A and Yambay-Bautista, XR and Carvajal Parra, ID and Valdevila Santiestevan, R and Altamirano Cárdenas, LF and Pico Cucalón, MJ and Rodas, JA},
title = {Epidemiology of dementia in an Ecuadorian mental health institution.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251396049},
pmid = {41267905},
issn = {2542-4823},
abstract = {BACKGROUND: This study examines the prevalence and incidence of dementia in Ecuador, with a focus on understanding demographic and social factors associated with increased risk. Data were obtained from the Institute of Neurosciences of Guayaquil, covering patient records from 2010 to 2022.

OBJECTIVE: The purpose was to identify prevalence trends and key risk factors to inform targeted prevention and early intervention efforts in high-risk groups.

METHODS: This observational, correlational study analyzed patient data to estimate dementia prevalence and incidence. Statistical analyses included descriptive statistics to calculate overall and age-specific prevalence rates, while incidence was calculated per 1000 person-years. Correlations and chi-square analyses were used to evaluate associations between dementia and potential risk factors, including age, gender, education level, and marital status.

RESULTS: The overall prevalence of dementia was 3.1%, with higher rates among women (1.8%) compared to men (1.3%). Dementia incidence was calculated at 2.4 per 1000 person-years. Prevalence increased significantly with age, from 1.2% in individuals aged 65-69 to 54.8% in those aged 95 and older. Advanced age, female gender, lower education levels, and lack of a marital partner were associated with higher dementia prevalence.

CONCLUSIONS: These findings highlight a rising dementia prevalence in Ecuador, particularly among women and older individuals, with social and educational factors contributing to increased risk. The results underscore the need for tailored dementia prevention and early intervention strategies, especially as prevalence rates continue to rise across Latin America.},
}

@article {pmid41267904,
year = {2025},
author = {Zhao, F and Li, Y and Yi, C and Li, X and Huang, G and Chen, X and Li, Y and Zhang, J},
title = {Global, regional, and national burdens of early-onset Alzheimer's disease and other dementias in women, 1990 to 2021.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395223},
pmid = {41267904},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease and other dementias disproportionally impacts women. Novel treatment makes understanding of early-onset cases unprecedentedly important.

OBJECTIVE: We aimed to examine Alzheimer's disease and other dementias incidence, DALYs, trends, and risk factors among women aged under 65 years from 1990 to 2021.

METHODS: Using Global Burden of Diseases Study, we estimated the trend of Alzheimer's diseases and other dementias age-standardized incidence and disability-adjusted life-years (DALYs) among women aged under 65 years by social development index (SDI) worldwide during 1990 to 2021.

RESULTS: Globally, in 2021 there were 4.3 million prevalent cases among middle-aged women, with the incident cases doubled from 0.4 million to 0.8 million during 1990-2021. The largest increases in incidence and DALYs were found in high-middle SDI countries (0.27%/year) and low-middle SDI countries (0.19%/year), respectively. The incidence rate doubled once with every five years of age increase. The two contributors, which were high body mass index and high fasting plasma glucose, rapidly grew from 1990 to 2021.

CONCLUSIONS: The substantial increase of early-onset Alzheimer's disease and other dementias among middle-aged women requires attention, especially targeted at the increasing reversible lifestyle risk factors.},
}

@article {pmid41267903,
year = {2025},
author = {Bergamino, M and Nelson, MR and Keeling, E and Stokes, AM and , },
title = {Assessment of microstructural changes in white matter hyperintensities in aging and mild cognitive impairment revealed by advanced diffusion MRI.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395938},
pmid = {41267903},
issn = {2542-4823},
abstract = {BACKGROUND: White matter hyperintensities (WMHs) are common in older adults and appear as abnormal signal on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). They are often linked to demyelination, axonal damage, and gliosis, as well as vascular changes. WMHs occur in both normal aging and mild cognitive impairment (MCI), where they may contribute to cognitive decline.

OBJECTIVE: The study objectives were to determine whether advanced diffusion MRI (dMRI) techniques can detect distinct microstructural changes within WMHs in individuals with MCI compared to healthy controls and to evaluate relationships between these measures and cognitive performance.

METHODS: Advanced dMRI techniques were used to assess WMH microstructural changes in normal aging (n = 55) and MCI (n = 46) participants from the ADNI database. WMHs and their surrounding penumbra were identified using an automated approach. Microstructural characteristics, derived from free-water (FW) diffusion tensor imaging and diffusion kurtosis imaging, were evaluated between groups and white matter regions. Associations between these measures and cognitive performance (assessed by the Mini-Mental State Exam) were examined.

RESULTS: Across both groups, WMHs showed higher FW and lower FW-fractional anisotropy and kurtosis metrics compared to normal-appearing white matter, indicating widespread microstructural alterations. No groupwise microstructural differences were observed within corresponding tissue types. In the MCI group, kurtosis metrics within WMHs correlated with cognitive performance.

CONCLUSIONS: These findings highlight the complexity of WMH-related microstructural changes and suggest that advanced dMRI biomarkers may offer valuable insights into the role of white matter changes in aging and cognitive decline.},
}

@article {pmid41267515,
year = {2025},
author = {Ünal, D and Sarıköse Özgüven, A},
title = {Exosomes: New Biomarker and Therapeutic Candidates in Autism Spectrum Disorder Research.},
journal = {Acta neuropsychiatrica},
volume = {},
number = {},
pages = {1-47},
doi = {10.1017/neu.2025.10047},
pmid = {41267515},
issn = {1601-5215},
abstract = {BACKGROUND: There is no recognized cure or specific biomarker for autism spectrum disorder (ASD). Exosomes are small vesicles that carry proteins, lipids, and nucleic acids. They have been investigated for diseases such as Parkinson's and Alzheimer's. As the conclusions were on the biological utility of exosomes as a non-invasive brain biopsy, some animal, human, and in vitro exosome studies have also been presented in the ASD field. The purpose of this review is to compile the studies that have established a relationship between ASD and exosomes so far and discuss their potential for linking the gap between the laboratory and clinic.

METHODS: In this systematic review, 31 PubMed articles were identified using the keywords "exosomal," "exosome," and "autism spectrum disorder." After excluding 16 reviews, 4 irrelevant studies, and 1 preprint, and adding 5 relevant articles, 15 research articles were included based on PRISMA criteria. The articles were investigated and reviewed by both authors. Their methodology and results are also discussed according to two main streams in studies.

RESULTS: Numerous studies have identified potential biomarkers, including mitochondrial DNA (mtDNA7S), cytokines including IL-1β, TNF-α, and IL-6, and different types of RNAs by comparing the exosomal contents of ASD patients or models with controls. In studies that focused on treatment, behavioral improvements were shown in ASD model mice.

CONCLUSION: Since there are presently no reliable biomarkers or effective treatments for ASD, exosome-based research offers a promising avenue for early diagnosis and the creation of tailored therapies.},
}

@article {pmid41267138,
year = {2025},
author = {Zafari, R and Goudarzi, N and Kamroo, A and Tafti, MF and Ghorbani, A and Talebian, N and Najafi, S and Shahbazian, S and Rahmanian, M and Parvardeh, S and Dargahi, L and Nassiri-Asl, M},
title = {The effects of polyphenols on gut microbial metabolites and composition in neurodegenerative diseases: a systematic review.},
journal = {Nutrition & metabolism},
volume = {22},
number = {1},
pages = {142},
pmid = {41267138},
issn = {1743-7075},
}

@article {pmid41266915,
year = {2025},
author = {Veloso-Luis, A and Diaconu, S and Mendes, M and Ferreira, JJ},
title = {Towards effective interventions: scoping review on prevention and modifiable risk factors of neurodegenerative diseases.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {41266915},
issn = {1590-3478},
abstract = {BACKGROUND: Life expectancy is increasing with help of modern medicine, but well-being is not always guaranteed for elderly, especially when affected by diseases that hinder autonomy and to which there is still no cure. Amongst late-life related diseases are those affecting cognition, such as dementias and Alzheimer's Disease, which occurrence has been reported as one of the top Global Burden of Disease with prospective exponential growth for the next 30 years. Other reasons for dependency of elderly are health conditions affecting movement. Some of these are associated with neurodegenerative diseases (NDD), such as Parkinson's Disease, whose rise in prevalence is equally concerning and attending a pandemic status.

METHODS: This scoping review is based on selected systematic reviews of interventions for the prevention or risk reduction of NDD. It summarizes existing studies, their efficacy and limitations, the coverage of topics and diseases to which scientific evidence of protective effect has become available in the last decade.

RESULTS: 75 systematic reviews were included, from which 75% were dedicated to risks associated with cognitive disorders. Movement disorders are facing scarcity of studies on prevention cues. Although growing in number, studies remain cautious in concluding preventive efficacy.

CONCLUSIONS: Nevertheless, our synthesis reveals strong evidence supporting the protective role of several non-genetic factors in delaying NDD onset. This review provides a practical resource for clinicians and policymakers in developing integrated, community-level prevention strategies. Findings suggest that interdisciplinary, multifactorial approaches may offer the greatest potential for reducing the burden of neurodegenerative diseases.},
}

@article {pmid41266692,
year = {2025},
author = {Shafi, A and Akmal, M and Sethi, A and Chauhdary, Z},
title = {A mechanistic insight of neuro-inflammation signaling pathways and implication in neurodegenerative disorders.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41266692},
issn = {1568-5608},
abstract = {Neuroinflammation is a multifaceted and carefully regulated process within the central nervous system (CNS) that serves a dual function in both protecting neurons and contributing to neurodegenerative processes. This process is mainly driven by activated microglia, astrocytes, and immune cells that infiltrate in response to neuronal damage, infections, or toxic exposures. This review emphasizes the key molecular pathways involved in neuroinflammatory reactions, such as the JAK/STAT, NF-κB, NLRP3 inflammasome, and MAPK signaling pathways. Each of these pathways plays a role in the generation and release of pro-inflammatory substances that maintain and increase inflammation in the CNS. Furthermore, the review examines the significance of crucial pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) as well as the chemokines CCL2 and CXCL10, which coordinate the recruitment of immune cells and contribute to neuronal injury. Gaining an understanding of the interactions among these signaling pathways and mediators sheds light on the molecular mechanisms connected to various neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Targeting these inflammatory signaling networks may provide valuable therapeutic approaches to manage neuroinflammation and avert its long-lasting neurotoxic effects.},
}

@article {pmid41266616,
year = {2025},
author = {Heininger, H and Feng, X and Altunkaya, A and Zheng, F and Stockinger, F and Wefers, B and Müller, SA and Giesbertz, P and Tschirner, SK and Shqau, D and Adelsberger, H and Ponomarenko, A and Fenzl, T and Alzheimer, C and Lichtenthaler, SF and Huth, T},
title = {BACE1 regulates sleep-wake cycle through both enzymatic and non-enzymatic actions.},
journal = {EMBO reports},
volume = {},
number = {},
pages = {},
pmid = {41266616},
issn = {1469-3178},
support = {HU 2358/1-1//Deutsche Forschungsgemeinschaft (DFG)/ ; PO1799/6-1//Deutsche Forschungsgemeinschaft (DFG)/ ; EXC 2145 SyNergy - ID 390857198//Deutsche Forschungsgemeinschaft (DFG)/ ; FKZ161L0214C,ClinspectM//Bundesministerium für Bildung und Forschung (BMBF)/ ; },
abstract = {The β-secretase BACE1 has become a prime target in Alzheimer's disease (AD) therapy, because it drives the production of pathogenic amyloid β peptides. However, clinical trials with BACE1-targeting drugs were halted due to adverse effects on cognitive performance. We propose here that cognitive impairment by BACE1 inhibitors may be a corollary of a higher function of BACE1 related to proper sleep regulation. To address non-enzymatic effects of BACE1 on ion channels likely involved in the sleep-wake cycle, we analyze sleep patterns in both BACE1-KO mice and a newly generated transgenic line expressing a proteolysis-deficient BACE1 variant (BACE1-KI). We find that BACE1-KI and BACE1-KO mice display common and distinct sleep-wake disturbances. Compared with their respective wild-type littermates, both mutant lines sleep less during the light phase (when they preferentially rest). Furthermore, transition rates between wake and sleep states are altered, as are sleep spindles and EEG power spectra mainly in the gamma range. Thus, a better understanding of how BACE1 interferes with sleep-modulated behaviors is needed if clinical trials with BACE1-targeted inhibitors are to resume.},
}

@article {pmid41266593,
year = {2025},
author = {Trudel, L and Therriault, J and Macedo, AC and Woo, MS and Rahmouni, N and Aumont, É and Servaes, S and Hosseini, SA and Ferrari-Souza, JP and Bellaver, B and Ferreira, PL and Chan, T and Wang, YT and Fernandez-Arias, J and Zheng, Y and Hall, B and Stevenson, J and Hopewell, R and Hsiao, CH and Montembeault, M and Klostranec, J and Iturria-Medina, Y and Vitali, P and Karikari, TK and Benedet, AL and Ashton, NJ and Zimmer, E and Gauthier, S and Pascoal, TA and Zetterberg, H and Blennow, K and Rosa-Neto, P},
title = {APOE ε4 potentiates tau related reactive astrogliosis assessed by cerebrospinal fluid YKL40 in Alzheimer's disease.},
journal = {Communications medicine},
volume = {5},
number = {1},
pages = {484},
pmid = {41266593},
issn = {2730-664X},
support = {NIRG-12-92090, NIRP-12-259245/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: Glial responses are involved in neurodegenerative processes, with tau pathology often associated with increased glial inflammatory responses in Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele, the major genetic susceptibility gene for AD, might contribute to this process by modulating both tau pathology and inflammatory cascades in the brain.

METHODS: We used data from the Translational Biomarkers of Alzheimer's Disease (TRIAD) cohort (n = 137) to investigate the association between YKL-40, a marker of reactive astrogliosis, and tau burden measured with PET imaging, while also exploring the involvement of APOE ε4 carriership. Statistical analyses included correlation and regression models controlling for age and sex.

RESULTS: Here we show that tau pathology is positively associated with YKL-40 levels, reflecting regional patterns of astrocyte activity in the brain. Furthermore, this association is more widespread in individuals carrying the APOE ε4 allele, suggesting a genotype-specific modulation of the glial neuroinflammatory response.

CONCLUSIONS: Our findings demonstrate a link between tau accumulation and astrocyte-mediated neuroinflammation in AD and highlight the modulatory role of APOE ε4 in this process. Taken together, our findings help inform the multifaceted role of tau-associated neuroinflammation in the progression of AD.},
}

@article {pmid41266291,
year = {2025},
author = {Prasad, H},
title = {NHE9 and Endosomal pH: Converging Mechanisms in Neurodevelopmental, Psychiatric and Neurodegenerative Disorders.},
journal = {The European journal of neuroscience},
volume = {62},
number = {10},
pages = {e70334},
doi = {10.1111/ejn.70334},
pmid = {41266291},
issn = {1460-9568},
support = {ANRF/ECRG/2024/002999/LS//Prime Minister Early Career Research Grant/ ; //Centre for Brain Research/ ; },
mesh = {Humans ; *Sodium-Hydrogen Exchangers/metabolism/genetics ; *Endosomes/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/genetics ; Hydrogen-Ion Concentration ; *Mental Disorders/metabolism/genetics ; *Neurodevelopmental Disorders/metabolism/genetics ; },
abstract = {The Na[+](K[+])/H[+] exchanger NHE9 (SLC9A9), a key regulator of endosomal pH, is increasingly recognized as a contributor to a shared pathomechanism-endosomal dysfunction-across neurodevelopmental, psychiatric and neurodegenerative disorders. Enriched in the brain, NHE9 acts as a leak pathway for protons to balance vacuolar ATPase-driven acidification, fine-tuning luminal pH essential for synaptic, circuit and behavioural functions. Structurally, NHE9 operates as a dimer via an elevator-like transport mechanism. Functionally, it modulates neuronal and glial processes-such as presynaptic Ca[2+] dynamics, synaptic vesicle exocytosis, endocytic recycling and glutamate clearance-all critical to neurotransmission and synaptic plasticity. Consequently, NHE9 has been implicated in a range of brain disorders, including autism, schizophrenia and Alzheimer's disease. Genetic studies also associate NHE9 with interferon-β therapy response in multiple sclerosis and chronic pain, underscoring broader neurological significance. Despite growing evidence, mechanistic links between NHE9 dysfunction and clinical phenotypes across the neurodevelopmental-neurodegenerative continuum remain poorly defined. This narrative review synthesizes conceptual advances and findings from cellular models, animal studies and human genetics to construct a model positioning NHE9 dysfunction as an upstream pathogenic factor across diverse brain disorders. Critical knowledge gaps include genotype-phenotype correlations, isoform-specific roles and neuron-glia interactions. Patient-derived systems and in vivo models will be essential for elucidating mechanisms and developing targeted therapies. Identifying a convergent mechanism of endosomal pH dysregulation across disorders would enable pharmacological control of NHE9. Future research should define strategies to restore endosomal homeostasis, with potential to interrupt pathogenic feedforward loops that worsen symptoms and drive disease progression.},
}

Humans
*Sodium-Hydrogen Exchangers/metabolism/genetics
*Endosomes/metabolism
Animals
*Neurodegenerative Diseases/metabolism/genetics
Hydrogen-Ion Concentration
*Mental Disorders/metabolism/genetics
*Neurodevelopmental Disorders/metabolism/genetics

@article {pmid41266285,
year = {2025},
author = {Lee, ML and Choi, SE and Mukherjee, S and Scollard, P and Nakano, C and Gibbons, LE and Culhane, J and Gauthreaux, K and Chan, KCG and Biber, S and Stephens, K and Kukull, W and Trittschuh, E and Mez, J and Saykin, AJ and Turner, S and Archer, D and Durant, A and Dumitrescu, L and Hohman, T and Crane, PK},
title = {Bridging the gap: addressing NACC's evolving cognition batteries across UDS versions.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70832},
doi = {10.1002/alz.70832},
pmid = {41266285},
issn = {1552-5279},
support = {U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG062429 (to J.B.)/AG/NIA NIH HHS/United States ; P30 AG066468 (to O.L.)/AG/NIA NIH HHS/United States ; P30 AG062421 (to B.H.)/AG/NIA NIH HHS/United States ; P30 AG066509 (to T.G.)/AG/NIA NIH HHS/United States ; P30 AG066514 (to M.S.)/AG/NIA NIH HHS/United States ; P30 AG066530 (to H.C.)/AG/NIA NIH HHS/United States ; P30 AG066507 (to M.A.)/AG/NIA NIH HHS/United States ; P30 AG066444 (to D.H.)/AG/NIA NIH HHS/United States ; P30 AG066518 (to L.S.)/AG/NIA NIH HHS/United States ; P30 AG066512 (to T.W.)/AG/NIA NIH HHS/United States ; P30 AG066462 (to S.S.)/AG/NIA NIH HHS/United States ; P30 AG072979 (to D.W.)/AG/NIA NIH HHS/United States ; P30 AG072972 (to C.D.)/AG/NIA NIH HHS/United States ; P30 AG072976 (to A.S.)/AG/NIA NIH HHS/United States ; P30 AG072975 (to J.A.S.)/AG/NIA NIH HHS/United States ; P30 AG072978 (to A.M.)/AG/NIA NIH HHS/United States ; P30 AG072977 (to R.V.)/AG/NIA NIH HHS/United States ; P30 AG066519 (to F.L.)/AG/NIA NIH HHS/United States ; P30 AG062677 (to R.P.)/AG/NIA NIH HHS/United States ; P30 AG079280 (to J.L.)/AG/NIA NIH HHS/United States ; P30 AG062422 (to G.R.)/AG/NIA NIH HHS/United States ; P30 AG066511 (to A.L.)/AG/NIA NIH HHS/United States ; P30 AG072946 (to L.V.E.)/AG/NIA NIH HHS/United States ; P30 AG062715 (to S.A.)/AG/NIA NIH HHS/United States ; P30 AG072973 (to R.S.)/AG/NIA NIH HHS/United States ; P30 AG066506 (to G.S.)/AG/NIA NIH HHS/United States ; P30 AG066508 (to S.S.)/AG/NIA NIH HHS/United States ; P30 AG066515 (to V.H.)/AG/NIA NIH HHS/United States ; P30 AG072947 (to S.C.)/AG/NIA NIH HHS/United States ; P30 AG072931 (to H.P.)/AG/NIA NIH HHS/United States ; P30 AG066546 (to S.S.)/AG/NIA NIH HHS/United States ; P30 AG086401 (to E.R.)/AG/NIA NIH HHS/United States ; P30 AG086404 (to G.R.)/AG/NIA NIH HHS/United States ; P20 AG068082 (to A.J.)/AG/NIA NIH HHS/United States ; P30 AG072958 (to H.W.)/AG/NIA NIH HHS/United States ; P30 AG072959 (to J.L.)/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Neuropsychological Tests/standards ; Aged ; Magnetic Resonance Imaging ; Executive Function/physiology ; *Cognition/physiology ; Apolipoproteins E/genetics ; *Cognitive Dysfunction/diagnosis ; Reproducibility of Results ; },
abstract = {INTRODUCTION: The Uniform Data Set (UDS) version 3 neuropsychological battery replaced old tests used in UDS 1&2. Here, we validate domain scores for memory, executive functioning, and language co-calibrated across UDS eras.

METHODS: We compared co-calibrated and harmonized domain scores to traditional equipercentile equating in a crosswalk sample. We also validated domain scores by evaluating associations with magnetic resonance imaging (MRI) findings and APOE genotype across UDS eras.

RESULTS: We co-calibrated cognitive domain scores for 49,396 participants, about 25% of whom had data spanning UDS 1&2 and UDS 3 eras. Crosswalk sample (n = 955) correlations between UDS 1&2 and UDS 3 domain scores and equipercentile scores were similar. Harmonized domain scores had statistically significant associations in imaging (n = 2458) and APOE validity assessments (n = 27,857). Significant differences in domain scores were found across UDS eras.

DISCUSSION: Longitudinal co-calibrated and harmonized cognitive domain scores bridge the gap across UDS versions and are available from the National Alzheimer's Coordinating Center.

HIGHLIGHTS: Co-calibrated domain scores are validated in the NACC crosswalk sample. Co-calibrated domain scores are validated with neuroimaging measures. Co-calibrated domains scores are validated with APOE genotype. Co-calibrated domain scores reveal cognitive performance differences in enrollment visit depending on UDS era. Co-calibrated domain scores are readily available to investigators utilizing NACC's rich dataset.},
}

Humans
Male
Female
*Neuropsychological Tests/standards
Aged
Magnetic Resonance Imaging
Executive Function/physiology
*Cognition/physiology
Apolipoproteins E/genetics
*Cognitive Dysfunction/diagnosis
Reproducibility of Results

@article {pmid41266256,
year = {2025},
author = {Hoenig, MC and Dzialas, V and Doering, E and Bischof, GN and van Eimeren, T and Drzezga, A and , },
title = {Modifiable Factors Associated with the Longitudinal Increase and Spatial Extent of Tau Pathology in Alzheimer Disease.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.270593},
pmid = {41266256},
issn = {1535-5667},
abstract = {There are 14 modifiable factors that are associated with a significantly lower risk of dementia. We tested the interactive effect of modifiable factors, genetic determinants, and initial pathologic burden on the spatial progression and local amplification of tau pathology. Methods: In total, 162 amyloid-positive individuals were included, for whom longitudinal [[18]F]AV-1451 PET scans, baseline information on global amyloid burden, ApoE4 status, body mass index (BMI), hypertension, education, neuropsychiatric symptom severity, and demographic information were available in the Alzheimer Disease Neuroimaging Initiative. All [[18]F]AV-1451 scans were intensity-standardized (reference: inferior cerebellum), z-transformed (control sample: 147 amyloid-negative subjects), thresholded (z score, >1.96), and converted to volume maps. Longitudinal tau changes were then assessed in terms of tau spatial extent (i.e., newly affected volume at follow-up) and tau level rise (i.e., tau increase in previously affected volume). These 2 measures were entered as dependent variables in linear mixed-effects models, including baseline modifiable risk factors (BMI, education, hypertension, neuropsychiatric symptom severity), global amyloid, tau volume or tau burden, ApoE4 status, clinical stage, sex, and age as predictors. Next, we tested the interactive effects between baseline amyloid or tau burden with the 4 modifiable factors on tau extent or tau level rise, respectively. Results: Greater tau extent was linked to higher BMI (β = 0.002; 95% CI, 0.0003-0.003), ApoE4 status (β = 0.024; 95% CI, 0.001-0.046), and baseline tau volume (β = 0.207; 95% CI, 0.107-0.308) across groups. In terms of tau level rise, we observed that absence of hypertension (β = 0.295; 95% CI, -0.477 to -0.114), dementia group (β = 0.305; 95% CI, 0.088-0.522), and BMI (β = 0.011; 95% CI, 0.00004-0.022) were linked to increased tau burden. A load-dependent effect of baseline amyloid and tau volume/burden was found for both tau extent (β = -0.005; 95% CI, -0.008 to -0.002) and tau level rise (β = -0.003; 95% CI, -0.005 to -0.001). Higher amyloid and BMI (β = 0.001; 95% CI, 0.0004-0.001) and lower education and higher tau burden (β = -0.035; 95% CI, -0.064 to -0.006) were linked to greater tau level rise. Conclusion: Education, BMI, and hypertension differentially influence tau's spatial extent and increase by its interaction with initial pathologic burden. Timely modification of these factors may overall slow tau progression.},
}

@article {pmid41265806,
year = {2025},
author = {Zhang, M and Wei, W and Zu, H},
title = {DHCR24 knockdown-induced cellular cholesterol deficiency triggers tau hyperphosphorylation at Thr181, Ser199 and Ser202/Thr205 via p38 MAPK/JNK signaling.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112254},
doi = {10.1016/j.cellsig.2025.112254},
pmid = {41265806},
issn = {1873-3913},
abstract = {Cholesterol deficiency is implicated in Alzheimer's disease (AD) pathogenesis, yet its regulatory role in tau phosphorylation remains unclear. We investigated whether the loss of 24-dehydrocholesterol reductase (DHCR24), a key enzyme in cholesterol biosynthesis, drives tau hyperphosphorylation via p38 MAPK and JNK signaling pathways in SH-SY5Y neuroblastoma cells. Using lentiviral vectors encoding DHCR24-cDNA or DHCR24-shRNA, we established stable DHCR24-overexpression and DHCR24-knockdown SH-SY5Y cell models. Filipin III staining and UPLC-MS/MS demonstrated that DHCR24 knockdown significantly reduced cellular cholesterol levels, whereas overexpression raised cholesterol levels. Immunoblotting showed selective increases in tau phosphorylation at Thr181, Ser199 and Ser202/Thr205 under DHCR24 deficiency; total tau remained unchanged. Concomitantly, phospho-p38 and phospho-JNK rose 1.5- to 2.5-fold without alterations in total kinase levels, indicating pathway activation. To test causality, DHCR24-silenced cells were treated with escalating doses of the p38 inhibitor SB203580 (0-40 μM) or the JNK inhibitor SP600125 (0-40 μM). Both compounds restored tau phosphorylation to baseline in a concentration-dependent manner, with maximal suppression at 40 μM (SB203580) and 20-40 μM (SP600125). Collectively, these data establish DHCR24-controlled cholesterol homeostasis as a molecular rheostat of tau pathology through p38/JNK signaling, and nominate this axis for therapeutic intervention in AD.},
}