@article {pmid41559842,
year = {2026},
author = {Sánchez Milán, JA and Mulet, M and Molet, I and Lisa-Molina, J and Font-Alberich, M and Lorca, C and Gea-Sánchez, M and Bellon, F and Batalla, I and Meana, JJ and Callado, LF and Morentin, B and Ramos-Miguel, A and Kalaria, RN and Serra, A and Gallart-Palau, X},
title = {Brain and circulating EV proteome signatures in schizophrenia as prognostic markers for age-related dementia.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02223-z},
pmid = {41559842},
issn = {2051-5960},
support = {IT1512/22//Eusko Jaurlaritza/ ; PID2020-114885RB-C21//Agencia Estatal de Investigación/ ; 2022 DI 100//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; 2023 LLAV 00056//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; PIRS23/02//Diputació de Lleida, Spain/ ; PIRS22/03//Diputació de Lleida, Spain/ ; X25022//Universitat de Lleida/ ; PI22/00443//Instituto de Salud Carlos III/ ; PRTR-C17.I1//NextGenerationEU/ ; },
abstract = {Schizophrenia (SZ) is epidemiologically linked to an increased risk of developing age-related dementias (ARD) predominantly characterized by Alzheimer's disease and vascular dementia. However, the molecular mechanisms underlying this association remain insufficiently elucidated. Extracellular vesicles (EVs) play a critical role in neuropathological processes and offer a promising avenue for identifying shared disease mechanisms and potential circulating markers for patient stratification. Here we used a two-phase systems biology approach integrating discovery-driven proteomics with a targeted validation strategy using data-independent acquisition mass spectrometry (DIA-MS) in a large, independent SZ cohort. First, we analyzed brain-derived EVs (bEVs) from post-mortem SZ and ARD subjects to identify shared molecular signatures. Next, we validated the presence and circulation of these bEV markers in circulating plasma EVs (pEVs) using DIA-MS data. Remarkably, SZ and ARD bEV proteome and peptidome showed overlapping alterations in neuronal connectivity, synaptic integrity, neuroinflammation, and metabolism. Unsupervised clustering analysis of correlated bEV/pEV markers stratified SZ patients into two clusters: high dementia risk and control-like profiles. Collectively, these data emphasize the significance of bEVs as crucial mediators of shared neuropathogenic mechanisms in SZ, and ARD. Furthermore, we identified a set of pEVs markers, including proteins and specific peptides, with a robust and promising bench-to-bedside trajectory that may facilitate the stratification of SZ patients at risk for ARD.},
}

@article {pmid41559829,
year = {2026},
author = {Ma, C and Ye, Y and Shi, X and Li, N and Mu, Z and Tan, T and Yin, H and Dai, J and Liu, Y and Chen, H},
title = {Correction: Photobiomodulation mitigates blood-brain barrier disruption in APP/PS1 mouse model of Alzheimer's disease by activating the AMPK pathway.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {16},
pmid = {41559829},
issn = {1758-9193},
}

@article {pmid41559471,
year = {2026},
author = {Liu, T and Chen, D and Liu, F and Sun, Y},
title = {ZFP36-mediated ZBP1 degradation inhibits microglia pro-inflammatory and NLRP3 inflammasome activation in Alzheimer's disease.},
journal = {Cell biology and toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10565-026-10139-6},
pmid = {41559471},
issn = {1573-6822},
abstract = {Alzheimer's disease (AD) is a heterogeneous disease with limited treatment efficacy. Identifying novel molecular targets and mechanisms is therefore crucial for developing therapeutic strategies. Zinc finger protein 36 (ZFP36) has not been reported in AD. This study found that the hippocampus of APP/PS1 mice showed ZFP36 upregulation. Using recombinant adeno-associated virus to overexpress ZFP36 improved the cognitive function of APP/PS1 mice, as assessed by Morris maze and Y maze tests. Furthermore, ZFP36 overexpression reduced Aβ deposition, expression of pro-inflammatory markers, and inhibited NLRP3 inflammasome activation in the hippocampus. These inhibitory effects of ZFP36 overexpression on the aforementioned proteins were also observed in Aβ1-42-treated BV-2 cells. mRNA sequencing identified Z-DNA Binding Protein 1 (ZBP1) as a target of ZFP36. After ZFP36 overexpression, ZBP1 was downregulated in the hippocampus and Aβ1-42-treated BV-2 cells. The interaction between ZFP36 and ZBP1 RNA was verified by RIP-PCR, and ZFP36 was shown to promote the degradation of ZBP1 mRNA. The inhibitory effects of ZFP36 on the NLRP3 inflammasome activation and microglial pro-inflammatory activation was reversed by ZBP1 overexpression. In summary, ZFP36 inhibits microglia pro-inflammatory and NLRP3 inflammasome activation through promoting the degradation of ZBP1 mRNA, thereby ameliorating cognitive deficits of APP/PS1 mice.},
}

@article {pmid41559358,
year = {2026},
author = {Wang, K and Shao, B and Zeng, Q and Liu, X and Li, K and Luo, X},
title = {Trajectory of stratum radiatum, lacunosum and moleculare integrity in Alzheimer's disease continuum.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-35610-6},
pmid = {41559358},
issn = {2045-2322},
support = {82202090//National Natural Science Foundation of China/ ; 82271936//National Natural Science Foundation of China/ ; },
abstract = {The atrophy of the hippocampus and its subfields represents a critical hallmark of neurodegeneration in Alzheimer's Disease (AD). However, the trajectories of stratum radiatum, lacunosum, and moleculare (SRLM) integrity along the AD continuum are still unclear. This study encompassed 178 amyloid-negative cognitively unimpaired controls (CU A-), 91 amyloid-positive cognitively unimpaired individuals (CU A+), 90 amyloid-positive patients with mild cognitive impairment (MCI A+), and 14 amyloid-positive AD patients (AD A+), to model the AD continuum. T1-weighted images facilitated the hippocampal volume segmentation, while T2-weighted images enabled both visual hippocampal atrophy and SRLM assessments. Furthermore, the associations between hippocampal metrics and cognitive function were evaluated. Across the AD continuum, CU A+ individuals exhibited lower visual SRLM integrity score compared to their CU A- counterparts. Both MCI A+ and AD A+ groups displayed reduced SRLM integrity score, increased visual hippocampal atrophy score, and decreased hippocampal volume compared to CU A-. Correlational analyses revealed significant associations between hippocampal metrics and cognitive function. Hippocampal atrophy progresseses along the AD continuum, with visual SRLM integrity score declining in the early stages of AD. These results suggest that SRLM integrity may serve as a sensitive marker for early detection of AD.},
}

@article {pmid41559192,
year = {2026},
author = {Hu, EY and Oleshko, S and Firmani, S and Cheng, H and Zhu, Z and Ulmer, M and Arnold, M and Colomé-Tatché, M and Tang, J and Xhonneux, S and Marsico, A},
title = {Enhancing link prediction in biomedical knowledge graphs with BioPathNet.},
journal = {Nature biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {41559192},
issn = {2157-846X},
abstract = {Understanding complex interactions in biomedical networks is crucial for advancements in biomedicine, but traditional link prediction (LP) methods are limited in capturing this complexity. We present BioPathNet, a graph neural network framework based on the neural Bellman-Ford network (NBFNet), addressing limitations of traditional representation-based learning methods through path-based reasoning for LP in biomedical knowledge graphs. Unlike node-embedding frameworks, BioPathNet learns representations between node pairs by considering all relations along paths, enhancing prediction accuracy and interpretability, and allowing visualization of influential paths and biological validation. BioPathNet leverages a background regulatory graph for enhanced message passing and uses stringent negative sampling to improve precision and scalability. BioPathNet outperforms or matches existing methods across diverse tasks including gene function annotation, drug-disease indication, synthetic lethality and lncRNA-target interaction prediction. Our study identifies promising additional drug indications for diseases such as acute lymphoblastic leukaemia and Alzheimer's disease, validated by medical experts and clinical trials. In addition, we prioritize putative synthetic lethal gene pairs and regulatory lncRNA-target interactions. BioPathNet's interpretability will enable researchers to trace prediction paths and gain molecular insights.},
}

@article {pmid41559153,
year = {2026},
author = {Peter, Q and Taylor, C and Lapinska, U and Wei, J and Michaels, TCT and Arosio, P and Linse, S and Knowles, TPJ},
title = {Oligomers mediate the spatial transmission of Aβ peptide aggregation.},
journal = {Communications chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42004-025-01837-z},
pmid = {41559153},
issn = {2399-3669},
support = {674979//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; },
abstract = {Alzheimer's disease (AD) is marked by the abnormal aggregation of amyloid-beta peptides within the central nervous system. The formation of amyloid fibrils from amyloid-beta peptides is a hallmark of AD Here, we demonstrate that the aggregation of amyloid-beta 42 spreads both spatially and temporally. By measuring the spatial propagation of amyloid-beta in macroscopic capillaries and performing Monte Carlo simulations, we show that this spreading occurs through a diffusion mechanism involving oligomers in solution. These species, catalytically produced through spontaneous secondary nucleation, significantly accelerate the propagation velocity of the reaction wavefront. Our findings suggest that, in addition to their potential role in toxicity, these oligomers in solution are key drivers of the spatial spreading of aggregation and can therefore be considered key targets for therapeutic intervention.},
}

@article {pmid41558999,
year = {2026},
author = {Hiransuthikul, A and Thanapornsangsuth, P and Luechaipanit, W and Haethaisong, T and Ubolyam, S and Apornpong, T and Han, WM and Kerr, S and Avihingsanon, A and , },
title = {Blood-based Alzheimer's disease biomarkers and cognitive trajectories in older people with HIV with undetectable viral loads.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71101},
doi = {10.1002/alz.71101},
pmid = {41558999},
issn = {1552-5279},
support = {//U.S. National Institutes of Health's (NIH)/ ; },
mesh = {Humans ; Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/blood/diagnosis ; *HIV Infections/blood/complications ; *tau Proteins/blood ; *Viral Load ; *Cognitive Dysfunction/blood ; Middle Aged ; Neurofilament Proteins/blood ; *Glial Fibrillary Acidic Protein/blood ; Aged ; Mental Status and Dementia Tests/statistics & numerical data ; Thailand ; },
abstract = {INTRODUCTION: Cognitive impairment among people with HIV (PWH) remains common, yet underlying mechanisms remain unclear. Alzheimer's disease (AD) is the leading cause of dementia, and blood-based biomarkers offer a promising diagnostic alternative. We evaluated phosphorylated-tau 217 (p-tau217), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) as predictors of cognitive decline among virologically suppressed older PWH.

METHODS: Thai PWH aged ≥50 years with plasma viral loads <50 copies/mL completed the Montreal Cognitive Assessment (MoCA) at baseline (2015-2017) and a follow-up visit (2021-2024). Associations between each biomarker and cognitive trajectories were assessed using multivariate mixed-effects models.

RESULTS: Among 255 participants followed for a median of 5.9 years, those in Q4 of p-tau217 and GFAP had greater MoCA decline than Q1-3 (p-tau217: -3.3 vs. -1.4, p-interaction = 0.02; GFAP: -2.9 vs. -1.3, p-interaction = 0.03).

DISCUSSION: Elevated p-tau217 and GFAP predict cognitive decline in PWH, underscoring AD and inflammatory biomarker relevance.},
}

Humans
Biomarkers/blood
Male
Female
*Alzheimer Disease/blood/diagnosis
*HIV Infections/blood/complications
*tau Proteins/blood
*Viral Load
*Cognitive Dysfunction/blood
Middle Aged
Neurofilament Proteins/blood
*Glial Fibrillary Acidic Protein/blood
Aged
Mental Status and Dementia Tests/statistics & numerical data
Thailand

@article {pmid41558820,
year = {2026},
author = {Nishioka, K and Ikezaki, M and Iwahashi, N and Arakawa, M and Fukushima, M and Mori, N and Mizoguchi, M and Horiuchi-Tanizaki, Y and Fujino, M and Tomiyama, T and Ihara, Y and Uchimura, K and Ino, K and Nishitsuji, K},
title = {Amyloid-β fibrils accumulated in preeclamptic placentas suppress cytotrophoblast syncytialization.},
journal = {Life science alliance},
volume = {9},
number = {4},
pages = {},
doi = {10.26508/lsa.202503453},
pmid = {41558820},
issn = {2575-1077},
mesh = {Humans ; *Pre-Eclampsia/metabolism/pathology ; Pregnancy ; Female ; *Trophoblasts/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *Placenta/metabolism/pathology ; Amyloid Precursor Protein Secretases/metabolism ; Aspartic Acid Endopeptidases/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Peptide Fragments/metabolism ; Adult ; Amyloid/metabolism ; },
abstract = {Cerebral deposition of fibrillar amyloid-β (Aβ) is a pathological hallmark of Alzheimer's disease. Although Aβ is present in human placentas and accumulates in preeclamptic placentas characterized by poor placentation, the production and role of Aβ in the human placenta remain unclear. Because hypoxia in mid-to-late pregnancy is a risk for preeclampsia, we found that levels of hypoxia-inducible factor 1-α and β-secretase (BACE-1) increased concurrently with placental Aβ deposition in late-stage preeclamptic placentas. We also found that a human cytotrophoblast (CTB) model, BeWo cells, actually produced Aβ species and that hypoxia increased Aβ production and BACE-1 protein levels. Aβ42 fibrils inhibited CTB syncytialization, a critical step in maintaining pregnancy, by inducing loss of membrane localization of cell-cell adhesion molecules. Primary human CTBs confirmed these observations. Taken together, our results suggest that increased Aβ production in CTBs by hypoxia may lead to the formation of Aβ fibrils, which inhibit syncytiotrophoblast formation and are detrimental to pregnancy. Thus, our results reveal the novel role of Aβ fibrils in the pathogenesis of preeclampsia.},
}

Humans
*Pre-Eclampsia/metabolism/pathology
Pregnancy
Female
*Trophoblasts/metabolism/pathology
*Amyloid beta-Peptides/metabolism
*Placenta/metabolism/pathology
Amyloid Precursor Protein Secretases/metabolism
Aspartic Acid Endopeptidases/metabolism
Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
Peptide Fragments/metabolism
Adult
Amyloid/metabolism

@article {pmid41558720,
year = {2026},
author = {Zhou, R and Li, J and Liu, W and Zheng, R and Han, J and Liao, Z and Ning, W and Tang, C},
title = {[Systematic review and mechanistic exploration of "intelligence three-needling" in treatment of Alzheimer's disease].},
journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion},
volume = {46},
number = {1},
pages = {153-160},
doi = {10.13703/j.0255-2930.20250723-k0001},
pmid = {41558720},
issn = {0255-2930},
mesh = {*Alzheimer Disease/therapy/metabolism/genetics ; Humans ; Animals ; *Acupuncture Therapy ; Acupuncture Points ; Brain/metabolism ; },
abstract = {The "intelligence three-needling" therapy, developed by Professor JIN Rui, the eminent acupuncture- moxibustion master in the south of Five Ridges, is effective on cognitive dysfunction in practice. The paper reviews the animal experiment researches of Alzheimer's disease (AD) treated with this therapy, aiming to explain its core mechanism and effect characteristics for AD. The results showed that the "intelligence three-needling" therapy exerts its effect through multiple targets and diverse pathways. It improves cholinergic system function, enhances glucose metabolism in brain regions, reduces oxidative stress damage, suppresses neuroinflammation, regulates the Wnt/β-catenin signaling pathway, promotes autophagy-lysosomal clearance of pathological proteins, activates the transmembrane receptor protein (Notch) pathway to strengthen synaptic plasticity, demonstrates neuroprotective and anti-apoptotic effects, and modulates gut microbiota. In experiments, this therapy demonstrated specific effect in brain regions of 5xFAD mouse models. Compared with the single application at "Benshen" (GB13) or "Shenting" (GV24), the acupoint combination in this therapy displayed the synergistic advantages, regulating more comprehensively adenosine monophosphate activated protein kinase (AMPK)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) kinase network. This review provides the theoretical basis for optimizing the protocol of acupuncture and moxibustion for AD, and is conducive to promoting the deep integration of traditional acupuncture-moxibustion therapy with modern neuroscience.},
}

*Alzheimer Disease/therapy/metabolism/genetics
Humans
Animals
*Acupuncture Therapy
Acupuncture Points
Brain/metabolism

@article {pmid41558522,
year = {2026},
author = {Shimizu, T and Mizushima, N},
title = {[Autophagy and Neurological Diseases].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {1},
pages = {65-72},
doi = {10.11477/mf.188160960780010065},
pmid = {41558522},
issn = {1881-6096},
mesh = {Humans ; *Autophagy/genetics/physiology ; *Nervous System Diseases/genetics ; Animals ; Neurodegenerative Diseases ; },
abstract = {Autophagy is an essential degradation mechanism that maintains intracellular homeostasis. In recent years, an increasing number of cases with mutations in autophagy-related genes, such as ATG7, have been reported. These findings highlight the crucial role of autophagy in human neurodevelopment. However, the severity of clinical symptoms does not always correlate with the degree of autophagy impairment observed in patient-derived cells, and phenotypic manifestations can vary widely. These findings indicate that autophagy dysfunction alone does not fully explain disease mechanisms, even in neurological disorders directly associated with mutations in autophagy-related genes. Currently, no established methods exist to quantitatively assess autophagy activity in vivo, making it challenging to determine whether autophagy dysfunction serves as a primary driver of disease pathogenesis in adult-onset neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Although several lines of indirect evidence indicate impaired autophagy in these conditions, it remains uncertain whether such changes are causative or secondary to the disease process. Further research is warranted to elucidate the precise role of autophagy in both developmental and degenerative neurological disorders and to determine whether targeting autophagy holds promise as a therapeutic strategy.},
}

Humans
*Autophagy/genetics/physiology
*Nervous System Diseases/genetics
Animals
Neurodegenerative Diseases

@article {pmid41558515,
year = {2026},
author = {Nishio, Y},
title = {[Dementia in the Lewy Body Disease Spectrum].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {1},
pages = {5-12},
doi = {10.11477/mf.188160960780010005},
pmid = {41558515},
issn = {1881-6096},
mesh = {Humans ; *Lewy Body Disease/complications/pathology ; *Dementia/etiology ; Parkinson Disease/complications ; },
abstract = {The timing of dementia onset in patients with Parkinson's disease varies significantly. Predictors of the early development of dementia include postural instability, gait disturbance, REM sleep behavior disorder, and visuo-spatial impairment. The main neuropathological basis of dementia in Parkinson's disease involves the co-occurrence of α-synuclein pathology in the cerebral cortex and Alzheimer's disease co-pathology. Cholinergic system degeneration significantly affects symptom expression, making cholinesterase inhibitors effective for alleviating visual hallucinations and cognitive deficits.},
}

Humans
*Lewy Body Disease/complications/pathology
*Dementia/etiology
Parkinson Disease/complications

@article {pmid41558401,
year = {2026},
author = {Zhao, X and Zhu, Z and Wang, Y and Sun, M and Li, N and Su, Z and Huang, W},
title = {A sulfur-atom-enhanced strategy for NIR imaging of soluble and insoluble amyloid-β species.},
journal = {Talanta},
volume = {302},
number = {},
pages = {129417},
doi = {10.1016/j.talanta.2026.129417},
pmid = {41558401},
issn = {1873-3573},
abstract = {Soluble Aβ oligomers, more neurotoxic than monomers and plaques, are the predominant drivers of Alzheimer's disease in its earliest phase. However, the severe scarcity of effective molecular design principles for constructing soluble Aβ oligomer-targeted imaging probes severely hampers early-stage Alzheimer's diagnosis and pathological mechanistic dissection. Herein, we propose a sulfur-atom hybridization enhancement strategy to boost the binding ability of probes towards Aβ species, especially soluble Aβ oligomers and successfully engineer a fluorescence (FL) intensity amplifying (91-fold) D-π-A probe F-BSTH-NM for Aβ oligomers. Specifically, we initially develop a novel non-planar chromophore by changing the CC of quinoline into C-S to improve the interaction towards Aβ species. Then, optimizing the π-bridge to improve sulfur content and integrating electron donor group to extend the emission into near-infrared (NIR) window and simultaneously enhance desirable targetability and binding affinity. The rational designed F-BSTH-NM exhibits larger FL turn-on ratios as well as NIR emissions after binding to Aβ species, especially Aβ oligomers. Moreover, the proper lipophilicity (cLogP = 2.61) enable itself with desirable BBB penetration ability, and in vivo NIR fluorescent imaging reveals that probe F-BSTH-NM is capable of differentiating transgenic (Tg) AD mice from normal controls. The ex vivo histology experiment demonstrate that F-BSTH-NM could co-localization with both plaque cores and oligomer-enriched peripheries, suggesting that F-BSTH-NM could serve as a potential imaging tool for the early diagnosis of AD.},
}

@article {pmid41558396,
year = {2026},
author = {Hsieh, PH and Chen, YF and Chen, TF and Wu, WC and , },
title = {Association between cognitive status and structural brain changes in Alzheimer's disease: Clinical implication of lightweight deep learning-aided diagnosis.},
journal = {European journal of radiology},
volume = {196},
number = {},
pages = {112678},
doi = {10.1016/j.ejrad.2026.112678},
pmid = {41558396},
issn = {1872-7727},
abstract = {BACKGROUND: The complex brain changes involved in Alzheimer's disease (AD) development constitute a high-dimensional nonlinear feature space where deep learning (DL) classification/diagnosis may be advantageous over classical non-learning methods. However, the practicality of DL remains under debate among healthcare professionals, largely because many models are computationally expensive and operate without explicit interpretability. This study aimed to construct a lightweight DL model to disclose the association between cognitive status and structural brain changes in AD.

METHODS: By using the data obtained from the Alzheimer's Disease Neuroimaging Initiative database, 418 AD patients and 418 age-matched cognitively normal (CN) subjects were included for DL model construction based on their T1-weighted magnetic resonance images at baseline visit. A lightweight design was achieved by incorporating group convolution, global pooling, and efficient channel attention.

RESULTS: The accuracy rate of our model was 90.6 %, competitive with previous models built with up-to-ten times more parameters. The occlusion maps showed that the medial temporal area and thalamus accounted the most for our model's differentiation between AD and CN, in line with current knowledge of the pathological trajectory. Hierarchical regression further revealed that the logit of the DL model output explained a significant amount of variance in the mini mental state examination score, above and beyond the clinical indices including age, sex, and education duration (R[2] change = 0.341, F(1, 91) = 57.623, p < 0.001).

CONCLUSIONS: Lightweight DL can be clinically practicable for AD diagnosis by focusing on pathologically interpretable structural changes and offering image-based assessment of cognitive status.},
}

@article {pmid41558095,
year = {2026},
author = {Santos, LTR and Costa, FL and Rosa, ID and Frota, AF and Bezerra, JR and Soares, MVR and Barbosa, CSN and Farias, JWF and da Silva, LRAM and Gonçalves, PVS and Coelho Filho, JM and Lôbo, RR and Teixeira, AL and Diniz, BS and Peixoto Junior, AA and Macedo, DS},
title = {Plasma but not salivary p-Tau181 reflects Alzheimer's disease in a Latin American Cohort.},
journal = {Journal of the neurological sciences},
volume = {481},
number = {},
pages = {125762},
doi = {10.1016/j.jns.2026.125762},
pmid = {41558095},
issn = {1878-5883},
abstract = {Identifying accessible and reliable biomarkers for Alzheimer's disease (AD) remains a major challenge, particularly in low- and middle-income countries. Phosphorylated tau at threonine 181 (p-tau181) measured in plasma has shown strong diagnostic performance, but its potential in saliva, a truly noninvasive biofluid, remains uncertain. This study compared plasma and salivary p-tau181 levels, assessed their agreement, and evaluated their diagnostic accuracy in a Latin American cohort. Eighty participants were clinically classified as cognitively unimpaired (CU, n = 25), mild cognitive impairment (MCI, n = 22), or Alzheimer's dementia (AD, n = 33). Plasma and salivary p-tau181 concentrations were quantified using Single Molecule Array (Simoa) assays. Salivary p-tau181 levels were markedly higher than plasma levels (900.26 vs. 26.67 pg/mL; p < 0.001) but showed no correlation. Bland-Altman analysis revealed a mean bias of -1.56 with significant proportional bias (β = 0.73; p < 0.001), and Passing-Bablok regression confirmed the absence of a linear relationship between matrices. Plasma p-tau181 showed a numerical increase across the cognitive continuum, reaching statistically significant differences only when AD was compared with CU and MCI (AUC = 0.82; 95% CI 0.73-0.92), whereas salivary p-tau181 failed to discriminate clinical groups (AUC = 0.55, ns). These results demonstrate that plasma and salivary p-tau181 are not interchangeable and that current saliva-based quantification methods lack clinical reliability. This study provides the first evidence from Latin America supporting the diagnostic validity of plasma, but not salivary, p-tau181, and highlights the need for further investigation into pre-analytical and biological determinants of salivary biomarker variability.},
}

@article {pmid41558007,
year = {2026},
author = {Muthui, R and Paun, O and Inventor, B and Ruppar, T and Hickman, S and Zaman, A},
title = {Process of Addressing Advance Care Planning With African American Family Caregivers of Nursing Home Residents Diagnosed With Alzheimer's Disease and Related Dementias.},
journal = {Research in gerontological nursing},
volume = {19},
number = {1},
pages = {17-24},
doi = {10.3928/19404921-20260105-01},
pmid = {41558007},
issn = {1938-2464},
mesh = {Humans ; *Nursing Homes ; *Black or African American ; *Caregivers/psychology ; *Advance Care Planning ; *Alzheimer Disease/nursing/ethnology ; Female ; Male ; *Dementia/nursing/ethnology ; Aged ; Middle Aged ; Decision Making ; Aged, 80 and over ; Terminal Care ; White ; },
abstract = {PURPOSE: To explore advance care planning (ACP) and end-of-life (EOL) communication and decision-making experiences of African American family caregivers of nursing home residents with Alzheimer's disease and related dementias (ADRD).

METHOD: The study used a descriptive qualitative design with semi-structured interviews. African American family caregivers of nursing home residents diagnosed with ADRD with documented POLST were interviewed. Sixteen participants were recruited from eight nursing homes in a large Midwestern city.

RESULTS: Three major themes were developed and highlighted that ACP and EOL conversations occurred at different points within the health care system and were facilitated by family caregivers' knowledge of residents' wishes for EOL care and the faith/spirituality of the family caregiver/resident. Conversations were challenged by caregivers' lack of understanding of medical terminology and lack of providers available to educate them.

CONCLUSION: ACP and EOL decision-making with African American family caregivers of nursing home residents with ADRD is a process that is affected by nursing home challenges, such as physician shortage. In making ACP and EOL decisions, African American family caregivers relied on their faith as well as their knowledge of wishes the resident with ADRD had verbalized or documented.},
}

Humans
*Nursing Homes
*Black or African American
*Caregivers/psychology
*Advance Care Planning
*Alzheimer Disease/nursing/ethnology
Female
Male
*Dementia/nursing/ethnology
Aged
Middle Aged
Decision Making
Aged, 80 and over
Terminal Care
White

@article {pmid41557840,
year = {2026},
author = {Smirnova, D and Ustinova, A and Chukanov, V and Pchitskaya, E},
title = {3D dendritic spines shape descriptors for efficient classification and morphology analysis in control and alzheimer`s disease modeling neurons.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag025},
pmid = {41557840},
issn = {1367-4811},
abstract = {MOTIVATION: Dendritic spines, postsynaptic structures characterized by their complex shapes, provide the essential structural foundation for synaptic function. Their shape is dynamic, undergoing alterations in various conditions, notably during neurodegenerative disorders like Alzheimer's disease. The dramatically increasing prevalence of such diseases highlights an urgent need for effective treatments. A key strategy in developing these treatments involves evaluating how dendritic spine morphology responds to potential therapeutic compounds. Although a link between spine shape and function is recognized, its precise nature is still not fully elucidated. Consequently, advancing our understanding of dendritic spines in both health and disease necessitates the urgent development of more effective methods for assessing their morphology.

RESULTS: This study introduces qualitatively new 3D dendritic shape descriptors based on spherical harmonics and Zernike moments and proposes a bases on them clustering approach for grouping dendritic spines with similar shapes applied to three-dimensional polygonal spines meshes acquired from Z-stack dendrite images. By integrating these methods, we achieve improved differentiation between normal and pathological spines represented by the Alzheimer's disease in vitro model, offering a more precise representation of morphological diversity. Additionally, the proposed spherical harmonics approach enables dendritic spine reconstruction from vector-based shape representations, providing a novel tool for studying structural changes associated with neurodegeneration and possibilities for synthetic dendritic spines dataset generation.

AVAILABILITY: The software used for experiments is public and available at https://github.com/Biomed-imaging-lab/SpineTool with the DOI: 10.5281/zenodo.17359066. Descriptors codebase is available at https://github.com/Biomed-imaging-lab/Spine-Shape-Descriptors with the DOI: 10.5281/zenodo.17302859.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}

@article {pmid41557715,
year = {2026},
author = {Rosal, AE and Torres-Carmona, E and Martin, SL and Boileau, I and Graff-Guerrero, A and Strafella, AP},
title = {The effect of Apolipoprotein E4 on cognitive function in Parkinson's disease: A structural MRI study in the PPMI cohort.},
journal = {PloS one},
volume = {21},
number = {1},
pages = {e0341240},
doi = {10.1371/journal.pone.0341240},
pmid = {41557715},
issn = {1932-6203},
mesh = {Humans ; *Parkinson Disease/genetics/diagnostic imaging/pathology/complications/physiopathology ; *Apolipoprotein E4/genetics ; Male ; Magnetic Resonance Imaging ; Female ; Aged ; *Cognition/physiology ; Middle Aged ; Gray Matter/diagnostic imaging/pathology ; *Cognitive Dysfunction/genetics ; Cohort Studies ; Heterozygote ; },
abstract = {BACKGROUND: Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD), yet its underlying mechanisms remain poorly understood. Apolipoprotein E4 (APOE4), a genetic risk factor of Alzheimer's Disease, has been associated with PD-related cognitive impairment. However, findings are inconsistent, highlighting the need for further investigation. Neuroimaging studies have found gray matter abnormalities, mainly reductions in gray matter volume (GMV) and cortical thickness (CTh), in both cognitively impaired PD patients and APOE4 carriers. Yet, APOE4's role in these structural changes and their cognitive impact in PD is underexplored.

AIM: This study aimed to determine whether APOE4 influences early structural brain differences in terms of GMV and CTh in PD prior to the emergence of cognitive dysfunction.

METHODS: A total of 51 PD APOE4 carriers and 120 non-carriers who were cognitively unimpaired from the Parkinson's Progression Markers Initiative (PPMI) database were included. T1-weighted MRI scans were used to calculate GMV and CTh in regions previously associated with PD-related cognitive impairment, including hippocampal subregions. Cognitive scores assessing global cognition and specific cognitive domains were used to examine associations between regions showing significant GMV or CTh group differences and cognitive performance.

RESULTS: PD APOE4 carriers showed increased GMV in the left angular gyrus (AnG) and decreased GMV in the left nucleus accumbens (NAcc) compared to non-carriers, though neither survived multiple comparison correction. Left AnG GMV correlated with visuospatial function in both groups but did not remain significant after co-variate adjustment. Left NAcc GMV correlated with visuospatial function and working memory, but only in non-carriers even after co-variate adjustment. No group differences were observed in CTh measures and hippocampal subregion GMVs.

CONCLUSIONS: This study suggests that APOE4 may not influence cognitive function in PD by affecting GMV and CTh. However, longitudinal analyses must confirm these observations.},
}

Humans
*Parkinson Disease/genetics/diagnostic imaging/pathology/complications/physiopathology
*Apolipoprotein E4/genetics
Male
Magnetic Resonance Imaging
Female
Aged
*Cognition/physiology
Middle Aged
Gray Matter/diagnostic imaging/pathology
*Cognitive Dysfunction/genetics
Cohort Studies
Heterozygote

@article {pmid41557600,
year = {2026},
author = {Fisher, DW and Borisovskaya, A and Lindley, E and Domoto-Reilly, K},
title = {Somatic Symptom Disorder as a Prodrome of Alzheimer Disease and Successful Treatment of Pain and Agitation With Electroconvulsive Therapy: A Case Report.},
journal = {The journal of ECT},
volume = {},
number = {},
pages = {},
doi = {10.1097/YCT.0000000000001229},
pmid = {41557600},
issn = {1533-4112},
support = {T32AG052354//National Institute of Aging/ ; },
abstract = {Neuropsychiatric symptoms in dementia can be heterogeneous and hard to treat, though electroconvulsive therapy (ECT) is becoming more widely accepted as a viable treatment option. Here, we describe a patient with Alzheimer disease (AD) who developed Somatic Symptom Disorder as a prodrome to cognitive and functional decline, though atypical, primary affective disorder in AD was also on the differential. This patient further developed debilitating anxiety and agitation that was refractory to multiple behavioral and pharmacological interventions. ECT was able to treat the patient's neuropsychiatric symptoms, resulting in sustained, full remission with minimal transient, cognitive side effects. This case depicts a rare presentation of AD and further adds to the growing body of literature that suggests ECT is safe and effective for treating neuropsychiatric symptoms in dementia.},
}

@article {pmid41557594,
year = {2026},
author = {Alves, F and Ayton, S},
title = {Missing tissue, missing data: Resolving brain volume loss caused by anti-amyloid therapies.},
journal = {PLoS medicine},
volume = {23},
number = {1},
pages = {e1004880},
doi = {10.1371/journal.pmed.1004880},
pmid = {41557594},
issn = {1549-1676},
mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology ; *Brain/pathology/drug effects ; Organ Size/drug effects ; *Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Disease Progression ; Clinical Trials as Topic ; },
abstract = {Anti-amyloid drugs modestly slow Alzheimer's disease progression, albeit with uncertainty of sustained benefit, particularly as they cause paradoxical acceleration of brain volume changes. Here, we examine explanations for these volume changes and argue for transparent release of clinical trial data.},
}

Humans
*Alzheimer Disease/drug therapy/pathology
*Brain/pathology/drug effects
Organ Size/drug effects
*Amyloid beta-Peptides/antagonists & inhibitors/metabolism
Disease Progression
Clinical Trials as Topic

@article {pmid41557565,
year = {2026},
author = {Erickson, P and Borgh Skillbäck, T and Kern, S and Skoog, I and Jönsson, L and Andreasson, U and Blennow, K and Eriksdotter, M and Zetterberg, H},
title = {Limited diagnostic performance of cerebrospinal fluid glial fibrillary acidic protein in dementia.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1-17},
doi = {10.1159/000550601},
pmid = {41557565},
issn = {1421-9824},
abstract = {INTRODUCTION: Cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) is a neuroinflammatory marker reflecting reactive astrogliosis and is measured regularly in clinical practice. However, its diagnostic utility in differentiating dementia subtypes remains unclear. This study aimed to evaluate differences in CSF GFAP concentrations and its associations with markers of disease severity and amyloid pathology.

METHODS: We conducted a retrospective cohort study using three datasets encompassing a broad range of dementia diagnoses. Included variables were CSF GFAP, β-amyloid 42 (Aβ42), the Aβ42/Aβ40 ratio, mini-mental state exam (MMSE) scores, and time from sampling to death.

RESULTS: A total of 1345 individuals were included. In Parkinson's disease dementia (PDD) and Lewy body dementia (LBD), GFAP levels were similar (p>.05). Lower levels were observed in PDD compared to early-onset Alzheimer's disease (AD), late-onset AD (LAD), and vascular dementia (VaD) (all p<.05); however, the discriminative performance was low-to-moderate: PDD versus LAD (AUROC=.74, CI=.64-.84, p<.001), VaD (AUROC=.71, CI =.61-.81, p<.001) and EAD (AUROC=.59, CI=.47-.71, p=.13). Associations were seen with MMSE in mixed AD and VaD (MIX) (p=.027), but not in the other diagnostic categories. GFAP levels did not differ between subjects grouped according to Aβ42/Aβ40 status (p>.05).

CONCLUSION: CSF GFAP did not exhibit clinically relevant diagnostic or prognostic value in dementia. Further studies are needed to clarify its role in PDD.},
}

@article {pmid41557197,
year = {2026},
author = {Dos Santos, JFM and Mello, IS and da Cruz, ILS and Soares, MA},
title = {Non-Saccharomyces yeasts contribute to longevity, mitigated protein toxicity, and protection against abiotic stress in Caenorhabditis elegans.},
journal = {Archives of microbiology},
volume = {208},
number = {3},
pages = {128},
pmid = {41557197},
issn = {1432-072X},
support = {445388/2024-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
mesh = {Animals ; *Caenorhabditis elegans/microbiology/physiology/genetics ; *Longevity ; Caenorhabditis elegans Proteins/genetics/metabolism ; Oxidative Stress ; Probiotics ; *Stress, Physiological ; *Cryptococcus/physiology/isolation & purification ; Amyloid beta-Peptides/toxicity ; *Yeasts/physiology/isolation & purification ; Saccharomyces/physiology/isolation & purification ; DNA-Binding Proteins ; Receptor, Insulin ; Transcription Factors ; },
abstract = {The search for probiotic microorganisms that can be applied beyond gut health has advanced into areas that seek to promote longevity and to prevent neurodegenerative diseases. In this study, we have investigated non-Saccharomyces strains isolated from the Amazon, Cerrado, and Pantanal biomes and evaluated how they affect Caenorhabditis elegans. During our initial screening, based on increased body size and population, we selected eight yeast strains and characterized their cells. Then, we selected three of these strains for in vivo testing. Cryptococcus sp._T038 and Cryptococcus sp._T248 prolonged longevity and reduced the effects of thermal and oxidative stress in C. elegans. Hanseniaspora opuntiae_W164 and Saccharomyces boulardii_SB delayed beta-amyloid-induced paralysis in C. elegans CL4176. The antioxidant genes of the DAF-2/SKN-1 pathway were activated by Cryptococcus_T038 and _T248 and H. opuntiae_W164 in C. elegans strain LD1171 (GCS-1p::GFP) and by Cryptococcus_T038, H. opuntiae_W164, and S. boulardii_SB in C. elegans strain CF1553 (SOD-3p::GFP). These data reinforce that wild yeasts are potential functional probiotics.},
}

Animals
*Caenorhabditis elegans/microbiology/physiology/genetics
*Longevity
Caenorhabditis elegans Proteins/genetics/metabolism
Oxidative Stress
Probiotics
*Stress, Physiological
*Cryptococcus/physiology/isolation & purification
Amyloid beta-Peptides/toxicity
*Yeasts/physiology/isolation & purification
Saccharomyces/physiology/isolation & purification
DNA-Binding Proteins
Receptor, Insulin
Transcription Factors

@article {pmid41557069,
year = {2026},
author = {Yıldırım, M and Ünver, H and Necip, A and Hord, B and Ersatir, M},
title = {Novel triphenylphosphonium-hydrazone salts: ıntegrated experimental and computational ınsights into AChE ınhibition and resistance-overcoming antimicrobial and antibiofilm potential.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41557069},
issn = {1432-1912},
abstract = {Neurodegenerative disorders and multidrug-resistant (MDR) bacterial infections represent two major and interconnected global health challenges. However, current therapeutic strategies are largely limited by single-target approaches, insufficient efficacy against biofilm-forming MDR pathogens, and the lack of multifunctional small molecules capable of addressing both neurodegeneration and bacterial resistance simultaneously. These limitations constitute a critical technical bottleneck in contemporary drug discovery and underscore the urgent need for innovative, dual-action therapeutic scaffolds. In this study, five novel triphenylphosphonium-hydrazone derivatives (1a-1e) were rationally designed, synthesized, and fully characterized by FT-IR, 1H/13C NMR, and HR-MS/MS analyses to overcome these challenges by integrating neuroprotective and antimicrobial functionalities within a single molecular framework. All synthesized compounds exhibited potent acetylcholinesterase (AChE) inhibitory activity, with IC50 values ranging from 8.66 to 13.9 µM, highlighting their strong neuroactive profiles. Notably, compound 1b emerged as the most effective AChE inhibitor (IC50 = 8.66 µM), underscoring its promise as a lead scaffold for the development of next-generation anti-Alzheimer agents. Beyond enzyme inhibition, the compounds demonstrated significant antibacterial efficacy against clinically relevant carbapenem-resistant pathogens. In particular, compound 1d showed the strongest activity against Acinetobacter baumannii and Klebsiella pneumoniae, with MIC values of 32 µg/mL and 64 µg/mL, respectively. Importantly, all derivatives (1a-1e) exhibited dose-dependent antibiofilm activity, achieving up to 83.4% biofilm disruption in Acinetobacter baumannii and 72.8% in Escherichia coli at 1024 µg/mL, directly addressing a major resistance-associated bottleneck in antibacterial therapy. Molecular docking studies provided mechanistic validation of this multifunctional design, revealing a strong binding affinity of compound 1d toward PBP1A (PDB: 6OWS) and the AcrB efflux pump protein (PDB: 6PT1), suggesting a previously unexplored dual antibacterial mechanism involving simultaneous inhibition of cell-wall biosynthesis and efflux-mediated drug resistance. Overall, this study introduces a novel triphenylphosphonium-hydrazone platform, establishes a clear structure-activity relationship, and highlights its potential as a multifunctional therapeutic strategy against both neurodegenerative disorders and MDR bacterial infections.},
}

@article {pmid41557057,
year = {2026},
author = {Xu, Z and Dai, S and Wu, Y and Zhu, Y and Qiu, P and Xu, S and Qiu, F and Peng, X and Liu, W and Wang, H},
title = {Atractylenolide III Attenuated Neurotoxicity in Alzheimer's Disease via AMPK/GSK3β/Nrf2/HO-1 Signaling Pathway.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {377},
pmid = {41557057},
issn = {1559-1182},
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; *NF-E2-Related Factor 2/metabolism ; *Sesquiterpenes/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Lactones/pharmacology/therapeutic use ; *Heme Oxygenase-1/metabolism ; Mice ; *AMP-Activated Protein Kinases/metabolism ; Humans ; Male ; Neuroprotective Agents/pharmacology/therapeutic use ; Cell Line, Tumor ; Amyloid beta-Peptides/metabolism ; Hippocampus/drug effects/pathology ; Apoptosis/drug effects ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and widespread neuroinflammation. Atractylenolide III (AT-III), the primary active compound in Atractylodes macrocephala Koidz, has shown various health-promoting effects, including antioxidant properties and neuroprotection. However, the anti-AD molecular mechanism of AT-III remains to be further investigated. FAD[4T] mice were treated with AT-III for 4 weeks, and the neuroprotective effect of AT-III was subsequently evaluated by cognitive performance, histopathology, transcriptomic profiling, and 16S rRNA sequencing. SH-SY5Y cells were also used to verify the roles of AT-III on the AMPK/GSK3β/Nrf2/HO-1 pathway. AT-III significantly improved cognitive function, evidenced by a decreased escape latency and increased number of platform crossings in the Morris water maze (MWM) test and an increased alternation ratio in the Y-maze test. Histological analysis revealed that AT-III alleviated neuronal loss, reduced apoptosis and glial activation, and reduced Aβ deposition in the hippocampus. Biochemical assessments indicated that AT-III decreased oxidative stress and reduced neuroinflammation. Additionally, AT-III improved the diversity of the gut microbiota, including an increase in Ileibacterium and a decrease in Candidatus_Saccharimonas. Mechanistically, AT-III activated the AMPK/GSK3β/Nrf2/HO-1 signaling pathway both in vivo and in vitro. We further confirmed that AT-III significantly ameliorates Aβ1-42-induced cytotoxicity, excessive ROS production, and apoptosis in SH-SY5Y cells. However, the protective effects of AT-III were partially abolished by Compound C (an AMPK inhibitor). Our study demonstrates that AT-III mitigated neurodegenerative damage in AD by suppressing microglial activation and neuroinflammation through the AMPK/GSK3β/Nrf2/HO-1 signaling, which suggests that AT-III might be a novel therapeutic strategy for the inhibition of AD.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology
Animals
*NF-E2-Related Factor 2/metabolism
*Sesquiterpenes/pharmacology/therapeutic use
*Signal Transduction/drug effects
*Glycogen Synthase Kinase 3 beta/metabolism
*Lactones/pharmacology/therapeutic use
*Heme Oxygenase-1/metabolism
Mice
*AMP-Activated Protein Kinases/metabolism
Humans
Male
Neuroprotective Agents/pharmacology/therapeutic use
Cell Line, Tumor
Amyloid beta-Peptides/metabolism
Hippocampus/drug effects/pathology
Apoptosis/drug effects

@article {pmid41556772,
year = {2026},
author = {Lin, H and Macaden, L and Chandler, C},
title = {The Impact of Inappropriate Sexual Behaviors in People With Dementia on Family Caregivers: A Scoping Review.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261418909},
doi = {10.1177/15333175261418909},
pmid = {41556772},
issn = {1938-2731},
mesh = {Humans ; *Caregivers/psychology ; *Dementia/nursing/psychology ; *Sexual Behavior/psychology ; Psychological Distress ; },
abstract = {This scoping review examines the impact of inappropriate sexual behaviors (ISBs) in people with dementia on their family caregivers. Through synthesizing 15 studies from 8 countries, 6 themes were identified: complex emotional responses, psychological distress, increased caregiver burden, practical caregiving challenges, impaired marital relationships, and social isolation. Findings reveal caregivers frequently experience helplessness, embarrassment, anger, anxiety, depression, and social withdrawal, exacerbated by societal taboos surrounding sexuality and limited professional support. Spousal caregivers are particularly affected, reporting increased emotional strain and marital distress. Practical caregiving difficulties, including safety and privacy concerns, limited access to care services, and challenging institutionalization decisions, further intensify caregiver burden. The review highlights significant research gaps, including the need for specialized assessment tools, broader and culturally diverse studies, and exploration of ISBs as distinct phenomena. Addressing these gaps is crucial for developing targeted interventions and adequately supporting caregivers, particularly within home-based and culturally sensitive dementia care services.},
}

Humans
*Caregivers/psychology
*Dementia/nursing/psychology
*Sexual Behavior/psychology
Psychological Distress

@article {pmid41556651,
year = {2026},
author = {Nguyen, VTT and König, S and Formes, H and Al Taleb, Z and Steinert, F and Bufe, B and Eggert, S and Stegmüller, S and Schermer, Y and Richling, E and Kins, S and Reinhardt, C and Endres, K},
title = {Monocolonization with Bacteroides thetaiotaomicron exerts region-specific effects on Alzheimer's disease-related traits in the murine brain.},
journal = {Microbiology spectrum},
volume = {},
number = {},
pages = {e0074425},
doi = {10.1128/spectrum.00744-25},
pmid = {41556651},
issn = {2165-0497},
abstract = {UNLABELLED: Bacteroides thetaiotaomicron (B. theta) dominates the gut microbiome of most mammals. This strictly anaerobic gut symbiont colonizes the mucus layer of host intestinal epithelial cells in both healthy and diseased conditions. Reduced neuronal and vagal afferent innervation observed in germ-free mice was found to be normalized by colonization with B. theta. In addition to deficits in gut innervation, germ-free mice have been reported to have reduced neuronal number and neurotransmitter levels in the brain. Here, we investigated the hallmarks of Alzheimer's disease (AD) in the brain of germ-free mice compared to mice mono-colonized with B. theta. We analyzed the number of mature neurons, neurotransmitter transporters, amyloid precursor protein processing, and inflammatory status in three brain regions: the hippocampus, prefrontal cortex (PFC), and cerebellum. The hippocampus and the PFC are regions thought to be highly susceptible to pathogenesis, whereas the cerebellum is thought to be only mildly affected. Interestingly, secretion of neuroprotective sAPPα decreased in hippocampus and remained unchanged in PFC, while levels were increased in the cerebellum in response to bacterial colonization. In addition, the number of presynaptic boutons increased in the hippocampus but remained unaffected in the cerebellum.

IMPORTANCE: The gut microbiome has been reported to not only contribute to diseases of the gastrointestinal tract but also to interfere with and potentially even initiate diseases of other organ systems, such as the brain. Interference with the gut microbiome has been shown to elicit cognitive changes, for example, in rodent models of AD. Colonization with the common gut microbe B. theta not only affected the brain per se in our study but also showed specific brain region-dependent effects related to AD. This implies that evaluating the impact the microbiome might have on brain disorders needs a much more detailed investigation in the future with spatial and also potentially time resolution.},
}

@article {pmid41556609,
year = {2026},
author = {Candow, DG and Pratt, J and Fabiano, N and Gordji-Nejad, A and Smith, A and Rawson, ES and Moriarty, T and Forbes, SC and Kerksick, CM},
title = {Creatine Supplementation and the Brain: Have We Put the Cart Before the Horse?.},
journal = {Journal of dietary supplements},
volume = {},
number = {},
pages = {1-30},
doi = {10.1080/19390211.2026.2616440},
pmid = {41556609},
issn = {1939-022X},
abstract = {Creatine is an important regulator of brain bioenergetics, yet the efficacy of creatine supplementation (CrS) in the brain remains largely unknown. Measurement of brain creatine using proton ([1]H) and phosphorus ([3][1]P) magnetic resonance spectroscopy is highly sensitive to voxel placement, signal quality, analysis pipelines, and reporting conventions which can obscure the detection of biological responses to CrS. There is evidence that CrS increases brain creatine, but this response may be dose and/or duration dependent. CrS provides some benefits during acute periods of metabolic stress such as sleep deprivation, mental fatigue, and hypoxia. Emerging clinical data also suggest potential therapeutic effects from CrS for Alzheimer's disease, major depressive disorder, and mild traumatic brain injury (mTBI), although findings across conditions remain preliminary and inconsistent. Further, CrS shows some promise for improving aspects of sleep quality. The purpose of this narrative review is to: (1) outline methodological considerations in the quantification of brain creatine, (2) discuss the divergent effects of CrS on brain creatine levels and measures of brain function, (3) examine the purported mechanistic actions of CrS for improving brain health and function, (4) highlight critical gaps and limitations which should be considered moving forward, and (5) identify future research directions involving CrS and the brain.},
}

@article {pmid41556545,
year = {2026},
author = {Trudel, L and Therriault, J and Macedo, AC and Hosseini, SA and Fernandez-Arias, J and Chan, T and Rahmouni, N and Bezgin, G and Tissot, C and Woo, MS and Aumont, É and Zheng, Y and Hall, B and Oliva-Lopez, D and Mitchell, SW and Hopewell, R and Hsiao, CH and Toga, AW and Braskie, MN and Meeker, KL and Soucy, JP and Guiot, MC and Gauthier, S and Vitali, P and O'Bryant, SE and Pascoal, TA and Rosa-Neto, P},
title = {Clinical-biological Alzheimer's disease stage concordance: insights from cohorts and autopsy data.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag018},
pmid = {41556545},
issn = {1460-2156},
abstract = {Alzheimer's disease (AD) is defined by its characteristic neuropathologic changes, which allow for diagnosis and assessment of severity. Recently, the Alzheimer's Association proposed a framework to stage Alzheimer's disease biologically based on tau-PET. Furthermore, the framework hypothesizes a degree of alignment between biological Alzheimer's disease severity and clinical symptom severity. We aimed to investigate the concordance between clinical and biological stages of Alzheimer's disease and explore factors contributing to discordance using in vivo and postmortem neuropathological data. Data from 768 amyloid-β positive individuals were drawn from four observational cross-sectional in vivo cohorts-TRIAD, ADNI, HABS-HD, and SCAN-as well as a postmortem autopsy dataset from the National Alzheimer's Coordinating Center (NACC; n = 3,188). All in vivo participants had tau-PET imaging, clinical diagnosis, and neurobehavioral assessments. Participants were assigned a biological Alzheimer's disease stage based on their tau-PET scan according to the Alzheimer's Association revised criteria stages. The autopsy dataset included individuals with moderate-to-frequent neuritic plaques (CERAD scores 2-3), along with premortem clinical and neurobehavioral data. Clinical-biological concordance was quantified using squared-weighted Cohen's Kappa. Ordinal and linear regression models assessed associations between biological stage and clinical severity (CDR-Sum of Boxes, MMSE), adjusting for age, sex, and cohort. Postmortem analyses evaluated the impact of comorbid neuropathologies on clinical-biological discordance using adjusted odds ratios and ordinal regression. Overall concordance between clinical and biological Alzheimer's disease staging was moderate (Cohen's Kappa=0.52, p < 0.001). Approximately 70% of individuals classified as cognitively unimpaired or with dementia exhibited biological stages consistent with their clinical diagnoses. In contrast, transitional decline and mild cognitive impairment (MCI) groups were more heterogenous. Notably, 25% of Aβ-positive individuals with MCI demonstrated no detectable tau-PET abnormality. Nonetheless, advanced tau-PET stage was reliably associated with clinical impairment. In the NACC autopsy dataset, nearly all individuals with more severe clinical stage than their proposed biological stage exhibited comorbid neuropathologies, including FTLD-TDP-43, FTLD-tau, Lewy bodies, LATE, and cerebrovascular disease. The number of comorbid pathologies was strongly associated with increased odds of clinical dementia (t = 8.45, p < 0.001). While there is moderate agreement between clinical and biological stages of Alzheimer's disease across the entire disease spectrum, strong agreement is found in clinically unimpaired and dementia stages. Comparison of clinical and biological Alzheimer's disease stages provides a framework for understanding the large contributions of non-AD neurodegenerative diseases to dementia in Aβ-positive individuals. Our results have important implications for clinical trial recruitment strategies and highlight the urgent need for biomarkers for non-AD pathological processes.},
}

@article {pmid41556177,
year = {2026},
author = {Xiao, J and Liu, M and Zhou, M and Deng, G and Yang, Q and Li, Q},
title = {The causal effects of dementia on systemic sclerosis: a two-sample bidirectional Mendelian randomization study.},
journal = {International journal of surgery (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1097/JS9.0000000000004881},
pmid = {41556177},
issn = {1743-9159},
abstract = {BACKGROUND: Recent studies suggest that systemic sclerosis (SSc) may be associated with cognitive impairment and dementia. However, the causal relationship and its direction remain unclear. This study employed a two-sample bidirectional Mendelian randomization (MR) approach to systematically evaluate the genetic causal relationship between five types of dementia and SSc.

METHODS: Based on genome-wide association study (GWAS) summary data, we investigated the relationship between five types of dementia and SSc. The inverse variance weighted (IVW) method served as the primary analytical approach, supplemented by validation using the weighted median method, MR-Egger regression, simple mode, and weighted mode methods. Sensitivity analyses (leave-one-out, funnel plot, MR-PRESSO), pleiotropy tests (Egger intercept), and heterogeneity assessments (Cochran's Q) were conducted to ensure the robustness and reliability of the results. Additionally, reverse MR analysis was performed to further confirm the directionality of the causal relationship.

RESULTS: Forward MR analysis revealed a significant negative association between Alzheimer's disease (AD) and the risk of SSc (IVW OR = 0.530, 95% CI: 0.290-0.969, P = 0.039). In contrast, no significant causal relationships were found between SSc and frontotemporal dementia, vascular dementia, dementia with Lewy bodies, or Parkinson's disease dementia. Reverse MR analysis did not identify any causal effects of SSc on the aforementioned types of dementia, further supporting the directionality of the causal relationship. Sensitivity analyses, pleiotropy tests, and heterogeneity assessments did not reveal significant horizontal pleiotropy or heterogeneity.

CONCLUSION: Our study provides evidence of a potential causal relationship between AD and a reduced risk of SSc, highlighting the need for further research to explore the underlying mechanisms of this complex disease relationship.},
}

@article {pmid41556110,
year = {2026},
author = {Xia, W and Xu, C and Xiao, Z and Zhou, X and Zhao, Q and Ding, D and Deng, W},
title = {Plasma phosphorylated tau 217 and neurofilament light chain on the association between depressive symptoms and cognitive decline: The Shanghai Aging Study.},
journal = {Psychological medicine},
volume = {56},
number = {},
pages = {e25},
doi = {10.1017/S0033291725103115},
pmid = {41556110},
issn = {1469-8978},
support = {82173599, 82473701, 82071200, 82371429//National Natural Science Foundation of China/ ; },
mesh = {Humans ; Male ; Female ; *tau Proteins/blood ; China/epidemiology ; Aged ; *Neurofilament Proteins/blood ; *Cognitive Dysfunction/blood/epidemiology ; *Depression/blood/epidemiology ; Biomarkers/blood ; Aged, 80 and over ; Phosphorylation ; *Alzheimer Disease/epidemiology/blood ; *Aging/blood ; Middle Aged ; *Dementia/epidemiology/blood ; },
abstract = {BACKGROUND: Depressive symptoms are closely associated with cognitive decline and risk of incident dementia, and plasma biomarkers may play a significant role in this relationship. We aimed to investigate the influence of plasma biomarkers and explore the underlying mechanisms.

METHODS: This study included 1,658 dementia-free community residents recruited in 2009-2011 from the Shanghai Aging Study. At baseline, we assayed plasma phosphorylated tau 217 (p-tau217) and neurofilament light chain (NfL), and assessed depressive symptoms using the Center for Epidemiologic Studies Depression scale. Cox regression models were performed to estimate the risks of incident dementia and Alzheimer's disease (AD) during the 5-year follow-up. Parallel and serial mediation models were applied to investigate whether plasma p-tau217 and NfL mediated the relationship between depressive symptoms and cognitive decline.

RESULTS: Older adults with depressive symptoms had higher risks of dementia and AD, especially among those with higher concentrations of baseline plasma p-tau217/NfL. Sex-specific analysis revealed that depressive symptoms combined with high plasma NfL increased AD risk in men (hazard ratio, HR [95% confidence interval, CI] = 5.89 [2.01, 17.27], p = 0.001), whereas women with depressive symptoms and high plasma p-tau217 showed higher AD risk (HR [95%CI] = 6.07 [2.82, 13.09], p < 0.001). Parallel mediation analysis revealed that plasma p-tau217/NfL mediated the relationship between depressive symptoms and cognitive decline, respectively. Additionally, serial mediation analysis found p-tau217 precedes NfL within the mediating pathway (β = 0.403, bootstrap 95% CI: 0.347, 0.452).

CONCLUSIONS: Plasma p-tau217 and NfL could individually or jointly mediate the relationship between depressive symptoms and cognitive decline.},
}

Humans
Male
Female
*tau Proteins/blood
China/epidemiology
Aged
*Neurofilament Proteins/blood
*Cognitive Dysfunction/blood/epidemiology
*Depression/blood/epidemiology
Biomarkers/blood
Aged, 80 and over
Phosphorylation
*Alzheimer Disease/epidemiology/blood
*Aging/blood
Middle Aged
*Dementia/epidemiology/blood

@article {pmid41555829,
year = {2026},
author = {Daly, T},
title = {Nothing about us without us? Using public consensus for priority setting in Alzheimer's disease research.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261415592},
doi = {10.1177/13872877261415592},
pmid = {41555829},
issn = {1875-8908},
abstract = {Getting the public involved upstream in priority setting in the form of consensus-building activities in Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) research is necessary to make that research more impactful for people affected. AD/ADRD research should focus on questions related to significant truths that society cares about.},
}

@article {pmid41555828,
year = {2026},
author = {Merten, N and Dawes, P and Munro, KJ and Brenowitz, WD},
title = {Hearing impairment and cognitive decline: Alternative explanations to causality.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410502},
doi = {10.1177/13872877251410502},
pmid = {41555828},
issn = {1875-8908},
abstract = {Despite growing interest in hearing impairment as a potentially modifiable risk factor for dementia, the association is poorly understood. This has implications for whether treating hearing impairment can prevent or delay onset of dementia, as causation is not the only explanation for the association. In this editorial, we highlight how biases in research studies might account for the reported associations. We suggest future research using different study designs and novel biomarkers to help us overcome methodological limitations. This may allow us to determine the strength of the causal pathways linking hearing impairment to dementia, ultimately informing prevention and treatment strategies.},
}

@article {pmid41555826,
year = {2026},
author = {Klusek, J and Gierman, J and Fairchild, AJ and Benitez, AM and Berry-Kravis, E and Mailick, MR},
title = {Cognitive dysfunction in women with the FMR1 premutation during midlife: The LASSI-L reveals curvilinear CGG-dependent risk buffered by college education.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251414950},
doi = {10.1177/13872877251414950},
pmid = {41555826},
issn = {1875-8908},
abstract = {BackgroundThe FMR1 premutation (FXPM) is a common genetic variant (∼1:151 females) linked to increased risk for neurodegenerative disease. Midlife cognitive phenotypes remain poorly defined.ObjectiveTo characterize episodic memory performance in midlife FXPM women and examine potential risk moderation via genetic (i.e., FMR1 CGG repeat expansion size) and environmental (i.e., college degree attainment) influences.MethodsEighty-eight FXPM women and 84 matched controls, aged 30-55, completed the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a measure of specific episodic memory processes sensitive to subtle Alzheimer's disease (AD)-related cognitive and neuropathological changes.ResultsFXPM women demonstrated deficits in proactive semantic interference (PSI), recovery from PSI, and intrusion errors relative to controls. College education buffered these effects: college-educated FXPM women performed comparably to controls, while those without a college degree showed deficits. Gene-environment interactions showed patterns consistent with differential susceptibility: LASSI-L performance in women with mid-range CGG repeats (∼80-100) was strongly influenced by educational attainment, whereas education effects were absent in women with lower/higher CGG lengths.ConclusionsMidlife FXPM women showed episodic memory deficits, paralleling LASSI-L deficits seen in prodromal AD. College education offered protective benefits, particularly for women with mid-range CGG expansions. Findings highlight a critical midlife window for cognitive monitoring, identify education as a potential protective factor, and inform personalized risk assessment based on CGG length to promote earlier detection and targeted prevention for FXPM women. Findings suggest potential overlapping mechanisms with AD that merit further study.},
}

@article {pmid41555825,
year = {2026},
author = {Wang, EJ and Oğuztüzün, Ç and Xu, R and Gao, Z},
title = {Comparative evaluation of large language models in retrieving known and predicting novel drug combinations.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261415635},
doi = {10.1177/13872877261415635},
pmid = {41555825},
issn = {1875-8908},
abstract = {BackgroundLarge language models (LLMs) are increasingly used in the biomedical field for information retrieval, information extraction and knowledge discovery. However, their potential in retrieving and discovering drug combinations for diseases remains underexplored.ObjectiveThis study aims to evaluate the effectiveness of LLMs in retrieving known drug combinations and to identify novel drug combinations for treating Alzheimer's disease (AD).MethodsWe developed a series of prompts to guide LLMs in retrieving drug combinations. Their performance was evaluated using both FDA-approved combinations and combinations identified through PubMed literature mining. We then assessed the feasibility of identifying novel drug combination candidates for AD. In collaboration with domain experts, we performed pathway enrichment analyses to evaluate their potential mechanisms of action within the context of AD.ResultsIn a comparative evaluation of multiple LLMs, GPT-5 demonstrated the strongest overall performance, achieving an accuracy of 0.95 and a balanced F1 score of 0.95 in identifying FDA-approved drug combinations. Among the top 10 drug-combination candidates for AD treatment suggested by GPT-5, the combination of donepezil and memantine is already FDA-approved. Three other combinations have been tested in AD clinical trials, and three have supporting evidence in the literature. We also identified 10 off-label drug combinations, with pathway enrichment analyses indicating that several target key AD-related biological pathways.ConclusionsLLMs is effective in retrieving drug combinations for a given disease and the performance varies among different language models with best performance for GPT-5. However, the suggestions from LLM models require further validation to be considered reliable.},
}

@article {pmid41555821,
year = {2026},
author = {Kärkkäinen, V and Saari, T and Rusanen, M and Uusitalo, H and Leinonen, V and Thiede, B and Koivisto, AM and Kaarniranta, K and Utheim, TP},
title = {Altered tear fluid protein expression in persons with mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251413291},
doi = {10.1177/13872877251413291},
pmid = {41555821},
issn = {1875-8908},
abstract = {BackgroundTear fluid (TF) is a protein-rich fluid reported to reflect pathophysiological changes in several neurodegenerative diseases, including Alzheimer's disease. TF proteins are increasingly being considered as putative biomarker candidates to help in the diagnosis of disease. However, little information is available on TF protein changes in persons with mild cognitive impairment (MCI).ObjectiveThis study aimed to determine alterations in the expression of proteins in TF collected from persons with MCI compared with cognitively healthy controls.MethodsWe analyzed data from 54 study participants, including 34 controls (mean age, 71 years; mean Mini-Mental State Examination [MMSE] score ± standard deviation, 28.9 ± 1.4) and 20 persons with MCI (mean age, 71 years; mean MMSE score, 27.1 ± 1.9). All participants underwent cognitive, neurological, and ophthalmological examinations. TF was collected using Schirmer strips and evaluated using mass spectrometry-based proteomics and label-free quantification.ResultsThe expression of 33 TF proteins involved in oxidative stress, clearance mechanism, cytoskeleton stability, and inflammation were altered in persons with MCI compared with controls (p ≤ 0.05).ConclusionsOur findings reveal that numerous cellular stress-related biomarker candidate proteins are upregulated or downregulated in the TF of persons with MCI, a condition that may increase the risk of developing AD or other memory disorder. These data encourage TF protein studies in neurodegenerative diseases and TF provides an additive source of biomarkers for early diagnostics of memory diseases.},
}

@article {pmid41555820,
year = {2026},
author = {Smith, PJ and Blumenthal, JA and Ingle, K and Watkins, LL and Avorgbedor, F and Mabe, SK and Kraus, W and Tyson, C and Hinderliter, A and Sherwood, A},
title = {Lifestyle, sleep quality, and cognitive function in resistant hypertension: One-year follow-up from the TRIUMPH trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409716},
doi = {10.1177/13872877251409716},
pmid = {41555820},
issn = {1875-8908},
abstract = {BackgroundTreatment resistant hypertension (TRH) is associated with increased risk of cognitive decline, which may be reduced by healthy lifestyle changes.ObjectiveTo examine the effects of a comprehensive, rehabilitation-based lifestyle hprogram on cognitive function during a one-year follow-up of participants from the TRIUMPH clinical trial.MethodsAmong the 140 TRIUMPH participants originally randomized, 91 (65%) were available for one-year assessments prior to the COVID-19 lockdown. Participants were originally randomized to a Cardiac rehabilitation-based LIFEstyle program (C-LIFE) or to a Standardized Education and Physician Advice (SEPA) condition for 4-months. During their one-year follow-up, participants underwent assessments of sleep quality, body mass index, actigraphy-assessed physical activity levels, and cerebrovascular reactivity using functional near infrared spectroscopy (fNIRS). Cognitive function was assessed using a 45-min test battery incorporating tests of Executive Function/Learning, Memory, and Processing Speed. Regression-based models incorporating reliable change indices were used to assess cognitive change.ResultsParticipants included 91 individuals (mean age = 63.6 [SD = 8.6]), evenly distributed in biological sex and race/ethnicity, and tended to be college-educated. The C-LIFE group had more preserved cognitive functioning compared to SEPA (C-LIFE: z = -0.26 [-0.40, -0.12] versus SEPA: -0.60 [-0.81, -0.39]; d = 0.44, p = 0.008), with reduced PSQI sleep symptoms associating with more preserved cognitive function (B = -0.18, p = 0.050 per 3-points). Treatment did not improve fNIRS markers, although changes in weight and physical activity associated with fNIRS outcomes.ConclusionsLifestyle modification may help preserve cognitive functioning among individuals with resistant hypertension.},
}

@article {pmid41555802,
year = {2026},
author = {Lim, EY and Hong, YJ and Jeong, JH and Park, KH and Kim, S and Wang, MJ and Shim, Y and Choi, SH and Yang, DW},
title = {Hand Grip Strength Predicts Cognitive Decline in Subjective Cognitive Decline: 2-Year Follow-up Results.},
journal = {Journal of Korean medical science},
volume = {41},
number = {3},
pages = {e36},
doi = {10.3346/jkms.2026.41.e36},
pmid = {41555802},
issn = {1598-6357},
support = {HI18C0530/MOHW/Ministry of Health and Welfare/Korea ; },
mesh = {Humans ; *Hand Strength/physiology ; Male ; Female ; *Cognitive Dysfunction/diagnosis/pathology ; Aged ; Positron-Emission Tomography ; Follow-Up Studies ; Longitudinal Studies ; Neuropsychological Tests ; Logistic Models ; Odds Ratio ; Middle Aged ; Aged, 80 and over ; Muscle Weakness ; Executive Function ; },
abstract = {BACKGROUND: Hand grip strength (HGS) has been proposed as a potential clinical marker for cognitive decline. However, its association with domain-specific cognitive changes and underlying amyloid pathology remains unclear.

METHODS: This longitudinal study included 107 older adults with subjective cognitive decline (SCD) who completed a 24-month follow-up. Participants were categorized based on the presence of HGS weakness using Asian Working Group of Sarcopenia criteria. Logistic regression analyses were performed to examine the association between baseline HGS and cognitive decline across multiple domains, adjusting for relevant covariates. Repeated measures analysis of variance evaluated longitudinal changes in neuropsychological performance.

RESULTS: Participants with HGS weakness had significantly higher amyloid positron emission tomography (PET) positivity (47.1% vs. 18.9%, P = 0.012). HGS weakness was associated with poorer baseline performance and greater decline in visuospatial and executive function over 24 months. Baseline HGS weakness predicted decline in visuospatial function (odds ratio [OR], 3.517; 95% confidence interval [CI], 1.072-11.535) and verbal memory (OR, 3.503; 95% CI, 1.046-11.729), but these associations lost significance after adjusting for amyloid positivity.

CONCLUSION: HGS weakness is associated with cognitive decline, particularly in visuospatial and executive domains, and may serve as an early indicator of amyloid-related neurodegeneration in older adults with SCD. HGS assessment could be a practical clinical tool for identifying individuals at risk, especially when amyloid PET is not available.},
}

Humans
*Hand Strength/physiology
Male
Female
*Cognitive Dysfunction/diagnosis/pathology
Aged
Positron-Emission Tomography
Follow-Up Studies
Longitudinal Studies
Neuropsychological Tests
Logistic Models
Odds Ratio
Middle Aged
Aged, 80 and over
Muscle Weakness
Executive Function

@article {pmid41555795,
year = {2026},
author = {Roth, S and Yan, J and Patru, MM and Mattke, S and Gustavsson, A and Ortsater, G},
title = {The capacity for Alzheimer's disease confirmatory testing in the United States: The current situation and simulations for future increase.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406909},
doi = {10.1177/13872877251406909},
pmid = {41555795},
issn = {1875-8908},
abstract = {BackgroundWith recent advances in disease-modifying therapies for Alzheimer's disease (AD), demand for confirmatory biomarker testing such as via cerebrospinal fluid (CSF) analysis or amyloid positron emission tomography (PET) will increase considerably for diagnosis.ObjectiveTo assess the current capacity and estimating the anticipated future need of AD confirmatory testing in the United States (US).MethodsA population-based decision tree model was employed to simulate the AD diagnostic pathway for patients presenting with symptoms of mild cognitive impairment or mild dementia in primary and secondary care in the US. All patients were assumed to be enrolled in Medicare. The study was conducted from the US payer's perspective over a 5-year period. Four scenarios assessed the impact of different utilization patterns: (1) reference scenario (current use in AD diagnostic pathway: < 1% amyloid-PET; 3.5% CSF analysis); (2) increased CSF analysis utilization scenario (50% utilization); (3) amyloid-PET only; and (4) CSF analysis only.ResultsScenario 1 fails to meet the growing demand for AD confirmatory testing (assumed annual care-seeking rate of 50%), with approximately 0.3% of all amyloid-β-positive patients receiving a timely and accurate diagnosis with amyloid-PET, and 1.7% with CSF analysis. Scenarios 2 and 4 resulted in the highest proportion of accurate and timely diagnoses for amyloid-β-positive patients (24.8% and 44.6%, respectively) versus 15.1% of patients in scenario 3.ConclusionsIt is imperative to address capacity issues for AD confirmatory testing to facilitate timely diagnosis and initiation of amyloid-targeting therapies. Increasing CSF analysis utilization has the capacity to meet this growing demand.},
}

@article {pmid41555782,
year = {2026},
author = {Francis, L and Beiser, A and Lu, S and Kujawa, SG and Heard-Costa, N and Kolo, FB and Kamboh, MI and Bernal, R and Welling, DB and Alcabes, RL and Himali, JJ and Seshadri, S},
title = {Hearing loss in the young-old is associated with increased risk for Alzheimer's disease and vascular dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251407211},
doi = {10.1177/13872877251407211},
pmid = {41555782},
issn = {1875-8908},
abstract = {Hearing loss is a risk factor for dementia, but dementia subtypes underlying this association and effect modifiers are unknown. Using data collected from 2000 Framingham Heart Study participants we found that hearing loss increases risk for Alzheimer's disease and vascular dementia in participants aged 60-70 years ("young-old") at time of hearing assessment (Alzheimer's disease: HR 1.46[CI 1.07-2.0] p = 0.017; vascular dementia: HR 2.08[CI 1.22-3.56] p = 0.007). Longer duration of hearing loss determines increased risk for Alzheimer's disease and vascular dementia, and screening and intervention for hearing loss from mid-life may help reduce dementia.},
}

@article {pmid41555553,
year = {2026},
author = {Liu, Z and Li, X and Wang, Q and Liu, K and Zeng, W and Li, D and Zhao, K and Ma, Y and Long, H and Zhang, S and Li, D and Sun, B and Le, W and Wang, C and He, Z and Kang, W and Xiao, W and Liu, C},
title = {Dopamine-Induced Tau Modification Prevents Pathological Phosphorylation and Generates a Distinct Fibril Polymorph.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c22156},
pmid = {41555553},
issn = {1520-5126},
abstract = {Amyloid aggregation of tau is the key pathological event in various tauopathies including Alzheimer's and Pick's disease. Recently, dopamination was identified to modify tau on cysteine, which protects against tau pathology, yet its structural and functional consequences remain unclear. Here, we show that dopamination of the three-repeat (3R) tau fragment K19 alleviates disease-associated tau phosphorylation and alters the tau fibril structure. Solution NMR analysis reveals that dopamine modification at Cys322 of tau suppresses phosphorylation at several pathogenic sites across the microtubule-binding region. Dopaminated tau also exhibited greatly diminished fibrillization in vitro and reduced seeding activity in cells. Finally, we determined the cryo-EM structure of dopaminated tau fibrils at 3.55 Å resolution, revealing a unique fibril polymorph with the smallest core region reported to date for tau. The dopaminated fibril core comprises only 11 residues (centered on the VQIVYK motif) and is stabilized by a minimal hydrophobic interface, explaining its decreased stability compared to that of unmodified tau fibrils. Our results provide atomic-level insight into how dopamine modification imparts a protective effect on tau and underscore the profound influence of post-translational modifications in modulating amyloid protein structure and pathology.},
}

@article {pmid41408289,
year = {2025},
author = {Kantor, AB and Rickert, M and Cheng, H and Flanagan, K and Salgotra, V and Suppahia, A and Ryu, JK and Widboom, PF and Warfield, JR and Akassoglou, K and Stavenhagen, JB},
title = {Development of a humanized anti-fibrin monoclonal antibody for the treatment of neuroinflammatory and retinal diseases.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {19},
pmid = {41408289},
issn = {1742-2094},
abstract = {UNLABELLED: Vascular dysfunction and subsequent innate immune activation are key players of neurodegenerative, retinal, and inflammatory diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), diabetic retinopathy (DR), and age-related macular degeneration (AMD). At sites of vascular damage, conversion of the blood coagulation protein fibrinogen to fibrin exposes a cryptic inflammatory epitope, γ377–395, which can bind CD11b/CD18 and CD11c/CD18 complement receptors on microglia, macrophages, and dendritic cells. Genetic targeting of the fibrin γ377–395 epitope or its pharmacologic inhibition with the mouse monoclonal antibody 5B8 protects from inflammation and neurodegeneration in AD and MS mouse models. Here, we present the development of THN391, a first-in-class humanized antibody, to neutralize fibrin toxicity without adverse anticoagulant effects for the treatment of neurodegenerative, retinal, and inflammatory diseases. THN391 was affinity matured with 100-fold greater affinity than 5B8, engineered to lack Fc effector function, and have improved developability properties for clinical use. THN391 blocks the interaction of fibrin with CD11b/c and does not bind fibrinogen nor interfere with coagulation, consistent with the crystal structure of its binding interface to the γ377–395 epitope. THN391 and its Fc wild-type counterpart THN313 showed preclinical efficacy in experimental autoimmune encephalomyelitis (EAE) mouse models of MS and in a rodent model of retinal disease. Both THN391 and THN313 reduced demyelination, inflammatory foci, and clinical scores in EAE, demonstrating that anti-fibrin γ377-395 antibodies function as pure antagonists, blocking fibrin from activating CD11b/c complement receptors. THN391 was as effective as the standard of care vascular endothelial growth factor (VEGF) antagonists in reducing laser-induced neovascular lesions in a rat model of neovascular macular degeneration. Taken together, these results support the clinical development of THN391 for neurological diseases and ophthalmic indications.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03650-w.},
}

@article {pmid41555076,
year = {2026},
author = {Sasmita, AO and Depp, C},
title = {A Question of Origins: Non-neuronal Sources of Amyloid-β.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41555076},
issn = {1995-8218},
abstract = {Amyloid-β (Aβ) plaques and neurofibrillary tau tangles are hallmarks of Alzheimer's disease (AD). While the intracellular localization of tau tangles within neurons nominates them as the primary producers of tau, the cellular origin of Aβ is less clear as plaques accumulate extracellularly. Neurons have been considered the sole source of Aβ, leading to the generation of many AD animal models expressing familial AD protein variants specifically in neurons. However, emerging evidence showed that non-neuronal cells abundantly express amyloid precursor protein (APP) and its processing machinery. Among these, oligodendrocytes (OLs) exhibit the highest expression of amyloidogenic components, produce Aβ, and contribute to plaque burden in vivo. Here, we highlight reports on non-neuronal Aβ production in the context of AD and the function of APP processing in these cells. Understanding Aβ processing in non-neuronal cells might enable the identification of novel therapeutic targets, especially in humans whose brain structures differ greatly from animal models.},
}

@article {pmid41554957,
year = {2026},
author = {Burns, AP and Duran, MI and Fortel, I and Lazarov, O and Zhan, L and Bendlin, B and Leow, A},
title = {Excitation-inhibition homeostasis in Alzheimer's disease: a selective multiscale review of mechanisms, sex differences, and therapeutic opportunities.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41554957},
issn = {1740-634X},
support = {R21AG087888-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21AG087888-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21AG087888-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21AG087888-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21AG087888-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21AG087888-01//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
abstract = {Alzheimer's disease is increasingly viewed as a breakdown of balanced excitation-inhibition (E/I) homeostasis layered atop classical proteinopathy. Restoring circuit-level neural excitation and inhibition is rapidly becoming a tractable therapeutic strategy, guiding trials of circuit-modulating drugs such as levetiracetam. To date, however, findings across species and modalities remain fragmented, and it is unclear how to contextualize AD-focused E/I findings across scales and methodologies. Synthesizing over 150 studies of E/I homeostasis in AD, we organize the results into several prevailing themes: excitatory/inhibitory effects of amyloid and tau, whether hyperexcitation precedes amyloid plaque deposition, progressive oscillatory slowing (a shift of aggregate neural signal frequencies towards lower frequencies) as AD worsens, early preclinical hyperexcitation peaking in MCI and transitioning to hypoexcitation in AD, sex differences in E/I trajectories, APOE4 as a mediating factor, the contribution of neuroinflammation and metabolic dysfunction to E/I imbalance, and E/I-focused trials/experiments, particularly involving levetiracetam. These dominant themes are interpreted in a framework of multidimensional E/I homeostasis, rather than a single-axis imbalance. To support this integration, we first outline the microscale, mesoscale, and macroscale techniques used to assess E/I in AD, ranging from patch clamping and extracellular recordings to EEG/MEG and fMRI. By charting these multiscale E/I shifts, our synthesis offers a unifying framework to guide future experimental work and accelerate the design of biomarker-driven trials of E/I-targeted therapies in Alzheimer's disease.},
}

@article {pmid41554903,
year = {2026},
author = {Tuo, QZ and Bush, AI and Lei, P},
title = {Ferroptosis in neurological diseases: moving towards therapeutic intervention.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41554903},
issn = {1476-5578},
abstract = {Ferroptosis is a regulated cell death driven by iron-dependent lipid peroxidation and has been implicated in major neurological diseases. The brain is enriched in polyunsaturated fatty acids (PUFAs) and iron, which makes it particularly susceptible to lipid peroxidation, leading to ferroptosis. In neurological diseases such as Alzheimer's disease (AD) and stroke, such mechanisms are dysregulated and contribute to neuronal loss. Physiologically, the lipid peroxidation resistance systems in the brain, including defenses (such as SOD, CAT, Prxs, GPxs) and repair systems (such as GPx4, FSP1), prevent ferroptosis and repair damaged phospholipid membranes. However, the efficacy of endogenous resistance systems is often compromised in pathological states, positioning exogenous antioxidants as promising therapeutic candidates. Future research could optimize the delivery of these compounds and explore new candidates that specifically target the ferroptosis signaling pathway to prevent neurodegeneration occurring in neurological diseases.},
}

@article {pmid41554668,
year = {2026},
author = {Masood, F and Al-Hyari, A and Al-Wajidi, W and , },
title = {Comparison Study of Different Feature Selection Techniques for the Diagnosis of Alzheimer's Disease.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261418472},
doi = {10.1177/15333175261418472},
pmid = {41554668},
issn = {1938-2731},
mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; *Neuroimaging/methods ; Bayes Theorem ; Aged ; Male ; Female ; Biomarkers ; Machine Learning ; Magnetic Resonance Imaging ; },
abstract = {Objective: Alzheimer's disease (AD) continues to be a major challenge because handling high-dimensional data is time-consuming and expensive due to its complexity. A large feature space often increases computational costs and reduces model interpretability. This study addresses this problem by evaluating and comparing multiple feature selection techniques to identify the most informative biomarkers for AD diagnosis.Methods: Our study used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to implement and test three feature selection approaches, visualization-based, filter-based, and wrapper-based, within a Naive Bayes (NB) classification framework.Results: Based on the results of the analysis, the wrapper method achieved 96.77% classification accuracy, outperforming both visualization and filter methods with 86.19 and 91.87%, respectively. Interestingly, even when over 92.5% of the original features were removed the classifier still performed well, indicating that only a small set of features is necessary to ensure reliable diagnosis.Discussion: This study illustrates that strategically selecting features improves diagnostic accuracy while reducing computational burden, providing a more efficient framework for machine learning applications in Alzheimer's disease research.},
}

*Alzheimer Disease/diagnosis/diagnostic imaging
Humans
*Neuroimaging/methods
Bayes Theorem
Aged
Male
Female
Biomarkers
Machine Learning
Magnetic Resonance Imaging

@article {pmid41554659,
year = {2026},
author = {Srimaharaj, W},
title = {Corrigendum to "Brain dysfunction assessment in Alzheimer's disease: A phase-space projection and interactive signal decomposition framework" [Comput. Biol. Med. (2026) 111440 201].},
journal = {Computers in biology and medicine},
volume = {},
number = {},
pages = {111483},
doi = {10.1016/j.compbiomed.2026.111483},
pmid = {41554659},
issn = {1879-0534},
}

@article {pmid41554532,
year = {2026},
author = {Kang, S and Lim, JI and Stenzel, L and Kim, KY and Kim, E and Jeon, HJ and Park, DH and Lim, HK and Shim, Y and Jang, JW and Kim, Y and Lee, S and Park, KH},
title = {Efficacy and Safety of Mobile App-Based Metamemory Cognitive Training for Mild Cognitive Impairment: Multicenter Randomized Clinical Trial.},
journal = {JMIR mHealth and uHealth},
volume = {14},
number = {},
pages = {e73464},
doi = {10.2196/73464},
pmid = {41554532},
issn = {2291-5222},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/psychology/therapy ; Aged ; *Mobile Applications/standards/statistics & numerical data ; Middle Aged ; *Cognitive Behavioral Therapy/methods/standards/instrumentation/statistics & numerical data ; Aged, 80 and over ; Treatment Outcome ; Neuropsychological Tests/statistics & numerical data ; Quality of Life/psychology ; Cognitive Training ; },
abstract = {BACKGROUND: Metamemory training (MMT) offers a potential nonpharmacological approach to enhance cognitive function in individuals with mild cognitive impairment (MCI). While digital cognitive training improves accessibility, the effectiveness of mobile app-based MMT has not been evaluated in a randomized clinical trial.

OBJECTIVE: We aimed to evaluate the efficacy and safety of a mobile app-based MMT program, ET-101 (Cogthera), compared to a sham device control group in individuals with MCI.

METHODS: This multicenter, randomized controlled trial enrolled participants with MCI, recruited from 7 medical centers, and randomly assigned them to the ET-101 or control group (1:1 ratio). The intervention lasted 12 weeks, with a 12-week follow-up. The ET-101 group received metamemory-based multimemory strategy training and real-time feedback. Assessments of cognition, the daily activities of living, and the quality of life were conducted at baseline, week 12, and week 24. The primary outcome was the proportion of participants who showed cognitive improvement as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)-14 at weeks 12 and 24. Secondary outcomes included changes in the scores of scales assessing cognition, daily activities, and quality of life. Safety analysis assessed adverse events and their relation to digital therapeutics.

RESULTS: In the full analysis set, 49 participants were included in the ET-101 group and 50 in the control group. At week 24, the proportion of responders who maintained or improved their ADAS-Cog-14 scores was significantly higher in the ET-101 group than in the control group (P=.002). Additionally, the ET-101 group showed a significant improvement in ADAS-Cog-14 scores at week 24 compared to baseline levels (estimates=-2.53; t265=-3.05; Bonferroni-adjusted P=.003). A subdomain analysis revealed significant improvements in the memory (estimates=-2.50; t264=-4.03; Bonferroni-adjusted P<.001) and language (estimates=-0.807; t290=-3.68; Bonferroni-adjusted P<.001) domains at week 24 in the ET-101 group compared to the control group. In the safety analysis, 6 adverse events occurred in the ET-101 group and 4 in the control group, but none were related to the interventions. The attrition rate in the ET-101 group was 22.4% (11/49).

CONCLUSIONS: ET-101 significantly improved cognitive function compared to the sham device, with effects observed not only in the memory domain but also in the language domain, indicating a transfer effect. Therefore, ET-101 has the potential to provide effective MMT to a broader population with MCI by overcoming location and personnel limitations through a mobile app-based platform.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05938426; https://clinicaltrials.gov/study/NCT05938426.},
}

Humans
Male
Female
*Cognitive Dysfunction/psychology/therapy
Aged
*Mobile Applications/standards/statistics & numerical data
Middle Aged
*Cognitive Behavioral Therapy/methods/standards/instrumentation/statistics & numerical data
Aged, 80 and over
Treatment Outcome
Neuropsychological Tests/statistics & numerical data
Quality of Life/psychology
Cognitive Training

@article {pmid41554530,
year = {2026},
author = {Okabe, K and Nagata, T and Nukariya, K and Kito, S and Shinagawa, S},
title = {Executive and General Cognitive Domain as a Relevant Factor of Specific Neuropsychiatric Symptoms in Alzheimer's Disease.},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {1},
pages = {e70345},
doi = {10.1111/ggi.70345},
pmid = {41554530},
issn = {1447-0594},
support = {24K10690//JSPS KAKENHI (Japan Society for the Promotion of Science)/ ; JP24wm0625505//AMED (Japan Agency for Medical Research and Development) under Grant Numbers/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis/physiopathology ; Male ; Female ; Cross-Sectional Studies ; Aged ; *Executive Function/physiology ; Aged, 80 and over ; Neuropsychological Tests ; Severity of Illness Index ; *Cognition/physiology ; Mental Status and Dementia Tests ; },
abstract = {AIM: To elucidate the pathophysiological mechanisms between neurocognition and neuropsychiatric sub-symptoms in Alzheimer's disease (AD), the present cross-sectional study compared severity of each subitem in a neuropsychiatric symptom (NPS) scale among four neurocognitive groups classified based on the pattern of executive and general cognitive function.

METHODS: Of 546 consecutive outpatients who visited Memory Clinic at Jikei University Kashiwa Hospital, we selected 160 with AD and classified them into four neurocognitive groups based on score in the MMSE (Mini-Mental State Examination: ≥ 21 point was general cognitive preserved) or FAB (Frontal Assessment Battery: ≥ 13 was executive cognitive preserved): BPC (both cognitive preserved); GCP (general cognitive preserved); ECP (executive cognitive preserved); NCP (neither cognitive preserved). We compared the severity of each subitem of the Behavioral Pathology in Alzheimer's Disease (Behave-AD) scale among the four groups.

RESULTS: Among seven subitems of Behave-AD, the scores for diurnal rhythm disturbances and anxieties/phobias differed significantly among the four groups. The score for diurnal rhythm disturbances was significantly higher in GCP than BCP, and the score for anxiety/phobias was significantly higher in ECP than BCP. However, no significant difference was shown between each cognitive group and the NCP.

CONCLUSION: The general cognitive preservation without executive preservation may be relevant to the diurnal rhythm disturbances by self-correction for own behavior, and the executive preservation without general cognition preservation may contribute to the transient anxiety as emotional reaction. Such dissociative relations between executive and general neurocognition may be relevant to specific neuropsychiatric sub-symptoms emergence or severity in AD.},
}

Humans
*Alzheimer Disease/psychology/diagnosis/physiopathology
Male
Female
Cross-Sectional Studies
Aged
*Executive Function/physiology
Aged, 80 and over
Neuropsychological Tests
Severity of Illness Index
*Cognition/physiology
Mental Status and Dementia Tests

@article {pmid41554349,
year = {2026},
author = {Roddick, KM and Northrup, PA and Schellinck, HM and Brown, RE},
title = {Motor deficits in the McGill-R-Thy1-APP transgenic rat model of Alzheimer's Disease.},
journal = {Behavioural processes},
volume = {},
number = {},
pages = {105341},
doi = {10.1016/j.beproc.2026.105341},
pmid = {41554349},
issn = {1872-8308},
abstract = {The McGill-R-Thy1-APP rat is a transgenic model of Alzheimer's Disease (AD) which expresses APP with two mutations found in cases of familial AD, resulting in the development of amyloid pathology and cognitive deficits. Motor deficits are common symptoms of AD, emerging early in the disease, and are correlated with AD neuropathology and cognitive symptoms. This study evaluated hemizygous and homozygous McGill-R-Thy1-APP rats and their wildtype littermates for spontaneous alternation and locomotion in the T and Y mazes, and motor behaviour on an accelerating rotarod at 12 to 13 months of age. We found no genotype or sex effects in spontaneous alternation in either maze, nor a significant correlation of spontaneous alternation behaviour between the mazes. Female rats travelled greater distances than male rats in both mazes. While there was no genotype effect in the T maze on distance travelled, in the Y maze the hemizygous rats travelled shorter distances than the wildtype rats, while the homozygous rats travelled greater distances. There was a significant correlation between the distances travelled in each maze. Both hemizygous and homozygous rats performed worse than their wildtype littermates on the rotarod, while heavier rats performed worse than lighter rats, and female rats performed worse than male rats once their differences in weights were accounted for. These findings support the continued use of these rats as a model of AD and highlight the need to consider the possible confounding effect motor impairments have on other behavioural tests.},
}

@article {pmid41554303,
year = {2026},
author = {Çelik, H and Çelik, O and Aydın, Ş and Küçükler, S and Çomaklı, S and Topal, A and Akay, R and Gönüllü, S and Yıldız, MO and Alım, B and Özdemir, S},
title = {Small extracellular vesicles carrying miRNA34 in Alzheimer's disease: effects on oxidative stress, neuroinflammation, cognitive function, and mitochondrial/ferroptosis-related protein regulation.},
journal = {Gene},
volume = {},
number = {},
pages = {150014},
doi = {10.1016/j.gene.2026.150014},
pmid = {41554303},
issn = {1879-0038},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, oxidative stress, and persistent neuroinflammation. Recent studies have increasingly focused on the regulatory role of microRNAs in AD pathogenesis. In this study, we investigated the therapeutic potential of small extracellular vesicles (sEV) enriched with microRNA34 (miRNA34) to target key pathogenic mechanisms of AD. We hypothesized that miRNA34-loaded sEV could alleviate oxidative damage, inhibit neuroinflammatory responses and ferroptosis, reduce mitochondrial impairment, and ultimately improve cognitive function. We evaluated the effects of miRNA34 administration on oxidative stress markers, pro-inflammatory cytokines, synaptic plasticity indicators, and behavioral outcomes in an in vivo Aβ-induced mouse model of AD. The experimental design included five groups, each consisting of seven mice. The findings demonstrated that miRNA34-loaded sEV treatment significantly reduced oxidative stress and neuroinflammation while enhancing memory and learning performance. Overall, our results indicate that miRNA34-enriched sEV represent a promising and minimally invasive therapeutic strategy capable of modulating AD pathogenesis. This research provides a novel perspective on the potential clinical application of miRNA34 and sEVin neurodegenerative disorders.},
}

@article {pmid41553948,
year = {2026},
author = {Fang, Y and Cao, K},
title = {Estimates of Global Needs for Neurorehabilitation: A Systematic Analysis Based on the GBD-WHO Rehabilitation Database 2021.},
journal = {Neuroepidemiology},
volume = {},
number = {},
pages = {1-32},
doi = {10.1159/000550340},
pmid = {41553948},
issn = {1423-0208},
abstract = {BACKGROUND: Neurological disorders affect approximately 3.4 billion people worldwide and are the leading cause of disability. We conducted this study to explore global neurorehabilitation requirements and project trends from 2022 to 2036.

METHODS: The data on health conditions that may benefit from neurorehabilitation were sourced from the World Health Organization Rehabilitation Need Estimator. Prevalence and years lived with disability (YLDs) of neurorehabilitation needs were analyzed overall and by sex, age, region, country, and health condition. Estimated annual percentage changes (EAPCs) were calculated to quantify trends in age-standardized rates. A decomposition analysis was conducted to identify drivers of changes in neurorehabilitation needs. Projections of neurorehabilitation needs were made until 2036 using Bayesian age-period-cohort analysis (BAPC).

RESULTS: Globally, in 2021, neurological disorders requiring rehabilitation affected 225.38 million (95% UI 215.84-235.21) individuals, contributing to 52.35 million (95% UI 37.57-67.46) YLDs. The age-standardized prevalence rate (ASPR) and YLD rate (ASYR) were 2,758.37 (95% UI 2,644.02-2,878.23) and 640.5 (95% UI 459.39-824.44) per 100,000 persons, respectively. From 1990 to 2021, neurorehabilitation needs increased significantly, with prevalent cases and YLDs rising by 97.5% and 96.4%, respectively. This trend was reflected in a significant annual increase in both ASPR and ASYR, with an EAPC of 0.17 (95% CI 0.15-0.19) and 0.13 (95% CI 0.11-0.15), respectively, and is expected to continue increasing by 2036. Furthermore, decomposition analysis identified population growth and aging as the primary drivers of this increase. Most neurorehabilitation needs occur in low- and middle-income countries (LMICs). From 2021 to 2036, the highest contributors to the global need for neurorehabilitation will remain stroke, cerebral palsy, and Alzheimer's disease and dementia.

CONCLUSIONS: Our findings reveal a large and escalating global burden of neurological disorders requiring rehabilitation, driven by demographic aging and population growth. It is essential to expand rehabilitation services and integrate them into primary healthcare systems, particularly in LMICs.},
}

@article {pmid41553900,
year = {2026},
author = {Wang, C and Wang, Y and Xue, Q and Zhou, Z and Yan, G and Qi, X},
title = {Classification of Alzheimer's Disease by Modeling Brain Networks as Signed Networks under Deep Learning Frameworks.},
journal = {IEEE transactions on computational biology and bioinformatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCBBIO.2026.3655150},
pmid = {41553900},
issn = {2998-4165},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that remains a global challenge due to its complex pathology and the lack of definitive diagnostic tools. This paper introduces an innovative approach to predicting and analyzing Alzheimer's disease by constructing signed brain network models and leveraging signed graph neural network technologies. By modeling the brain network as a signed graph that incorporates both positive and negative correlations, we capture the nuanced interactions between brain regions more effectively than traditional methods. We utilize graph convolutional networks (GCNs) and their variants to process these signed brain networks, significantly improving the accuracy of Alzheimer's disease prediction. Comparative analysis reveals that the signed graph model outperforms its unsigned counterparts in diagnostic precision (with an improvement of at least $19\%$), emphasizing the importance of incorporating negative correlations in neural interactions. Furthermore, precisely because of the additional negative edge information that we can utilize both positive and negative attention matrices, derived from these prediction tasks, to determine important brain region biomarkers. This work is an attempt to systematically validate the role of negative information through comparisons of different signed graph variants, which holds particular promise for enhancing Alzheimer's disease diagnostic accuracy at early stages. We believe that this approach will have significant clinical applications in the future.},
}

@article {pmid41553746,
year = {2026},
author = {David, L and Maniewicz, S and Chebib, N and Gold, G and Srinivasan, M and Müller, F},
title = {Implant Therapy in Patients With Neurodegenerative Diseases-A Scoping Review.},
journal = {Clinical oral implants research},
volume = {},
number = {},
pages = {},
doi = {10.1111/clr.70080},
pmid = {41553746},
issn = {1600-0501},
abstract = {OBJECTIVES: The increasing longevity of populations has resulted in a growing number of older adults requiring prosthodontic care, including those with neurodegenerative diseases (NDs). Neurodegenerative diseases pose significant challenges to prosthodontic care, and it remains unclear whether implant therapy in this population achieves outcomes comparable to those observed in the general older population.

MATERIALS AND METHODS: A first systematic review was reframed to a scoping review using a PCC framework with Population (individuals with neurodegenerative diseases, who were partially or completely edentulous), Concept (implant therapy, planning, placement and maintenance, and any reported complications) and Context (dental and geriatric care settings).

RESULTS: The literature search identified 634 studies or case reports, of which none fulfilled the inclusion criteria. Seven papers (1 retrospective study, 2 prospective studies and 4 case reports) outside the inclusion criteria reported on patients with neurodegenerative diseases receiving implants, which suggest that dental implants seem to offer initial benefits in improving chewing efficiency, the quality of life and weight gain, especially in Parkinson's disease (PD) patients. However, their suitability for patients with advanced ND is uncertain.

CONCLUSION: Although high-level evidence on implant survival and success in patients with neurodegenerative diseases is lacking, the limited available evidence offers promising indications of reasonably successful implant treatments in early-stage cases. However, continuous monitoring of disease progression, oral health and denture management is crucial to retrofit the restoration when necessary.},
}

@article {pmid41553693,
year = {2026},
author = {Brandt, PJ and Pototska, O and Stys, PK},
title = {Fluorescence from dual molecular rotors allows sensitive detection of widespread brain pathology in a mouse model of Alzheimer's disease.},
journal = {Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology},
volume = {},
number = {},
pages = {},
pmid = {41553693},
issn = {1474-9092},
abstract = {Amyloid fibrils formed by the misfolding and aggregation of proteins are a pathological hallmark of many neurodegenerative conditions including Alzheimer's disease (AD). Although recent studies have shown that pre-fibrillar species including low molecular-weight oligomers are more toxic in vitro than mature fibrils, and correlate better with cognitive decline in AD patients, techniques to study this subtle pathology remain limited. Here, we describe the use of the dye pair 9-(dicyanovinyl)julolidine (DCVJ) and crystal violet (CV), two fluorescent molecular rotors, to detect widespread pathology in the 5xFAD mouse model of AD via fluorescence spectroscopy. DCVJ and CV individually displayed a limited ability to detect spectral differences between WT and non-plaque areas of 5xFAD brain samples. However, when used in combination, the two probes discerned subtle but significant differences in a much higher proportion of tissue compared to either dye alone. These spectral differences were eliminated after treatment to disaggregate macromolecular protein assemblies, providing evidence that the dye pair was able to detect subtle pathology present in the parenchyma of the 5xFAD mouse brain. These findings demonstrate that the combined use of DCVJ and CV could be a valuable addition to the tools currently available to study the early stages of protein misfolding, which is essential for advancing therapeutics and diagnostic technologies in many neurodegenerative diseases.},
}

@article {pmid41553625,
year = {2026},
author = {Kaur, S and Mannan, A and Singh, TG},
title = {The Interplay Between Nurr1 and Mitochondrial Biogenesis: Implications for Neurodegenerative Therapy.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {372},
pmid = {41553625},
issn = {1559-1182},
mesh = {Humans ; *Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism ; Animals ; *Organelle Biogenesis ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; *Mitochondria/metabolism ; Oxidative Stress ; Dopaminergic Neurons/metabolism ; },
abstract = {The transcription factor Nurr1 (NR4A2) serves as an essential element in dopaminergic neuron development since it functions predominantly in the substantia nigra, which becomes severely affected during Parkinson's disease (PD) and Alzheimer's disease (AD). Nurr1 regulates dopamine synthesis, survival-promoting, and oxidative stress genes that affect mitochondrial formation. Nurr1 binds to PGC-1α, allowing for mitochondrial activity regulation. This relationship supports mitochondrial biogenesis. Post-translational changes, including phosphorylation and acetylation, modify Nurr1 transcriptional regulation in order to enhance its ability to regulate mitochondrial genes. The assessment examines Nurr1's involvement in dopaminergic neuron development and mitochondrial formation while showing its role in reducing oxidative damage for an extensive understanding of its neurological disease functionality. Nurr1 serves as a therapeutic candidate for analysis, while the review explores obstacles and potential paths for using Nurr1-based treatments against Parkinson's disease alongside Alzheimer's disease and other neurodegenerative disorders. The extensive research utilized multiple databases, PubMed, Scopus, Medline, and EMBASE, with keywords "Nurr1," "NR4A2," "Neurodegenerative disorders," "Mitochondrial biogenesis," "Oxidative stress," "Parkinson's disease," "Alzheimer's disease," and "Therapeutic target." The analysis examined published research regarding Nurr1-mediated control of dopaminergic function and survival and mitigation of neurological and mitochondrial deficits within the past decade. Nurr1's interactions with important co-regulators like PGCα, its post-translational changes, and its effects on neuroinflammation have also received particular focus. In neurodegenerative illnesses, mitochondrial dysfunction adds to neuronal damage. Nurr1's regulation of mitochondrial biogenesis helps recover mitochondrial function, alleviate oxidative stress, and sustain neuronal survival. Dysregulation of Nurr1 expression is connected to decreased mitochondrial activity and accelerated neurodegeneration.},
}

Humans
*Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism
Animals
*Organelle Biogenesis
*Neurodegenerative Diseases/metabolism/therapy/pathology
*Mitochondria/metabolism
Oxidative Stress
Dopaminergic Neurons/metabolism

@article {pmid41553588,
year = {2026},
author = {Bjørklund, G and Butnariu, M and Caunii, A and Peana, M},
title = {Metallothioneins in Neurodegenerative Diseases: Metal Homeostasis, Autoimmunity, and Therapeutic Potential.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {373},
pmid = {41553588},
issn = {1559-1182},
mesh = {Humans ; *Homeostasis/physiology ; *Metallothionein/metabolism ; *Neurodegenerative Diseases/metabolism/immunology/drug therapy/therapy ; *Autoimmunity/physiology ; Animals ; *Metals/metabolism ; },
abstract = {Neurodegenerative diseases, including multiple sclerosis, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and are frequently linked to metal dysregulation, oxidative stress, and immune dysfunction. Metallothioneins (MTs), a family of cysteine-rich, metal-binding proteins, are critical in maintaining metal homeostasis, mitigating oxidative damage, and modulating immune responses, functions highly relevant in these pathologies. MTs regulate essential metals like copper and iron by preventing their participation in harmful redox reactions and control zinc availability for enzymatic and signaling processes. They also detoxify neurotoxic metal(oid)s such as cadmium, mercury, lead, and arsenic, thereby reducing their adverse neurological and immunological effects. In autoimmune neurodegeneration, MTs modulate pro- and anti-inflammatory cytokines (e.g., IL-6, TNF-α, IL-10) and influence immune cell activity, particularly microglia and T cells, which are central to neuroinflammation and autoimmunity. Through these mechanisms, MTs play a dual role in sustaining immune homeostasis and counteracting oxidative stress. Their capacity to integrate metal regulation with immune modulation positions them as promising therapeutic targets, with preclinical and some clinical evidence supporting strategies to enhance MT expression or develop MT-mimetic agents to address both metal dysregulation and immune imbalance. Additionally, MTs show emerging utility as biomarkers, as alterations in MT isoform expression and metal-bound complexes in biofluids have been associated with disease onset, progression, and therapeutic response in specific neurodegenerative conditions. This article reviews the multifaceted roles of MTs in neurodegenerative diseases, emphasizing their function in metal and immune regulation and their emerging potential as therapeutic targets and clinical biomarkers.},
}

Humans
*Homeostasis/physiology
*Metallothionein/metabolism
*Neurodegenerative Diseases/metabolism/immunology/drug therapy/therapy
*Autoimmunity/physiology
Animals
*Metals/metabolism

@article {pmid41553152,
year = {2026},
author = {Bačić Toplek, F and Maiorana, NV and Guidetti, M and Marceglia, S and Capelli, R and Priori, A and Camilloni, C},
title = {Electric field-induced destabilization and surface modulation of Aβ42 fibrils in molecular simulations: theoretical implications for direct current stimulation in Alzheimer's disease.},
journal = {Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/13506129.2026.2616753},
pmid = {41553152},
issn = {1744-2818},
abstract = {BACKGROUND: The amyloid-β peptide 42 (Aβ42) forms fibrillar aggregates that are a hallmark of Alzheimer's disease. While recent therapeutic strategies targeting Aβ42 fibrils and oligomers have shown promise, safer and more effective interventions are still needed. Noninvasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have emerged as potential complementary approaches, yet the molecular mechanisms by which electric fields influence amyloid aggregation remain poorly understood.

METHODS: We performed atomistic molecular dynamics simulations to investigate the response of Aβ42 fibrils to static electric fields of increasing strength. Simulations were based on an ex vivo fibril structure with reconstructed N-terminal regions, and different structural restraint conditions were used to disentangle surface and core effects.

RESULTS: Electric fields perturb the disordered N-terminal 'fuzzy coat', altering its conformational dynamics and weakening its interactions with the fibril core, thereby modifying the fibril surface properties. Simulations with unrestrained fibril ends further reveal increased fluctuations in core residues, indicating field-induced destabilization that may hinder elongation.

CONCLUSIONS: These findings provide molecular-level insight into how static electric fields can modulate amyloid fibril formation and propagation, offering a possible mechanistic basis for the effects of tDCS and related brain stimulation techniques.},
}

@article {pmid41553038,
year = {2026},
author = {Han, X and Zhu, S and Zhang, H and Xia, T and Gu, X},
title = {Multiplex Cerebrospinal Fluid Proteomics Identifies Biomarkers Predicting Neuropsychiatric Symptom Progression in Mild Cognitive Impairment and Alzheimer's Disease.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {2},
pages = {e71447},
doi = {10.1096/fj.202504014R},
pmid = {41553038},
issn = {1530-6860},
support = {82171193//the National Natural Science Foundation of China/ ; ZDXK202232//Jiangsu Provincial Medical Key Discipline/ ; },
mesh = {*Cognitive Dysfunction/cerebrospinal fluid/diagnosis ; Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Biomarkers/cerebrospinal fluid ; Male ; Female ; *Proteomics/methods ; Aged ; Disease Progression ; Mice ; Animals ; Aged, 80 and over ; Longitudinal Studies ; },
abstract = {Neuropsychiatric symptoms (NPS), commonly concomitant with Alzheimer's disease (AD), substantially impair the quality of life and accelerate disease progression, yet reliable biomarkers for early identification of individuals at high NPS risk remain elusive. In this study, we leveraged the data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), incorporating longitudinal data from 509 participants diagnosed with mild cognitive impairment (MCI) or mild AD at baseline and followed up for 1 and 2 years. The dataset included cerebrospinal fluid (CSF) proteomic profiles comprising 6361 proteins, along with comprehensive data on NPS diagnosis, cognitive function, and AD pathology. LASSO regression and recursive feature elimination were applied to identify NPS-related CSF proteins, followed by random forest modeling to predict NPS risk at baseline, 1 year, and 2 years. Incorporating selected CSF proteins significantly improved NPS prediction compared to the reference model, with AUCs increasing from 0.64 to 0.76 at baseline, 0.63 to 0.80 at 1 year, and 0.63 to 0.81 at 2 years. Notably, Cyclin-Dependent Kinase-Like 2 (CDKL2), Nidogen 2 (NID2), and Lin-7 Homolog B (LIN7B) were consistently associated with NPS across all time points. Among them, CDKL2 and NID2 were significantly associated with AD biomarkers and cognitive scores, and their expression changes were independently validated in cerebrospinal fluid from a mouse model, highlighting their potential as stable predictive biomarkers. Our findings highlight CSF proteomic signatures that robustly predict NPS progression in individuals with MCI and mild AD, offering a framework for early risk stratification and precision intervention in NPS.},
}

*Cognitive Dysfunction/cerebrospinal fluid/diagnosis
Humans
*Alzheimer Disease/cerebrospinal fluid/diagnosis
Biomarkers/cerebrospinal fluid
Male
Female
*Proteomics/methods
Aged
Disease Progression
Mice
Animals
Aged, 80 and over
Longitudinal Studies

@article {pmid41553037,
year = {2026},
author = {Shahid, N and Azhar, L and Hussain, I and Khan, MS},
title = {Emerging Alzheimer's therapies: clinical efficacy versus economic feasibility.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/17582024.2026.2617857},
pmid = {41553037},
issn = {1758-2032},
}

@article {pmid41552837,
year = {2026},
author = {Hirmiz, R},
title = {Dementia, Advance Directives, and Second-Order Volitions.},
journal = {Bioethics},
volume = {},
number = {},
pages = {},
doi = {10.1111/bioe.70085},
pmid = {41552837},
issn = {1467-8519},
abstract = {This paper contributes to the ongoing debate over the authority of advance directives in cases where patients with dementia express desires that conflict with their earlier wishes. Drawing on Harry Frankfurt's concept of second-order volitions, I argue that the preferences of the pre-dementia self (the "then-self") should, in most cases, take precedence over those of the post-dementia self (the "now-self")-particularly in instances where the now-self has lost the capacity to form second-order volitions and is no longer able to meaningfully repudiate prior values and commitments.},
}

@article {pmid41552820,
year = {2025},
author = {Fakhri, S and Gravandi, MM and Majnooni, MB and Farzaei, MH and Abbaszadeh, F and Rashidi, K and Echeverría, J},
title = {Ferula ammoniacum gum aqueous extract exerts anti-inflammatory and antioxidant mechanisms to combat aluminum chloride-induced Alzheimer's disease in rats: possible involvement of opioid pathways.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1708643},
pmid = {41552820},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, significantly affects memory and behavior due to dysregulated pathways involving oxidative stress, inflammation, and opioidergic systems. Currently, no effective treatments are available, underscoring the need for novel alternatives. Ferula ammoniacum (D.Don) Spalik, M. Panahi, Piwczyński, and Puchałka [Apiaceae] (FA), an Iranian medicinal plant, is known for its anti-seizure, anti-inflammatory, and analgesic properties, with its gum utilized as a nerve tonic.

PURPOSE: This study investigates the anti-AD effects of F. ammoniacum gum aqueous extract (FAGAE) using an aluminum chloride (AlCl3)-induced Wistar rat model of AD.

MATERIALS AND METHODS: The aqueous extract, prepared by macerating powdered gum in distilled water for 48 h at ambient temperature, was subjected to phytochemical analysis using ultraviolet, infrared, and nuclear magnetic resonance spectroscopy. Thirty rats were assigned to five different groups: one receiving saline, one receiving AlCl3 (100 mg/kg, i.p.), two receiving AlCl3 followed by oral treatment with FAGAE at doses of 50 or 100 mg/kg, and one receiving naloxone (an opioid receptor antagonist) along with AlCl3 and the effective dose of FAGAE. Behavioral changes were evaluated using the open-field, passive avoidance, and elevated plus maze tests. Furthermore, biochemical analyses were conducted to measure the serum nitrite levels, changes in weight, matrix metalloproteinase (MMP) activity, and histopathological changes in brain tissue.

RESULTS AND DISCUSSION: The phytochemical analysis of FAGAE revealed the presence of polysaccharide compounds with tentative arabinogalactan structures. FAGAE decreased step-through latency in the passive avoidance test and modified AlCl3-induced weight changes. FAGAE also significantly increased mobility, grooming, and crossing in the open-field test. Naloxone reversed the anti-AD effects of FAGAE, suggesting a possible role for opioidergic pathways in its therapeutic effects. Zymography results showed that FAGAE reduced MMP-9 activity while increasing MMP-2 activity. Histopathological analysis revealed a preserved number of intact neurons in the hippocampus, whereas reduced serum nitrite levels were observed after FAGAE administration in rats with AD.

CONCLUSION: Behavioral, biochemical, and histopathological impairments induced by AlCl3 were significantly attenuated by FAGAE, possibly through the opioidergic pathway, which combats inflammation and oxidative stress and supports neuronal survival.},
}

@article {pmid41552817,
year = {2025},
author = {Chen, Y and Xiao, W and Qian, C and Huang, L and Lv, J and Wang, Z and Luo, Y},
title = {System Xc-pathway as a potential regulatory target in neurological disorders.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1701320},
pmid = {41552817},
issn = {1663-9812},
abstract = {The System Xc-pathway is composed of the 12-transmembrane transporter protein SLC7A11 (xCT) and the single-channel transmembrane protein SLC3A2 (CD98hc). We detail the pathway's characteristics and distribution within the central nervous system, as well as its canonical role in maintaining glutathione synthesis and inhibiting ferroptosis, and its emerging non-canonical functions in metabolic coupling and neuroimmunity. A core theme is the pathway's context-dependent and often paradoxical role across major neurological disorders, including ischemic stroke, Alzheimer's disease, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. Critically, we analyze how pathological activation of N-methyl-D-aspartate receptors (NMDARs) can dysregulate System Xc-through mechanisms involving calcium overload, reactive oxygen species, and specific signaling axes (e.g., Nrf2, PP2A/AMPK/HMGB1), thereby exacerbating excitotoxicity and oxidative damage. Conversely, System Xc-dysfunction can further fuel NMDAR-mediated injury, creating vicious pathogenic cycles. This analysis reveals that System Xc-is not a unitary target but a dynamic node within a complex network. Consequently, effective therapeutic strategies must move beyond broad inhibition and instead aim for nuanced, cell-type-specific, and disease-stage-precise modulation. This approach will selectively correct the dysfunction of System Xc-while preserving its essential physiological roles. It presents both a significant challenge and a promising frontier for future neuroprotective drug development.},
}

@article {pmid41552642,
year = {2026},
author = {Badeji, AA and Olalekan, SO and Adeleke, AA and Edim, MM and Olaniyi, TO and Alli, OO and Quadri, ON and Oladipo, SD},
title = {Targeting Alzheimer's diseases via nitro-substituted Schiff base derivatives: synthesis, DFT, and molecular dynamics studies.},
journal = {In silico pharmacology},
volume = {14},
number = {1},
pages = {28},
pmid = {41552642},
issn = {2193-9616},
abstract = {UNLABELLED: Alzheimer's disease, a major neurodegenerative disorder, is strongly linked to cholinergic dysfunction, making cholinesterase inhibition a key therapeutic strategy. Herein, the synthesis and in-silico studies of nitro-substituted Schiff base derivatives were studied as potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) targeting Alzheimer's disease. The three synthesized compounds (B1-B3) were obtained in good yields (68-73%). DFT results showed that the vibrational frequencies agreed with the experimental data, and B3 had the smallest HOMO-LUMO gap (6.026 eV) from frontier molecular orbital analysis, indicating higher chemical reactivity. NBO analysis showed it exhibits a strong donor-acceptor interaction with a stabilization energy of 34.80 kcal/mol. Molecular docking results (kcal/mol) showed that B1 (-7.09/-6.59), B2 (-5.30/-6.78), and B3 (-7.42/-6.35) exhibited stronger interactions with AChE and BChE respectively, than the reference drug rivastigmine (-6.66/-5.21). Molecular dynamics simulations showed that rivastigmine had the most favourable binding affinity for AChE, while the Schiff bases, B1-B3 outperformed Rivastigmine against BChE with B3 showing the strongest binding affinity (ΔGbind = - 28.10 kcal/mol for AChE and - 26.31 kcal/mol for BChE) further confirming the result from DFT studies. Structural stability analyses revealed that AChE-B2 (RMSD = 1.384 Å, RoG = 22.817 Å) and BChE-B2 (RMSD = 1.619 Å, RoG = 23.211 Å) complexes were particularly stable, indicating that Schiff bases can form stable and energetically favorable interactions comparable to rivastigmine. Therefore, the study identifies B1 - B3 as promising dual cholinesterase inhibitors with favorable physicochemical properties, suggesting their potential as lead candidates for Alzheimer's disease therapy; however, further in-vitro and in-vivo investigations are essential to validate and confirm their efficacy and safety profiles.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00544-w.},
}

@article {pmid41552530,
year = {2026},
author = {Kurşun-Aktar, BS and Oruç-Emre, EE and Bulut, Z and Ekinci, E and Eyüpoğlu, V and Adem, Ş and Karaküçük-İyidoğan, A},
title = {New Sulfonate-Semicarbazone Hybrid Molecules: Synthesis, Theoretical Evaluations, Molecular Simulations, and Butyrylcholinesterase Inhibition Activity.},
journal = {ACS omega},
volume = {11},
number = {1},
pages = {1727-1744},
pmid = {41552530},
issn = {2470-1343},
abstract = {In the present work, 18 novel semicarbazone-sulfonate hybrids were synthesized to evaluate their potential as butyrylcholinesterase (BChE) inhibitors. Among all compounds, 4-[(E)-(2-carbamoylhydrazinylidene)-methyl]-phenyl 2-(trifluoromethoxy)-benzene-1-sulfonate (12), 4-[(E)-(2-carbamoylhydrazinylidene)-methyl]-phenyl naphthalene-1-sulfonate (17), and 4-[(E)-(2-carbamoylhydrazinylidene)-methyl]-phenyl naphthalene-2-sulfonate (18) exhibited the most potent BChE inhibition, with IC50 values of 61.88, 77.02, and 93.67 μM, respectively, outperforming the reference drug pyridostigmine bromide (IC50: 130.04 μM). As shown by molecular docking studies, numerous interactions, including hydrogen bonds, π-π stacking, π-sulfur contacts, and halogen bonds, supported the high binding of compounds' affinities to the BChE active site. Also, this study employed molecular dynamics (MD) simulations to assess the inhibitory potential of compounds 12, 17, and 18 against BChE. All ligands retained structural integrity during simulations. Compound 17 exhibited the highest conformational stability (minimal RMSD values) and formed robust interactions with critical binding site residues. Additionally, compound 18 demonstrated superior hydrogen bonding capacity, while compound 17 achieved the strongest binding affinity. Furthermore, in silico ADME predictions for the most active molecules showed good pharmacokinetic profiles and drug-likeness. Consequently, the results suggested that semicarbazone-sulfonate hybrid compounds 12, 17, and 18 were promising potential multifunctional agents targeting cholinergic dysfunction in Alzheimer's disease (AD).},
}

@article {pmid41551992,
year = {2025},
author = {Dias da Costa, M and Verdelho, A},
title = {Antipsychotic Use during the COVID-19 Pandemic in a Portuguese Dementia Outpatient Clinic.},
journal = {Portuguese journal of public health},
volume = {},
number = {},
pages = {},
pmid = {41551992},
issn = {2504-3145},
abstract = {BACKGROUND: The COVID-19 pandemic and its consequent confinement have caused a major impact on people living with dementia (PLD). We aimed to ascertain the use of antipsychotic medication in this population due to behavioural symptoms during confinement.

METHODS: We conducted a retrospective study evaluating clinical registrations, namely the use of psychoactive medication, of PLD followed regularly in a Portuguese dementia outpatient clinic during two different confinement periods.

RESULTS: A total of 101 patients were included. Alzheimer's disease was the most frequent diagnosis, most of them in moderate/severe stage. Antipsychotics were used in 21.7% of patients. During confinement, a residual number of patients needed antipsychotic dose increase.

CONCLUSION: Confinement due to COVID-19 in this population was not associated with a significant increase of antipsychotics use. We hope our work may help clarify issues related to the need for antipsychotic medication in behavioural symptoms during confinement in PLD.},
}

@article {pmid41551851,
year = {2026},
author = {Guevara, JE and Matusz, EF and Wang, WE and DeSimone, JC and Yawer, B and Fiala, J and Levy, SA and Arias, F and Rayaprolu, S and Barker, WW and Marsiske, MM and Cid, REC and DeKosky, ST and McFarland, NR and Armstrong, MJ and Adjouadi, M and Vaillancourt, DE and Smith, GE and Loewenstein, DA and Duara, R and Asken, BM},
title = {Factors associated with discordant visual and quantitative amyloid PET results.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70241},
pmid = {41551851},
issn = {2352-8729},
abstract = {INTRODUCTION: Factors underlying discordant visual and quantitative amyloid beta-positron emission tomography (Aβ-PET) results and their clinical implications are not well understood.

METHODS: Participants from the 1Florida Alzheimer's Disease Research Center (1FLADRC) underwent Aβ-PET, blood draw, brain magnetic resonance imaging (MRI), and neuropsychological testing. We evaluated differences in demographics, apolipoprotein E (APOE) status, biomarkers, and cognition among older adults with concordant and discordant visual-quantitative Aβ-PET. Discordance was defined as positive visual read (V) of Aβ-PET with below-threshold Centiloid quantification (Q; CL <25; V+/Q-) or negative visual read with CL ≥25 (V-/Q+).

RESULTS: We studied 386 participants (mean age ± SD: 70.7 ± 7.8, 55.2% female, 44.6% Hispanic White). Compared to V+/Q-, V-/Q+ had a higher frequency of APOE ε4 carriers (40%). Black/African American participants were overrepresented in V-/Q+ (40.9%). Both discordant groups had higher plasma phosphorylated tau 217 (p-tau217) and glial fibrillary acidic protein (GFAP) than V-/Q- but lower than V+/Q+. Discordant groups had greater gray matter volume and better cognitive performance than V+/Q+.

DISCUSSION: Discordant Aβ-PET findings likely hold clinical significance and may reflect early stages of neuropathological progression.

HIGHLIGHTS: Groups with concordant/discordant visual-quantitative amyloid beta-positron emission tomography (Aβ-PET) results were compared.Visual-/quant+ were more likely than visual+/quant- to be apolipoprotein E (APOE) ε4 carriers and Black/African American.Discordant groups had higher plasma phosphorylated tau 217 (p-tau217) and glial fibrillary acidic protein (GFAP) than concordant negative.Discordant groups had less atrophy and better cognition than concordant positive.Centiloid quantification should supplement visual reads in clinical settings.},
}

@article {pmid41551731,
year = {2025},
author = {Lim, S and Lee, HW and Yoon, S and Han, JW and Chung, JY and Yoon, S},
title = {Sex differences in efficacy/safety of anti-amyloid-beta monoclonal antibodies for the treatment of Alzheimer's disease.},
journal = {Translational and clinical pharmacology},
volume = {33},
number = {4},
pages = {212-223},
pmid = {41551731},
issn = {2289-0882},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia. AD exhibits notable sex-related disparities in prevalence, progression, and treatment response. With the recent approval of anti-amyloid-beta monoclonal antibodies-aducanumab, lecanemab, and donanemab-understanding sex differences in their clinical effects has become increasingly relevant. This review article investigates sex differences in the pharmacokinetics, efficacy, and safety of aducanumab, lecanemab, and donanemab and discusses the possible mechanism underlying the observed differences. Although sex-specific analyses were largely underreported in clinical trials, population pharmacokinetic models identified sex as a covariate affecting clearance and volume of distribution for aducanumab and lecanemab and higher exposure to lecanemab was predicted for females. Subgroup analyses of phase 3 trials revealed that males tended to experience greater benefit from aducanumab and lecanemab, whereas females showed better response to donanemab. The overall incidence of adverse events, including amyloid-related imaging abnormalities, did not show significant differences between sexes. Potential mechanisms underlying these differences include sex-related variations in blood-brain barrier permeability, apolipoprotein E4-associated neuroinflammatory responses, and baseline disease characteristics. These findings underscore the need for future AD clinical trials to incorporate sex-based analyses and to consider sex as a key factor in optimizing treatment strategies.},
}

@article {pmid41551727,
year = {2026},
author = {Singh, S and Singh, P and Varada, MP and Vijaivasudev, MJ and Kumar, R and Malik, I},
title = {eVGeMdb: a manually curated database for experimentally validated genetic modifiers of neurodegenerative disorders.},
journal = {NAR molecular medicine},
volume = {3},
number = {1},
pages = {ugaf044},
pmid = {41551727},
issn = {2976-856X},
abstract = {Genetic modifiers are genes that, while not directly causing disease, can alter the onset, progression, severity, or specific phenotypes of a disease by interacting with the primary disease-causing genes. Despite their importance, knowledge of these modifiers remains fragmented across different experimental models of neurodegenerative disorders (NDs). To address this lacuna, we developed eVGeMdb (https://project.iith.ac.in/cgntlab/eVGeMdb/), a manually curated, comprehensive database of experimentally validated genetic modifiers of major NDs, including Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Spinocerebellar ataxias, Fragile X-associated Tremor/Ataxia Syndrome, and other general PolyQ disorders. eVGeMdb integrates modifiers from commonly used diverse experimental model systems, including Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, cellular models (human, mice, Drosophila cells), and mouse. The database currently incorporates over 17000 entries, each annotated with experimental context, gene-specific functional information, relevant human orthologs, and links to protein-protein interaction networks and enriched pathways. The resource enables cross-disease and model-specific comparisons, allowing the identification of both universal and disease-specific modifiers. By consolidating dispersed genetic modifier information into a single, accessible platform, eVGeMdb provides a comprehensive tool for researchers in the field to explore modifier effects, prioritize experimental validations, formulate novel hypotheses, and investigate pathophysiological mechanisms underlying neurodegenerative disorders.},
}

@article {pmid41551313,
year = {2025},
author = {Zhu, T and Yang, D and Quan, F and Chen, Y and Cui, J},
title = {Neural mechanisms of acupuncture in amnestic mild cognitive impairment: a protocol for an fMRI-based systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1641297},
pmid = {41551313},
issn = {1664-2295},
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI), characterized by progressive memory decline, represents a prevalent transitional state in global aging populations and exhibits high conversion rates to Alzheimer's disease (AD), constituting a critical window for preventive interventions. While accumulating evidence supports acupuncture's efficacy in enhancing cognitive performance, the precise neural mechanisms underlying its therapeutic effects remain poorly characterized. This neuroimaging investigation aims to elucidate the cerebral reorganization patterns mediating acupuncture-induced cognitive improvement in aMCI pathophysiology.

METHODS AND ANALYSIS: A systematic search strategy was implemented across eight electronic databases supplemented by manual searches, covering publications from each database's inception to May 1, 2025. Eligible study designs included randomized controlled trials (RCTs), prospective case-control studies, and observational investigations. Two independent investigators performed literature screening and data extraction, with discrepancies resolved through consensus or third-party adjudication. Methodological quality appraisal was conducted using the validated Agency for Healthcare Research and Quality (AHRQ) checklist. Primary outcomes focused on resting-state functional MRI (rs-fMRI) whole-brain functional imaging parameters. Meta-analytic synthesis of neuroimaging data will utilize seed-based d mapping with permutation of subject images (SDM-PSI, version 6.21), while clinical outcome analyses will be performed using RevMan 5.3 software (Cochrane Collaboration). Reporting will strictly adhere to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.

CONCLUSION: This study synthesizes findings from independent neuroimaging investigations to establish comprehensive evidence supporting the neurotherapeutic effects of acupuncture in aMCI.

https://www.crd.york.ac.uk/prospero/, Identifier CRD420251033511.},
}

@article {pmid41551223,
year = {2026},
author = {Alam, MT and Rauf, MA and Khan, A and Hussain, R},
title = {Mechanistic Insights Into Protein Aggregation Inhibition by Green-Synthesized Silver Nanoparticles: A Study on Human Lysozyme.},
journal = {IET nanobiotechnology},
volume = {2026},
number = {},
pages = {2694374},
pmid = {41551223},
issn = {1751-875X},
mesh = {*Silver/chemistry/pharmacology ; *Metal Nanoparticles/chemistry ; Humans ; *Muramidase/chemistry/metabolism ; *Protein Aggregates/drug effects ; Green Chemistry Technology/methods ; },
abstract = {A characteristic of many neurodegenerative disorders, such as Parkinson's and Alzheimer's, is amyloidogenic protein aggregation, for which there are currently no proven cures. Aging, mutation, and physiological stress can cause proteins to deviate from their natural folding patterns, potentially leading to the formation of hazardous protein aggregates. Noble metal nanoparticles (NPs), due to their unique physicochemical properties, have emerged as promising tools in biomedicine, with applications ranging from tissue engineering to drug delivery and diagnostics. Although concerns regarding cytotoxicity exist, small-sized silver (Ag) NPs (AgNPs) have demonstrated potential in antiviral, anticancer, and antibacterial therapies. This study investigated the development of biocompatible AgNPs using a green synthesis approach and examined their chaperone-like activity against protein aggregation, emphasizing the role of meticulous in vitro design. Human lysozyme (HLZ) served as a model protein for aggregation inhibition assays. Biogenic AgNPs exhibited a concentration-dependent effect on HLZ aggregation, demonstrating an optimal inhibitory concentration, followed by a decrease in efficacy at higher concentrations. Furthermore, astrocytes treated with AgNPs displayed reduced protein aggregation, suggesting a chaperone-like behavior. The initial phase focused on the detailed characterization of AgNPs synthesized using orange juice extract. Subsequently, this study explored the mechanistic understanding of AgNP-mediated inhibition of protein aggregation under controlled conditions. A battery of biophysical techniques, including circular dichroism (CD), 8-anilino-1-naphthalene-sulfonic acid (ANS) fluorescence, thioflavin T (ThT) fluorescence, Congo red (CR) assay, and turbidity measurements, was employed to meticulously assess the inhibitory effect on HLZ aggregation in vitro.},
}

*Silver/chemistry/pharmacology
*Metal Nanoparticles/chemistry
Humans
*Muramidase/chemistry/metabolism
*Protein Aggregates/drug effects
Green Chemistry Technology/methods

@article {pmid41551043,
year = {2025},
author = {Sykora, M and Harmackova, M and Parobkova, E and Rusina, R and Matěj, R},
title = {An unexpected discovery of a novel potentially pathogenic APP gene variant: a case report of slowly progressive Alzheimer's disease with prominent cerebral amyloid angiopathy.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1703718},
pmid = {41551043},
issn = {1662-4548},
abstract = {Amyloid precursor protein (APP) plays an essential role in brain function and development. Variants in the APP gene are associated with both familial Alzheimer's disease and cerebral amyloid angiopathy. We report a case of early onset, slowly progressive mixed dementia with a newly identified APP variant. The patient developed mild cognitive impairment at age 51, followed by neuropsychiatric symptoms, seizures, and progressive white matter changes. Despite a fluctuating clinical course, significant deterioration occurred later, culminating in death at age 77. Genetic testing revealed an APP c.2086G > A (p.Gly696Ser) variant, currently classified as a variant of uncertain significance (VUS). Postmortem examination showed definite AD neuropathologic changes, with fully blown amyloid pathology including amyloid deposits in plaques as well as in severe generalized cerebral angiopathy with concomitant advanced FTLD-tau pathology. In silico analysis of the variant's impact was performed, and the inconclusive results are discussed later.},
}

@article {pmid41551000,
year = {2026},
author = {He, Y and Leng, Y and Vranceanu, AM and Ritchie, CS and Blacker, D and Das, S},
title = {A predictive model for cognitive decline using social determinants of health.},
journal = {JAR life},
volume = {15},
number = {},
pages = {100056},
pmid = {41551000},
issn = {2534-773X},
abstract = {BACKGROUND: Early diagnosis of Alzheimer's disease and related dementias (AD/ADRD) is critical but often constrained by limited access to fluid and imaging biomarkers, particularly in low-resource settings.

OBJECTIVE: To develop and evaluate a predictive model for cognitive decline using survey-based data, with attention to model interpretability and fairness.

METHODS: Using data from the Mexican Health and Aging Study (MHAS), a nationally representative longitudinal survey of adults aged 50 and older (N = 4095), we developed a machine learning model to predict future cognitive scores. The model was trained on survey data from 2003 to 2012, encompassing demographic, lifestyle, and social determinants of health (SDoH) variables. A stacked ensemble approach combined five base models-Random Forest, LightGBM, XGBoost, Lasso, and K-Nearest Neighbors-with a Ridge regression meta-model.

RESULTS: The model achieved a root-mean-square error (RMSE) of 39.25 (95 % CI: 38.12-40.52), representing 10.2 % of the cognitive score range, on a 20 % held-out test set. Features influencing predictions, included education level, age, reading behavior, floor material, mother's education level, social activity frequency, the interaction between the number of living children and age, and overall engagement in activities. Fairness analyses revealed model biases in underrepresented subgroups within the dataset, such as individuals with 7-9 years of education.

DISCUSSION: These findings highlight the potential of using accessible, low-cost SDoH survey data for predicting risk of cognitive decline in aging populations. They also underscore the importance of incorporating fairness metrics into predictive modeling pipelines to ensure equitable performance across diverse groups.},
}

@article {pmid41550978,
year = {2026},
author = {Moien, MAS and Saghravanian, SJ and Fereidoni, M},
title = {Evaluating the impact of intracerebroventricular norepinephrine on spatial memory in rats: Insights into sporadic Alzheimer's pathogenesis.},
journal = {IBRO neuroscience reports},
volume = {20},
number = {},
pages = {84-93},
pmid = {41550978},
issn = {2667-2421},
abstract = {One consequence of stress is the increased release of norepinephrine (NE) in the central nervous system, primarily driven by activation of the sympathetic nervous system. Given the importance of chronic stress in the development and progression of Alzheimer's disease (AD), clarifying the specific contributions of stress-related pathways, including the sympathetic axis and the hypothalamic-pituitary-adrenal (HPA) axis, is critical. In this study, we examined the effects of repeated central NE administration, as a potential contributor to stress-related cognitive impairment, on spatial memory in rats, alone or in combination with a low-dose streptozotocin (STZ) model of sporadic AD. Forty-nine rats were assigned to seven groups: control (no treatment), sham (saline; i.c.v.), low-dose streptozotocin (0.5 mg/kg, i.c.v.), norepinephrine administration at either 1 (adolescent) or 3 (adult) months of age (30 or 50 μg, respectively; i.c.v.), and co-administration of norepinephrine with streptozotocin at 1 or 3 months of age. Spatial memory was assessed using the Morris Water Maze test. Norepinephrine administration during adolescence and adulthood impaired spatial memory similar to streptozotocin in different parameters of the MWM, with adult rats showing the most significant vulnerability (p < 0.001). However, co-administration of both substances did not exacerbate the impairment caused by each alone. The results suggest that norepinephrine may impair cognition through mechanisms distinct from those of STZ-induced deficits. Additionally, they raise questions about the contribution of the sympathetic axis of chronic stress to the progression of sporadic AD.},
}

@article {pmid41550956,
year = {2025},
author = {Piccolino, I and Iannuzzi, F and Lionetti, L and Mazzonello, B and Barreca, V and Banaj, N and Arezzini, V and Piras, F and Bossù, P},
title = {The immunomodulating effect of palmitoylethanolamide on human myeloid dendritic cells and its possible impact on Alzheimer's disease.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1664164},
pmid = {41550956},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/drug therapy/metabolism ; *Palmitic Acids/pharmacology ; *Dendritic Cells/immunology/drug effects/metabolism ; *Ethanolamines/pharmacology ; *Amides/pharmacology ; *Myeloid Cells/immunology/drug effects/metabolism ; Cells, Cultured ; *Immunomodulation/drug effects ; *Immunologic Factors/pharmacology ; },
abstract = {Palmitoylethanolamide (PEA) is an endogenous fatty acid amide that has emerged as a promising therapeutic candidate for neurodegenerative disorders, particularly Alzheimer's disease (AD). Recognized for its inherent anti-inflammatory, analgesic, immunomodulatory, and neuroprotective properties, PEA possesses a good potential as a novel treatment addressing neuroinflammation associated with neurodegeneration, even though its precise mechanisms of action remain to be fully understood. Dendritic cells (DCs) are specialized migratory innate immune cells that play a crucial role in initiating and regulating immune responses and inflammation in both the body and the brain. In AD, DCs display a dysfunctional, pro-inflammatory profile, suggesting their involvement in disease pathology and progression. To explore the therapeutic potential of PEA, this study investigated its effects in vitro on human monocyte-derived DCs under both normal and AD-like conditions. The results show that PEA exerts significant immunomodulatory effects, promoting the maturation of DCs in both healthy and disease states. Notably, PEA treatment appears to correct the dysregulated state of DCs observed in AD conditions. This study reveals a novel mechanism by which PEA modulates immune activity through its action on DCs. By restoring normal DC function in neurodegenerative settings, PEA may help reduce inflammation, highlighting its potential as a therapeutic agent for Alzheimer's disease.},
}

Humans
*Alzheimer Disease/immunology/drug therapy/metabolism
*Palmitic Acids/pharmacology
*Dendritic Cells/immunology/drug effects/metabolism
*Ethanolamines/pharmacology
*Amides/pharmacology
*Myeloid Cells/immunology/drug effects/metabolism
Cells, Cultured
*Immunomodulation/drug effects
*Immunologic Factors/pharmacology

@article {pmid41550754,
year = {2026},
author = {Casanova-Pagola, J and Varriano, F and López-Gil, X and Campoy-Campos, G and Abellí-Deulofeu, E and García-González, C and López-Bravo, E and Tudela, R and Muñoz-Moreno, E and Aguado, F and Prats-Galino, A and Molina-Porcel, L and Malagelada, C and Soria, G},
title = {Early-life cognitive intervention preserves brain function in aged TgF344-AD rats with sex-specific effects.},
journal = {iScience},
volume = {29},
number = {1},
pages = {114381},
pmid = {41550754},
issn = {2589-0042},
abstract = {Alzheimer's disease is characterized by progressive cognitive decline, and its effects are mitigated by cognitive reserve. We investigated whether long-term cognitive stimulation, initiated before amyloid deposition, preserves brain function in male and female TgF344-AD rats. Transgenic and wild-type (WT) rats underwent cognitive training or remained untrained. Resting-state fMRI assessed functional connectivity, the novel object recognition test evaluated memory, and molecular analyses examined synaptic plasticity, inhibitory signaling, and microglial reactivity. At baseline, females showed greater task engagement and higher synaptic protein levels (PSD95, TrkB, and VGLUT) than males. Cognitive training improved connectivity and memory in males, with limited benefits in females. At 19 months, trained transgenic rats maintained entorhinal-hippocampal connectivity resembling WT rats, with males showing sustained plasticity markers and reduced parvalbumin-positive interneurons. Trained 11-month-old rats showed enhanced microglial recruitment to plaques and a less reactive phenotype. Overall, early and sustained cognitive stimulation enhances brain resilience, with sex-specific mechanisms shaping outcomes.},
}

@article {pmid41550689,
year = {2025},
author = {Pinky, and Wali, Z and Neha, and Tiwari, P and El-Tanani, M and Rabbani, SA and Parvez, S},
title = {Aging and Alzheimer's: the critical role of mitochondrial dysfunction and synaptic alterations.},
journal = {Frontiers in synaptic neuroscience},
volume = {17},
number = {},
pages = {1676317},
pmid = {41550689},
issn = {1663-3563},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder marked by cognitive decline, accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic dysfunction, and mitochondrial impairment. Despite multiple therapeutic strategies, currently available treatments only provide symptomatic relief without halting disease progression. Emerging evidence implicates mitochondrial dysfunction-including oxidative stress, impaired calcium signaling, mitophagy deficits, disrupted proteostasis, and electron transport chain abnormalities, as central to AD pathogenesis. These dysfunctions contribute to synaptic degeneration, increased reactive oxygen species, and neuronal death. This review consolidates current knowledge on the mechanistic pathways of mitochondrial impairment in AD and their downstream effects on neuronal health. We also explore the therapeutic potential of multitarget approaches, including agents targeting Aβ and tau pathology, oxidative stress mitigation, mitochondrial quality control, and synaptic restoration. By integrating evidence from recent preclinical and clinical studies, this work highlights mitochondrial homeostasis as a promising frontier for disease-modifying therapies in AD.},
}

@article {pmid41550591,
year = {2026},
author = {Madhi, I and Kim, JH and Shin, HS and So, YH and Jung, EM and Kim, Y},
title = {Ginsenoside Re mitigates Aβ1-42-induced neurotoxicity by promoting autophagy and suppressing NLRP3 inflammasome.},
journal = {Journal of ginseng research},
volume = {50},
number = {1},
pages = {100911},
pmid = {41550591},
issn = {1226-8453},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and neuroinflammation. Activation of NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome in microglia significantly contributes to AD-associated neuroinflammation and neuronal damage. Ginsenoside Re (G-Re), a major bioactive constituent of Panax ginseng, exhibits anti-inflammatory properties, but its role in modulating inflammasome activation in AD remains unclear.

METHODS: This study evaluated the therapeutic potential of G-Re in mice intracerebroventricularly injected with Aβ1-42 and delineated its molecular mechanisms in complementary cell-based models. We employed behavioral testing, immunohistochemistry, Western blotting, enzyme-linked immunosorbent assays, Annexin V apoptosis assays, and mitochondrial functional assays.

RESULTS: Intraperitoneal administration of G-Re significantly improved cognitive performance, as evidenced by enhanced outcomes in the T-maze and novel object recognition tests. G-Re treatment reduced microglial activation and interleukin-1β (IL-1β) levels in the cortex and hippocampus. In vitro, G-Re protected neurons from conditioned medium derived from Aβ1-42-stimulated microglia, showing neuroprotection comparable to anti-IL-1β treatment. G-Re also inhibited Aβ1-42-induced activation of the NLRP3 inflammasome, as indicated by diminished levels of NLRP3, cleaved caspase-1, cleaved gasdermin D (GSDMD), IL-1β, and IL-18 in brain tissues and cultured microglia. Mechanistically, G-Re reduced mitochondrial reactive oxygen species (mtROS), preserved mitochondrial membrane potential, and activated autophagy via SIRT1/AMPK/mTOR signaling, thereby suppressing inflammasome activation.

CONCLUSION: G-Re ameliorates Aβ1-42-induced neuroinflammation and cognitive impairment by restoring mitochondrial homeostasis, enhancing autophagy, and suppressing NLRP3 inflammasome activation. These findings suggest G-Re as a potential therapeutic intervention for neurodegenerative disorders including AD.},
}

@article {pmid41550584,
year = {2025},
author = {Britt, KC and Obeng Boateng, AC and Nwadiogbu, C and Ashida, S and Tranel, D and Thorpe, RJ and Dahodwala, N},
title = {Facets of Religion/Spirituality and Cognitive Health: Association Variations Across Gender and Race Among Older Adults.},
journal = {Religions},
volume = {16},
number = {9},
pages = {},
pmid = {41550584},
issn = {2077-1444},
abstract = {Religion and spirituality (R/S) may be associated with better cognitive health, yet most published studies have been conducted in primarily White populations without investigating association variations by gender and race. A cross-sectional analysis of 1,041 community-dwelling diverse older adults from the Philadelphia Healthy Brain Aging (PHBA) cohort study was conducted using multiple regression analysis. We examined associations between facets of R/S and total cognitive scores and performed stratification analysis separately by gender and race to explore potential gender- and race-specific variations. Higher non-organizational R/S was associated with lower cognitive scores, while greater religious and spiritual coping was associated with higher cognitive scores, controlling for age, education, chronic conditions, race, and financial constraints. Across gender and race variations, non-organizational R/S was associated with lower cognitive scores in women alone, with no variations across race. Higher religious and spiritual coping was associated with higher cognitive scores in both Black and White women, but not men, while higher religious and spiritual healing was associated with lower cognitive scores in Black women only. Associations between religious and spiritual facets and cognitive health differ across gender and race; longitudinal studies are needed.},
}

@article {pmid41550486,
year = {2026},
author = {Gao, H and Yang, S and Zhaorong, O and Wang, Y and Tang, J and Hou, Q and Fang, Z and Shao, N and Cai, B},
title = {Aloe-emodin attenuates Aβ25-35-induced HT22 cell pyroptosis via inhibiting NLRP3 inflammasome pathway.},
journal = {3 Biotech},
volume = {16},
number = {2},
pages = {71},
pmid = {41550486},
issn = {2190-572X},
abstract = {Neuronal death in Alzheimer's disease (AD) is closely associated with NLRP3 inflammasome-mediated pyroptosis. This study aimed to investigate the protective effects of Aloe-emodin (AE) in an AD cellular model and to explore the underlying mechanisms involving the NLRP3 inflammasome pathway. Molecular docking simulations predicted strong binding affinities between AE and key pyroptosis-related proteins (NLRP3, ASC, Caspase-1, GSDMD), with the highest affinity observed for NLRP3. In an Aβ25-35-induced AD cellular model, AE (6 µM) significantly enhanced cell viability and alleviated pyroptotic morphological changes, including cellular swelling and rupture. EdU staining and immunofluorescence analysis further revealed that AE promoted HT22 cell proliferation and reduced Aβ deposition. Moreover, assessments of plasma and mitochondrial membrane integrity, via Hoechst 33,342/PI staining and mitochondrial permeability transition pore (MPTP) assay, respectively, revealed that AE treatment reduced the population of PI-positive cells and suppressed MPTP opening. Western blot, immunofluorescence, and ELISA analyses consistently demonstrated that AE downregulated the expression of pyroptosis-related proteins (NLRP3, ASC, Caspase-1, GSDMD, GSDMD-N) and suppressed the release of inflammatory cytokines (IL-1β, IL-18, IL-6, TNF-α). The inhibitory effect of AE on the pyroptosis pathway was comparable to that of the specific NLRP3 inhibitor MCC950. These results suggest that AE exerts neuroprotective effects in the AD cellular model by inhibiting NLRP3 inflammasome activation, thereby blocking Caspase-1 and GSDMD-N activation, attenuating neuronal pyroptosis, reducing inflammatory responses, and mitigating Aβ-induced pathological damage. Collectively, these findings identify AE as a promising therapeutic candidate for AD.},
}

@article {pmid41550444,
year = {2026},
author = {Fabi, A and Alves, AS and Neutzner, A and Frank, S and Lariu, A and Muller, L and Ismail, T and Gkotsoulias, DG and Guzman, R and Schaefer, DJ and Grossman, N and Busche, MA and Kappos, EA},
title = {Neurolymphatic clearance in neurodegenerative disease: Emerging mechanisms and potential translational strategies.},
journal = {JPRAS open},
volume = {48},
number = {},
pages = {438-449},
pmid = {41550444},
issn = {2352-5878},
abstract = {INTRODUCTION: Neurolymphatic dysfunction has been linked to cognitive decline and implicated in the pathogenesis of neurodegenerative disorders such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). Despite its growing recognition, the potential role of pharmacological or surgical neurolymphatic modulation remains poorly understood.

OBJECTIVES: This review summarizes current evidence on the neurolymphatic system's anatomy, physiology and its involvement in neurodegenerative diseases. It also examines emerging pharmacological and lymphatic reconstructive techniques.

METHODS: A comprehensive literature search was conducted in PubMed, yielding 187 studies related to the neurolymphatic system. Studies were screened for the following topics: (1) Anatomy and physiology of the neurolymphatic system, (2) The association between neurolymphatic dysfunction and neurodegenerative diseases, (3) Pharmacological and (4) Microsurgical neurolymphatic modulation.

RESULTS: Current evidence suggests that the neurolymphatic system facilitates drainage of interstitial and cerebrospinal fluid to the deep cervical lymph nodes. Preclinical models suggest that enhancing their clearance may promote the clearance of neurotoxic proteins and potentially improve cognitive function.

CONCLUSIONS: Scientific evidence on neurolymphatic modulation in neurodegenerative diseases is scarce. Both pharmacological and microsurgical modulatory techniques remain experimental approaches for neurodegenerative diseases, with a significant potential to improve patients' quality of life. However, further research is warranted to establish their safety, feasibility, and efficacy. The current knowledge gaps underscore the need for a detailed mapping of the neurolymphatic pathways, preclinical evaluation, and translational interdisciplinary trials.},
}

@article {pmid41550364,
year = {2025},
author = {Schedlowski, J and Maes, JHR and van Asselt, RJ and Bertens, D and Egger, JIM and Kessels, RPC},
title = {Identity Matching and Stimulus Equivalence Learning Paradigms for Memory Rehabilitation of Explicit Memory Deficits: A Scoping Review.},
journal = {Perspectives on behavior science},
volume = {48},
number = {4},
pages = {759-802},
pmid = {41550364},
issn = {2520-8977},
abstract = {Explicit memory dysfunction, such as in Alzheimer's dementia, impairs learning and daily functioning, requiring effective rehabilitation strategies to promote functional independence. Relational learning paradigms such as stimulus equivalence learning (SEL) imply the formation of networks of relations in which trained relations give rise to emergent relations, potentially providing a novel approach to addressing deficits in remembering and stimulus control. We evaluated the scope and nature of research on the application of relational learning paradigms for memory rehabilitation. In particular, we outline the evidence for the efficacy of identity matching and SEL in specific disorders, the associated effective strategies, and challenges to guide future research. A systematic search following the PRISMA-ScR guidelines identified 23 reports categorized into identity matching, arbitrary matching, and differential outcome procedure (DOP) paradigms. Findings were mixed regarding the success of training procedures. Studies indicate particularly positive outcomes under the DOP and overall efficacy seemed to depend on impairment severity. However, current evidence on the efficacy of relational learning paradigms in individuals with explicit memory dysfunction remains inconclusive due to uncontrolled designs and methodological weaknesses in statistical analysis and patient reporting. Nevertheless, insights from the reviewed studies can inform more rigorous future research. The focus should be on identifying the necessary and sufficient conditions for training stimulus equivalence relations in this population, within meaningful and well-controlled experimental designs to validate the preliminary findings and assess SEL's potential as a cognitive intervention.},
}

@article {pmid41550299,
year = {2025},
author = {Dhaka, P and Pinky, and Neha, and Khan, MA and Rabbani, SA and El-Tanani, M and Parvez, S},
title = {Trazodone modulates behavioral alterations in scopolamine-induced cognitive deficit by targeting brain-derived neurotropic factor and cAMP response element-binding protein signaling.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1681080},
pmid = {41550299},
issn = {1662-5102},
abstract = {BACKGROUND: Trazodone, an antidepressant, may play a potential role in enhancing long-term memory by combining anxious behavior deficits induced by scopolamine. The current study proposes the potential novel mechanistic insights between oxidative stress and memory biomarkers, including BNDF and CREB pathways, to modulate the pathogenesis of AD-like symptoms.

METHODS: Behavioral deficits were studied in terms of biochemical determination of lipid peroxidation and acetylcholinesterase activities. In addition, the study looked at the immunohistochemistry of BDNF and CREB against scopolamine-induced AD-like symptoms. Moreover, histopathological alterations were also performed against an AD-like model. Aβ42 proteins immunofluorescence was performed due to its known mechanism under AD. Finally, scopolamine-induced intraperitoneal mechanisms were studied in rats to establish an AD-like model.

RESULTS: The present study findings showed that administration of TRAZ considerably improved cognitive impairments as validated by NOR and display of anti-anxiety behavior, as verified by EPM. In addition, biochemical findings confirmed that TRAZ lowered oxidative stress through LPO, reduced Aβ deposition, and decreased the AChE. Furthermore, there was a notable upregulation of BDNF and CREB signaling expression, as confirmed by the IHC.

CONCLUSION: Overall, the study findings confirmed that TRAZ could be useful in mitigating the negative effects of scopolamine-induced cognitive impairment and lowering oxidative stress by enhancing memory indicators.},
}

@article {pmid41550298,
year = {2025},
author = {Saminathan, P and McArdle, S and Corey, M and Nadig, N and Fang, C and Gibbons, A and Rayadurgam, M and Sharma, S},
title = {Unmasking early microglial remodeling in an Alzheimer's disease mouse model.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1720382},
pmid = {41550298},
issn = {1662-5102},
abstract = {Early neuroimmune remodeling is a critical yet understudied component of Alzheimer's disease (AD) pathogenesis. To investigate microglial contributions to AD development prior to overt plaque deposition, we developed an open-source morphometric pipeline to systematically quantify hippocampal microglial structure and activation states in pre-plaque 5xFAD mice. Across ∼11,000 cells, we extracted multidimensional parameters including area, circularity, convex hull, branch points, nearest-neighbor distance, and nuclear features, alongside Iba1 and CD68 intensity measurements. While no significant overt gliosis was observed at this early stage, microglia from 5xFAD mice exhibited subtle trends toward increased structural complexity compared to wild-type controls. Importantly, significant sex-specific differences were detected within the CA1 subregion: male 5xFAD microglia displayed hyper-ramified morphologies consistent with enhanced surveillance states, whereas female microglia demonstrated greater density and a more reactive phenotype. Correlation analyses revealed a conserved association between microglial complexity and Iba1/CD68 expression, independent of sex or genotype, underscoring a fundamental link between cytoskeletal remodeling and phagolysosomal activity. These findings highlight the capacity of morphometric profiling to sensitively detect early, region-specific, and sex-dependent shifts in microglial phenotype before amyloid deposition. By integrating quantitative morphology with canonical molecular markers, this framework provides a robust and unbiased approach for characterizing microglial activation trajectories. Such early readouts may inform biomarker discovery and therapeutic strategies aimed at modulating microglial responses to delay or prevent AD progression.},
}

@article {pmid41550140,
year = {2026},
author = {Bota, PM and Picón-Pagès, P and Fanlo-Ucar, H and Almabhouh, S and Bagudanch, O and Zeylan, ME and Senyuz, S and Gohl, P and Molina-Fernández, R and Fernandez-Fuentes, N and Barbu, E and Vicente, R and Nattel, S and Ois, A and Puig-Pijoan, A and Garcia-Ojalvo, J and Keskin, O and Gursoy, A and Muñoz, FJ and Oliva, B},
title = {Oxidative stress-driven transcriptomic remodeling in human astrocytes reveals network signatures associated with neurodegenerative and cardiovascular processes.},
journal = {Computational and structural biotechnology journal},
volume = {31},
number = {},
pages = {263-275},
pmid = {41550140},
issn = {2001-0370},
abstract = {Astrocytes are central to brain homeostasis, supporting neuronal metabolism, synaptic activity, and the blood-brain barrier. With aging, these glial cells undergo molecular and functional changes that weaken support functions and promote neuroinflammation, contributing to neurodegeneration. Yet the systems-level mechanisms by which astrocytes respond to aging-related stressors remain poorly defined in human models. Because aging also heightens risk for cardiovascular disease, cognitive impairment, type 2 diabetes, and systemic inflammation, clarifying shared astrocytic pathways is critical for understanding brain-body crosstalk. Using an in vitro human astrocyte model exposed to sublethal oxidative stress (10 µM H2O2) as a proxy for age-related cellular stress, we profiled transcriptomic changes and identified differentially expressed genes across antioxidant defenses, proteostasis, transcriptional regulation, vesicular trafficking, and inflammatory signaling. We then performed network-prioritization analyses on a curated human protein-protein interactome: one seeded with the astrocyte oxidative stress responsive genes and six with phenotype-associated gene sets (Alzheimer's disease, cardiovascular disease, cognitive impairment, type 2 diabetes, oxidative stress, and inflammation). Intersecting the top 5 % scoring genes from each run yielded a 127-gene core shared across all seven, enriched for proteostasis, DNA repair, mitochondrial regulation, and telomere and nuclear envelope maintenance. Structure-guided analyses highlighted vulnerable interfaces, including lamin A/C-lamin B1, α-actinin-filamins, 14-3-3 dimers, and aminoacyl-tRNA synthetase assemblies, where pathogenic variants are predicted to destabilize or aberrantly stabilize protein interactions. Structure-based interface predictions also highlight potential interactions between amyloid precursor protein (APP) and valosin-containing protein (VCP), and between p53 and 14-3-3ζ, potentially linking proteostasis and stress signaling. Together, these analyses identify a conserved astrocyte-centered network signature that may relate neurodegenerative and cardiovascular processes, and prioritize structurally testable candidates for biomarker and intervention hypothesis testing.},
}

@article {pmid41549952,
year = {2026},
author = {Alanazi, M and Al-Kuraishy, HM and Hussain, NR and Waheed, HJ and Al-Gareeb, AI and Albuhadily, AK and Waheeb, TS and Batiha, GE},
title = {Targeting of PCSK9 in the Management of Alzheimer's Disease: Expanding the New Potential Key Player.},
journal = {Drug development research},
volume = {87},
number = {2},
pages = {e70231},
doi = {10.1002/ddr.70231},
pmid = {41549952},
issn = {1098-2299},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Proprotein Convertase 9/metabolism ; Animals ; *PCSK9 Inhibitors ; Brain/metabolism/pathology ; Oxidative Stress/drug effects ; Receptors, LDL/metabolism ; },
abstract = {Alzheimer's disease (AD) represents the most common cause of dementia in the elderly population worldwide. However, most of the anti-AD medications did not resolve the underlying neuropathology. Consequently, targeting other signaling pathways may be helpful in the management of AD. Particularly, preprotein convertase subtilisin/kexin type 9 (PCSK9), which is a regulator protein of low-density lipoprotein (LDL), is intricate in the pathogenesis of AD. Normally expressed PCSK9 in the brain plays a critical role in the regulation of neuronal differentiation and apoptosis, and degradation of LDL receptors (LDLRs). However, exaggerated brain PCSK9 via induction of inflammation and oxidative stress and related neurodegeneration may induce AD development. Therefore, neuronal PCSK9 has dual role in the CNS. Nevertheless, the exact role of PCSK9 in AD neuropathology is still elusive. Therefore, in the review, we try to revise and discuss the potential role of PCSK9 in the pathogenesis of AD, and how targeting of this protein may be helpful in the management of AD.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Proprotein Convertase 9/metabolism
Animals
*PCSK9 Inhibitors
Brain/metabolism/pathology
Oxidative Stress/drug effects
Receptors, LDL/metabolism

@article {pmid41549803,
year = {2026},
author = {Cheng, S and Zhang, M and Zhang, J and Xie, X and Li, Y and Dou, X and Jiao, X and Tang, Y and Wang, X and Tang, B},
title = {Bioorthogonally Activatable Chemiluminescence for the N-Methyl-d-aspartate Receptors Intravital Imaging.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {e23648},
doi = {10.1002/anie.202523648},
pmid = {41549803},
issn = {1521-3773},
support = {22174089//National Natural Science Foundation of China/ ; 22134004//National Natural Science Foundation of China/ ; 92253304//National Natural Science Foundation of China/ ; 22377069//National Natural Science Foundation of China/ ; 22374093//National Natural Science Foundation of China/ ; YDZX2022012//Local Science and Technology Development Fund Guided by the Central Government of Shandong Province/ ; },
abstract = {The signal attenuation caused by skull/vertebrae remains a challenge in central nervous system (CNS) receptor imaging. Chemiluminescence (CL), free from external excitation, offers unparalleled tissue penetration in optical imaging. However, existing 1,2-dioxetane CL systems are shackled by two limitations: (i) short half-lives (<2 h) from rapid dioxetane decomposition and (ii) dependence on reactive biomolecules such as reactive oxygen species and enzymes to trigger dioxetane decomposition, rendering them incompatible with imaging nonreactive biomolecules like receptor proteins. Here we report a bioorthogonally activatable chemiluminescence (BACL) strategy that integrates click-to-release reactions with 1,2-dioxetane luminophores to enable tetrazine-triggered OFF-ON CL signals and bioorthogonally tunable half-lives (5.2-18 h). The tissue penetration depth was up to 6 cm. Through a tetrazine-conjugated specific ligand, BACL imaged N-methyl-d-aspartate receptors (NMDARs) in vivo with a signal background ratio of ∼182, allowing clear differentiation of NMDAR expression levels between Alzheimer's disease model mice and normal controls. Beyond imaging, the bioorthogonally spatiotemporally controlled CL emission positions BACL as a potential internal light source for deep-tissue precision phototherapeutics, bypassing external irradiation.},
}

@article {pmid41549419,
year = {2026},
author = {Singh, V and Rochakim, N and Ferraresso, F and Garg, K and Rizvi, AB and Choudhury, A and Kastrup, CJ and Ahn, HJ},
title = {Aquaporin-4 and caveolin-1 as mediators of fibrinogen-driven cerebrovascular pathology in cerebral amyloid angiopathy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71030},
doi = {10.1002/alz.71030},
pmid = {41549419},
issn = {1552-5279},
support = {NS104386/GF/NIH HHS/United States ; AG078245/GF/NIH HHS/United States ; HL168009/GF/NIH HHS/United States ; },
mesh = {*Caveolin 1/metabolism ; Animals ; *Cerebral Amyloid Angiopathy/pathology/metabolism ; *Aquaporin 4/metabolism ; *Fibrinogen/metabolism ; Mice ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Alzheimer Disease ; },
abstract = {INTRODUCTION: Cerebral amyloid angiopathy (CAA), marked by amyloid beta (Aβ) accumulation in perivascular spaces (PVSs), contributes to vascular injury and inflammation in Alzheimer's disease. The mechanisms underlying CAA-related vascular pathology remain unclear. Increasing evidence indicates fibrinogen, the main component in blood clots, interacts with Aβ and exacerbates inflammation and co-deposits in PVS of CAA-positive vessels, yet its role in cerebrovascular dysfunction remains poorly defined.

METHODS: Using TgSwDI transgenic mice, which develop robust CAA, we examined fibrin(ogen) deposition, aquaporin-4 (AQP4) polarization, and caveolin-1 (Cav-1) expression. We further assessed the effects of fibrinogen depletion via small interfering RNA.

RESULTS: TgSwDI mice showed increased fibrin(ogen) extravasation, colocalization with Aβ in PVS, AQP4 depolarization, and elevated Cav-1 expression. Fibrinogen depletion reduced CAA, restored AQP4 polarization, decreased Cav-1 levels, attenuated microglial activation, and improved spatial memory.

DISCUSSION: These findings suggest that modulating fibrinogen-related pathways could be a promising strategy for mitigating CAA pathology and its associated cerebrovascular pathology.

HIGHLIGHTS: Fibrin(ogen)-Aβ colocalization aggravates CAA. AQP4 depolarization links fibrinogen-Aβ deposits to impaired clearance in CAA. Cav-1 increase drives fibrinogen leakage and neuroinflammation. Fibrinogen depletion reduces CAA, restores AQP4 polarity, and improves memory.},
}

*Caveolin 1/metabolism
Animals
*Cerebral Amyloid Angiopathy/pathology/metabolism
*Aquaporin 4/metabolism
*Fibrinogen/metabolism
Mice
Mice, Transgenic
Amyloid beta-Peptides/metabolism
Disease Models, Animal
Alzheimer Disease

@article {pmid41549415,
year = {2026},
author = {Kang, S and Ye, BS and Yun, M and Lee, YG and , },
title = {Effect of tau burden and Lewy pathology on neuropsychiatric symptoms in Aβ-positive individuals.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71116},
doi = {10.1002/alz.71116},
pmid = {41549415},
issn = {1552-5279},
support = {U01AG024904/GF/NIH HHS/United States ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //Alzheimer's Drug Discovery Foundation/ ; /CAPMC/CIHR/Canada ; //Northern California Institute for Research and Education/ ; //Alzheimer's Therapeutic Research Institute/ ; //University of Southern California/ ; //Inje University/ ; HR22C141101//Korea Health Industry Development Institute/Republic of Korea ; RS-2025-25467534//Korea Health Industry Development Institute/Republic of Korea ; },
mesh = {Humans ; Male ; *Amyloid beta-Peptides/metabolism ; Female ; *tau Proteins/metabolism ; Aged ; Positron-Emission Tomography ; *Alzheimer Disease/pathology/metabolism/psychology/diagnostic imaging ; *Lewy Bodies/pathology/metabolism ; Aged, 80 and over ; Cohort Studies ; Brain/pathology/metabolism/diagnostic imaging ; Lewy Body Disease ; },
abstract = {INTRODUCTION: Neuropsychiatric symptoms (NPS) are common across the Alzheimer's disease (AD) spectrum. We aimed to evaluate the effects of amyloid beta (Aβ), tau, and Lewy body (LB) pathologies on NPS in Aβ-positive individuals.

METHODS: In 336 Aβ-positive participants from the Alzheimer's Disease Neuroimaging Initiative cohort, spanning from cognitively unimpaired to those with early dementia, NPS were assessed. Aβ and tau positron emission tomography were conducted. In a subgroup of 238 participants, dichotomized LB pathology was assessed by detecting α-synuclein seeding activity. The effects of Aβ, tau, and LB pathologies on NPS were evaluated using logistic regression analyses.

RESULTS: Greater tau burden was associated with delusion, agitation/aggression, irritability/lability, aberrant motor behavior, and appetite/eating disorder. In subgroup analyses, LB pathology was associated with delusion, anxiety, apathy, and sleep disturbance, independent of Aβ and tau burden.

DISCUSSION: Tau and LB pathologies are major determinants of NPS in Aβ-positive individuals, each contributing distinct symptom profiles.

HIGHLIGHTS: Tau burden was associated with delusion, agitation/aggression, irritability/lability, aberrant motor behavior, and appetite/eating disorder. Tau in frontal, temporal, and limbic cortices was associated with delusion. In amyloid beta (Aβ)-positive individuals, co-occurring Lewy body (LB) pathology is associated delusion, anxiety, apathy, and sleep disturbance, independent of tau. Tau and LB pathologies are associated with the distinct profiles of neuropsychiatric symptoms in Aβ-positive individuals.},
}

Humans
Male
*Amyloid beta-Peptides/metabolism
Female
*tau Proteins/metabolism
Aged
Positron-Emission Tomography
*Alzheimer Disease/pathology/metabolism/psychology/diagnostic imaging
*Lewy Bodies/pathology/metabolism
Aged, 80 and over
Cohort Studies
Brain/pathology/metabolism/diagnostic imaging
Lewy Body Disease

@article {pmid41549413,
year = {2026},
author = {Burns, JM and Alford, S and Coppinger, J and Jiménez-Mausbach, M and Ray, S and Pandey, H and Laird, R},
title = {Early Alzheimer's diagnosis: U.S. primary care physicians and use of blood biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e70986},
doi = {10.1002/alz.70986},
pmid = {41549413},
issn = {1552-5279},
support = {//Novo Nordisk Inc./ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Biomarkers/blood ; *Physicians, Primary Care/psychology ; United States ; Male ; Female ; *Attitude of Health Personnel ; Early Diagnosis ; Middle Aged ; },
abstract = {INTRODUCTION: We aimed to explore primary care physicians' (PCP) attitudes, perceptions, and barriers toward Alzheimer's disease (AD) diagnosis and incorporating blood biomarker (BBM) tests into the diagnostic workflow.

METHODS: Remote 60-min interviews with 20 PCPs were conducted (May 2023). Participants included generalists and geriatricians representing urban, suburban, and rural U.S. practices. Interviews encompassed early AD diagnosis, PCP role, and BBM test implementation.

RESULTS: Most PCPs view investigating cognitive decline as an important part of their role and are somewhat confident in diagnosing AD. Barriers include the complexity and inefficiency of current diagnostic workflows, lack of effective treatments, and stigma. PCPs consider BBM tests accurate and cost-effective but have concerns about reimbursement and diagnostic pathway placement.

DISCUSSION: PCPs are interested in AD diagnosis and receptive toward BBM testing. Education on BBM test use and AD diagnosis may benefit PCPs in the care of individuals with cognitive decline.

HIGHLIGHTS: Early Alzheimer's disease (AD) diagnosis is crucial for initiating treatment Primary care physicians (PCPs) find investigation of cognitive decline important PCPs consider blood biomarker (BBM) tests accurate and cost-effective PCPs seek clarity on reimbursement of BBM tests and their context of use Education on BBM test interpretation and AD diagnosis may benefit primary care.},
}

Humans
*Alzheimer Disease/diagnosis/blood
*Biomarkers/blood
*Physicians, Primary Care/psychology
United States
Male
Female
*Attitude of Health Personnel
Early Diagnosis
Middle Aged

@article {pmid41549411,
year = {2026},
author = {Crane, PK and Li, C and Cohen, T and Seitz, A and Rhodes, E and Choi, SE and Lee, M and Mukherjee, S and Nakano, C and Albertson, S and Asadollahi, A and Velderrain-Lopez, K and Gallée, J and Rabin, LA and Gaynor, L and Dumitrescu, L and Turner, S and Hohman, TJ and Gibbons, LE and Trittschuh, EH and Saykin, AJ and Mez, J},
title = {Cognitive data harmonization in the ADRC Network and beyond-Past, present, and future.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71086},
doi = {10.1002/alz.71086},
pmid = {41549411},
issn = {1552-5279},
support = {U24 AG074855/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis ; *Neuropsychological Tests ; *Psychometrics ; *Cognitive Dysfunction/diagnosis ; *Cognition ; United States ; },
abstract = {The National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) includes extensive cognitive data contributed by Alzheimer's Disease Research Centers (ADRCs) since 2005. The UDS has evolved over time and is on its fourth iteration. In addition to this core dataset, individual ADRCs have administered augmented neuropsychological batteries to research participants that go beyond the UDS. Here we describe ongoing efforts and future plans to optimize use of these data with modern psychometric methods. Modern psychometric methods address challenges from an evolving battery of cognitive tests. To date, most efforts using modern psychometric methods have focused on harmonization and co-calibration of ADRCs' UDS and non-UDS cognitive data, while recent efforts address additional areas such as subjective cognitive impairment. Modern psychometric methods provide a workable framework for anticipated future developments, including digital cognitive testing and analyses of spoken responses. These methods facilitate optimal use of NACC's data riches to further its mission to facilitate collaborative research. HIGHLIGHTS: National Alzheimer's Coordinating Center (NACC) data collection includes an extensive cognitive battery that has changed over time. An ambitious project has harmonized and co-calibrated cognitive domain scores for memory, executive functioning, and language. Scores and their standard errors are available from the NACC. Those scores are co-calibrated with domain scores from many additional studies, facilitating cross-study scientific investigation. Future opportunities include digital data collection, consideration of neuropsychiatric symptoms and subjective cognitive impairment, and other uses of the granular cognitive data.},
}

Humans
*Alzheimer Disease/psychology/diagnosis
*Neuropsychological Tests
*Psychometrics
*Cognitive Dysfunction/diagnosis
*Cognition
United States

@article {pmid41549404,
year = {2026},
author = {Kennedy, JT and Wisch, JK and Boerwinkle, AH and Millar, PR and McKay, NS and Brickman, AM and Chhatwal, JP and Mendez, PC and Christian, BT and Cohen, A and Cruchaga, C and Daniels, A and Flores, S and Handen, BL and Hartley, SL and Head, E and Ibanez, L and Krisnsky-McHale, SJ and la Fougere, C and Lai, F and Laymon, CM and Lee, JH and Lee, JH and Levin, J and Llibre-Guerra, J and Aguillon, DF and Lott, IT and Mapstone, M and McDade, E and Morris, J and O'Bryant, SE and Price, JC and Rafii, MS and Roh, JH and Rosas, HD and Schupf, N and Supnet-Bell, C and Xiong, C and Zaman, S and Benzinger, TLS and Gordon, BA and Ances, BM and , },
title = {Brain volume trajectories in Down syndrome and autosomal dominant Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71103},
doi = {10.1002/alz.71103},
pmid = {41549404},
issn = {1552-5279},
support = {U01 AG051406/AG/NIA NIH HHS/United States ; U01 AG051412/AG/NIA NIH HHS/United States ; U19 AG068054)//National Institute for Child Health and Human Development/ ; P50 AG008702/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P50 AG16537//National Institutes of Health Programs: The Alzheimer's Disease Research Centers Program/ ; P50 AG005133/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; U54 HD090256/HD/NICHD NIH HHS/United States ; U54 HD087011/HD/NICHD NIH HHS/United States ; P50 HD105353/HD/NICHD NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; U24 AG21886//National Centralized Repository for Alzheimer Disease and Related Dementias/ ; },
mesh = {Humans ; *Down Syndrome/pathology/diagnostic imaging ; *Alzheimer Disease/pathology/diagnostic imaging/genetics ; Male ; Female ; *Brain/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Middle Aged ; Longitudinal Studies ; Organ Size ; Adult ; Disease Progression ; Aged ; },
abstract = {INTRODUCTION: It is unknown if neurodegeneration trajectories differ between Down syndrome (DS) and autosomal dominant Alzheimer's disease (ADAD), both of which are genetic forms of Alzheimer's disease (AD).

METHODS: We compared brain volumes in DS, ADAD, and unaffected family members serving as controls. Participants underwent magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET), deriving volumetric and amyloid burden, respectively. Nonlinear associations between regional volumes and estimated years to clinical symptom onset (EYO) were evaluated using generalized additive mixed-models.

RESULTS: Longitudinal data from 267 controls, 341 participants with DS, and 358 participants with ADAD were included, totaling 1908 scans. DS volumes were lower than ADAD and controls initially and dropped linearly. ADAD had similar volumes to controls until diverging, beginning at EYO -7. Amyloid was negatively associated with volume, with similar slopes in DS and ADAD.

DISCUSSION: ADAD and DS demonstrate distinct patterns of brain volume decline prior to symptom onset despite being similarly affected by amyloid.},
}

Humans
*Down Syndrome/pathology/diagnostic imaging
*Alzheimer Disease/pathology/diagnostic imaging/genetics
Male
Female
*Brain/pathology/diagnostic imaging
Magnetic Resonance Imaging
Positron-Emission Tomography
Middle Aged
Longitudinal Studies
Organ Size
Adult
Disease Progression
Aged

@article {pmid41549403,
year = {2026},
author = {Martinez, JE and Lopez, KA and Properzi, MJ and Kirn, D and Vila-Castelar, C and Ramirez-Gomez, L and Gonzalez Catalan, M and Buckley, R and Amariglio, RE and Rentz, DM and Johnson, K and Sperling, RA and Quiroz, YT},
title = {Neuroimaging markers and cognition in cognitively unimpaired older Latinos from the Harvard Aging Brain Study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71126},
doi = {10.1002/alz.71126},
pmid = {41549403},
issn = {1552-5279},
support = {P01AG036694//U.S. National Institute on Aging (NIA)/ ; R01AG066823//U.S. National Institute on Aging (NIA)/ ; R01AG077627//U.S. National Institute on Aging (NIA)/ ; },
mesh = {Humans ; *Hispanic or Latino ; Male ; Female ; Aged ; *Neuroimaging ; *Cognition/physiology ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; *Brain/diagnostic imaging/pathology/metabolism ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Hippocampus/pathology/diagnostic imaging ; *Aging ; Aged, 80 and over ; Biomarkers ; Middle Aged ; White ; },
abstract = {INTRODUCTION: Research examining Alzheimer's disease (AD) neuroimaging markers of brain pathology and cognition in older Latino adults remains limited. We compared neuroimaging and cognitive profiles between cognitively unimpaired older Latino and non-Latino adults from the greater Boston area.

METHODS: Twenty Latino and 230 non-Latino cognitively unimpaired older adults from the Harvard Aging Brain Study were included. Participants underwent neuroimaging to assess amyloid beta (Aβ), inferior temporal tau and hippocampal volume, as well as cognitive testing with the Preclinical Alzheimer Cognitive Composite-5. Associations between ethnicity and these outcomes were examined using linear regressions adjusted for age, education attainment, and sex.

RESULTS: Latino participants had higher levels of inferior temporal tau (p = 0.02) and lower cognitive performance (p < 0.001) compared to non-Latinos, but comparable Aβ deposition and hippocampal volume (all ps > 0.05).

DISCUSSION: These results highlight potential differences in vulnerability to cognitive decline between Latinos and non-Latinos, underscoring the need for further investigation.},
}

Humans
*Hispanic or Latino
Male
Female
Aged
*Neuroimaging
*Cognition/physiology
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
*Brain/diagnostic imaging/pathology/metabolism
Magnetic Resonance Imaging
Neuropsychological Tests
Hippocampus/pathology/diagnostic imaging
*Aging
Aged, 80 and over
Biomarkers
Middle Aged
White

@article {pmid41549381,
year = {2026},
author = {Lee, S and Lee, J and Jeon, J and Lee, H and Choi, B and Hong, J and Lee, SJ},
title = {PLGA Nanoparticle-based Anti-TLR2 scFv Gene Delivery for the Treatment of Alzheimer's Disease.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en25047},
pmid = {41549381},
issn = {1226-2560},
abstract = {In Alzheimer's disease (AD), persistent microglial neuroinflammation and the poor brain exposure and durability of current therapies underscore the need for new, long-acting treatments. We developed a non-viral gene therapy that suppresses microglial Toll-like receptor 2 (TLR2) signaling using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with a plasmid encoding the anti-TLR2 single-chain variable fragment (scFv33). Following intra-cisterna magna delivery, PLGA NPs exhibited microglia-biased uptake and enabled brain-wide transgene expression in mice. In 5xFAD mice, a single administration of scFv33 NPs improved recognition memory in the novel object recognition (NOR) assay, outperforming 8 weeks of weekly recombinant scFv33-Fc dosing. Histology showed selective reduction of small hippocampal Aβ plaques and a shift toward a ramified microglial morphology, indicative of reduced activation. In primary neuron-microglia co-culture, scFv33 reduced microglial hypertrophy, restored process complexity, and enhanced Aβ phagocytosis. Together, these data indicate that sustained, local expression of an anti-TLR2 scFv via a clinically translatable PLGA platform recalibrates microglial state and preferentially limits early-stage plaque accumulation, yielding cognitive benefit after a single dose.},
}

@article {pmid41550177,
year = {2024},
author = {Bu, S and Ji, J and Yang, M and Sun, J and Zhang, J and Qian, S and Lou, H and Fan, P},
title = {Chemical composition and neuroprotective activity of hemp seed aqueous extract and their chemotaxonomic significance.},
journal = {Pharmaceutical science advances},
volume = {2},
number = {},
pages = {100051},
pmid = {41550177},
issn = {2773-2169},
abstract = {Fructus Cannabis (hemp seed) is important in food and traditional Chinese medicinal applications. Several studies have shown it has antioxidant, antiaging, anti-inflammatory, and neuroprotective properties. Studies have reported its anti-Alzheimer's disease effects. However, its active substances have not been defined, and little is known about the chemical constituents of the aqueous extract. The chemical profile of the aqueous extract of Fructus Cannabis (EFC) was obtained via isolation, structural identification, and qualitative and quantitative analyses. Twenty-seven compounds were identified, including seven nucleosides (1-7), five phenylpropanamides (8-11, and 24), three alkaloids (15, 16, and 26), two cyclic dipeptides (17 and 25), and one pyrimidine (19). Compounds 1, 3-7, 12, 14-19, and 21-27 were not reported previously in the Cannabis genus. Therefore, their chemotaxonomic significance is discussed. Neuroprotective activity screening revealed that EFC and the isolated compounds, particularly 9, 11, and 17, showed significant neuroprotective effects in PC12 cells (rat pheochromocytoma cells). The novel object recognition experiment and Nissl staining showed that EFC improved cognitive impairment in APP/PS1 mice and that EFC intervention reduced the number of senile plaques. These findings will contribute to the utility of Fructus Cannabis.},
}

@article {pmid41550171,
year = {2024},
author = {Kamaljeet, and Singh, S and Gupta, GD and Aran, KR},
title = {Emerging role of antioxidants in Alzheimer's disease: Insight into physiological, pathological mechanisms and management.},
journal = {Pharmaceutical science advances},
volume = {2},
number = {},
pages = {100021},
pmid = {41550171},
issn = {2773-2169},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss, cognitive decline, impairment in activities of daily living, and loss of independent function. Cognitive decline and brain shrinkage, particularly hippocampal atrophy, are associated with the accumulation of tau proteins. They cause inflammation, amyloid plaque deposition, neuronal loss, temporofrontal cortex atrophy, aberrant protein fragment clusters, and twisted fiber bundles. Given the significant role of oxidative processes in neurodegeneration, it is logical to consider the potential of antioxidants in the treatment of AD. Several antioxidants, including glutathione, astaxanthin, ascorbyl palmitate, catalase, and molecular hydrogen, play important roles in AD. Antioxidants interact with free radicals to neutralize them. Several studies have suggested that oxidative stress or damage is involved in the development of AD via different mechanisms and pathways. Thus, new approaches are needed to reduce the extent of oxidative damage that may be therapeutically effective against AD. Although certain antioxidants have exhibited notable benefits in animal models, their efficacy in human clinical trials has been limited, casting doubt regarding the efficacy of antioxidant treatments for AD. Therefore, a more focused and precise strategy that incorporates antioxidants is essential for slowing or stopping AD progression. The integrated role of antioxidants in reducing inflammation must be considered, because the link between inflammation and AD is undeniable. Therefore, the present study aimed to elucidate the role of antioxidants in AD, with the goal of aiding researchers in developing effective and potentially enhanced antioxidant-based therapeutic strategies.},
}

@article {pmid41549257,
year = {2026},
author = {Wang, C and Chen, H and Liu, M and Lu, W and Hao, Z and Wang, B},
title = {Efficacy of non-invasive neuromodulation technologies in improving cognitive function and activities of daily living in patients with Alzheimer's disease, Parkinson's disease, and stroke: a systematic review and network meta-analysis.},
journal = {Journal of neuroengineering and rehabilitation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12984-025-01842-2},
pmid = {41549257},
issn = {1743-0003},
}

@article {pmid41549054,
year = {2026},
author = {Collingridge, GL},
title = {Glutamate Receptors and Synaptic Plasticity in Health and Disease: A Personal Journey.},
journal = {Hippocampus},
volume = {36},
number = {1},
pages = {e70062},
doi = {10.1002/hipo.70062},
pmid = {41549054},
issn = {1098-1063},
mesh = {Animals ; *Neuronal Plasticity/physiology ; Humans ; *Receptors, Glutamate/physiology/metabolism ; *Hippocampus/physiology/metabolism ; *Synapses/physiology ; },
abstract = {I describe my progress in understanding synaptic plasticity in the hippocampus. Over the decades my lab has focused on the roles of glutamate receptors (AMPARs, NMDARs, mGluRs and KARs) and associated signaling molecules in LTP and LTD. Most of our studies have been conducted in area CA1 (Schaffer collateral-commissural pathway) with some conducted in CA3 (mossy fiber pathway). We have made extensive use of electrophysiology and pharmacological tools, complemented with knock-out (KO) and transgenic mice, biochemistry and dynamic imaging. From a starting point in 1980, with essentially no molecular insights available, we have developed a detailed, but still incomplete, mechanism for LTP at CA1 and CA3 synapses as well as providing insights into LTD at CA1 synapses. We have also explored how dysregulated synaptic plasticity contributes to brain disorders, with an emphasis on Alzheimer's disease. Indeed, through a molecular understanding of synaptic plasticity, now we can explain how plaques and tangles are related mechanistically and, in essence, how the early stages of dementia are triggered. Therapeutic strategies, both pharmacological and lifestyle, for tackling dementia are touched upon. Our work, together with that of many other groups, has resulted in massive progress in the understanding of synaptic plasticity in the mammalian CNS in health and disease.},
}

Animals
*Neuronal Plasticity/physiology
Humans
*Receptors, Glutamate/physiology/metabolism
*Hippocampus/physiology/metabolism
*Synapses/physiology

@article {pmid41548934,
year = {2026},
author = {Neghabi, M and Nategh, P and Stauffer, AM and Hahn, MK and Blakely, RD and Ranji, M},
title = {Elesclomol Diminishes Redox Imbalance in Peripheral Tissues of Mblac1 Knockout Mice.},
journal = {Journal of biophotonics},
volume = {19},
number = {1},
pages = {e70224},
doi = {10.1002/jbio.70224},
pmid = {41548934},
issn = {1864-0648},
support = {EY031533/NH/NIH HHS/United States ; 2154267//National Science Foundation/ ; //Florida Atlantic University I-SENSE Seed Funding to MR/ ; //Florida Department of Health award to RDB/ ; },
mesh = {Animals ; Oxidation-Reduction/drug effects ; Mice ; Mice, Knockout ; Male ; Female ; Liver/metabolism/drug effects ; Kidney/metabolism/drug effects ; Mitochondria/metabolism/drug effects ; Copper/metabolism ; *Hydrazines/pharmacology ; Organ Specificity/drug effects ; },
abstract = {OBJECTIVE: To determine whether loss of Mblac1, a gene implicated in copper metabolism and Alzheimer's disease, causes systemic mitochondrial redox imbalance and whether treatment with the copper chaperone elesclomol (ES) can restore this balance.

METHODS: We employed 3D cryoimaging to quantify redox ratio (RR) in kidneys and livers of Mblac1 knockout (KO) mice and their wildtype (WT) littermates. Mice of both sexes were administered either vehicle control (C) or ES (10 mg/kg, i.p.).

RESULTS: KO tissues exhibited reduced RR, indicating an oxidized metabolic state. ES treatment recovered 77% of the RR deficit in kidneys and 48% in livers, restoring RR to WT levels.

CONCLUSION: Mblac1 deletion disrupts mitochondrial redox homeostasis in peripheral tissues, while ES partially reverses this imbalance by restoring Cu(I)-dependent metabolism.

SIGNIFICANCE: Optical metabolic imaging reveals Mblac1 as a key regulator of systemic redox balance and supports ES as a potential therapy for Cu-linked metabolic dysfunctions.},
}

Animals
Oxidation-Reduction/drug effects
Mice
Mice, Knockout
Male
Female
Liver/metabolism/drug effects
Kidney/metabolism/drug effects
Mitochondria/metabolism/drug effects
Copper/metabolism
*Hydrazines/pharmacology
Organ Specificity/drug effects

@article {pmid41548855,
year = {2026},
author = {Jiang, A and Ma, Y and Bao, S and Shahbazi, MA and Reis, RL and Kundu, SC and Xiao, B and Shi, X},
title = {Metal-directed nanomedicines for imaging-guided disease treatment.},
journal = {Acta biomaterialia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.actbio.2026.01.032},
pmid = {41548855},
issn = {1878-7568},
abstract = {Metal-directed self-assembly, driven by metal-ligand coordination, represents a highly versatile and efficient strategy for constructing drug delivery systems with precisely tunable properties, inherent imaging capabilities, and broad biomedical applications. Stimuli-responsive metal-directed drug delivery systems (MDDSs), guided by advanced imaging techniques, enable precise control over their size and spatial architecture while facilitating site-specific drug release. Moreover, certain metal ions play a dual role, not only orchestrating the self-assembly process but also serving as therapeutic agents and regulatory components for the treatment of various diseases, including cancer, microbial infections, and Alzheimer's disease. This review provides a comprehensive overview of the self-assembly mechanisms underlying diverse MDDSs and their applications in image-guided therapy. Furthermore, we critically examine existing challenges in the field and propose strategic directions to propel the advancement of metal-directed self-assembly in drug delivery. Given the profound implications of this research, further exploration of the critical roles of metal coordination in self-assembly is imperative for the development of next-generation drug delivery platforms. STATEMENT OF SIGNIFICANCE: This review systematically summarize the self-assembly mechanisms of metal-directed drug delivery systems, outlines their applications in image-guided therapy and discusses the current challenges that remain. Furthermore, it elucidates the unique regulatory roles of metal ions in precise drug release and multimodal therapy, providing valuable insights and broad appeal for the development and clinical translation of next-generation smart nanomedicine platforms.},
}

@article {pmid41548752,
year = {2026},
author = {Li, B and Xu, J and Zhu, H and Ren, D and Xiao, L and Zhang, T and Li, R},
title = {The interaction between FLOT1 and FOSL2 promotes EphA2 transcription, regulating microglial polarization and affecting neuroinflammation in Alzheimer's disease.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110844},
doi = {10.1016/j.neuropharm.2026.110844},
pmid = {41548752},
issn = {1873-7064},
abstract = {BACKGROUND: Microglial activation plays a crucial role in Alzheimer's disease (AD), responding to amyloid-beta (Aβ) plaques and tau tangles. Initially protective, microglia clear Aβ deposits and support neuronal health, but later adopt a pro-inflammatory, neurotoxic state, releasing cytokines that exacerbate neuroinflammation and neuronal damage. Understanding the mechanisms driving this shift is essential for developing therapies to modulate microglial activation and slow AD progression.

METHODS: Quantitative PCR (qPCR), Western blotting, immunohistochemistry (IHC), and immunofluorescence (IF) assays were performed to confirm gene and protein expression levels. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (CoIP), and dual-luciferase assays were conducted to assess the interactions among FLOT1, FOSL2, and EphA2. The Morris water maze test was used to evaluate spatial learning and memory, with experiments conducted using the APP/PS1 mouse model.

RESULTS: In this study, we found that silencing of FLOT1 in APP/PS1 mice significantly reduced neuroinflammatory markers, prevented pro-inflammatory polarization, and improved spatial memory. Mechanistically, we observed that FLOT1 interacted with the transcription factor FOSL2, which upregulated EphA2 expression, leading to activation of the p38/MAPK signaling pathway. Disrupting EphA2 expression deactivated this pathway, reducing pro-inflammatory polarization in microglia. Our findings further confirmed that the FLOT1-FOSL2 axis regulated microglial polarization in vivo and that targeting this pathway improved cognitive outcomes in AD models.

CONCLUSION: Overall, these results highlight the FLOT1-FOSL2-EphA2 pathway as a potential therapeutic target for AD, as modulating this axis may reduce neurotoxic inflammation and help preserve cognitive function.},
}

@article {pmid41548720,
year = {2026},
author = {Wu, Y and Zhang, H and Qu, J and Zhu, R and Xu, G and Xu, W and Yan, G and Yang, J and Xin, J and Li, Y and Wang, D and , },
title = {Mapping structural disconnection and transcriptomic signatures in Alzheimer's disease with MIND networks.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111737},
doi = {10.1016/j.brainresbull.2026.111737},
pmid = {41548720},
issn = {1873-2747},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly conceptualized as a disconnection syndrome involving widespread alterations in large-scale brain networks. Previous studies using morphometric similarity networks (MSNs) have revealed broad structural and transcriptomic changes, yet vertex-level structural disconnection and its molecular basis remain poorly understood. We applied morphometric inverse divergence (MIND), an innovative approach for fine-grained mapping of structural disconnection and its transcriptomic correlates in AD.

METHODS: Utilizing two independent datasets: [ADNI (219 AD, 219 cognitively normal, CN) and the Qilu dataset (100 AD, 137 CN)], we mapped robust MIND network alterations in AD patients and examined their associations with cognitive performance and biomarker quantifications. Additionally, we linked MIND connectome to spatial gene expression using partial least squares regression, followed by gene enrichment analysis to identify relevant biological pathways. Finally, to validate the clinical utility of MIND, a residual deep neural network (ResDNN) was developed to compare its diagnostic performance against MSNs in distinguishing AD from CN.

RESULTS: Significantly decreased MIND degree was identified in the bilateral frontal, lateral occipital, and posterior temporal lobes (P FDR < 0.05), positively correlating with MMSE score and FDG-PET SUVR (all P < 0.001). Conversely, increased MIND degree was observed in the bilateral cuneus, entorhinal, lingual, and parahippocampal regions (P FDR < 0.05), negatively correlating with cognition assessment, CSF Aβ-42 levels and FDG-PET SUVR (all P < 0.001). These AD-related MIND alterations were spatially correlated with gene expression profiles crucial for synaptic function, neurotransmission, and metabolic regulation. Importantly, MIND achieved superior diagnostic efficacy (AUC=0.90/0.88 in ADNI/Qilu) over MSNs.

CONCLUSIONS: We mapped a robust pattern of structural disconnection in Alzheimer's disease with MIND approach and associate it with particular transcriptomic signatures. These findings not only improve our mechanistic understanding of AD as a disconnection syndrome but also demonstrate MIND as a sensitive tool for identifying disease-specific alterations, holding promise for future mechanistic and clinical investigations into AD pathology.},
}